- Open Access
Highlighting the gaps in hazard and risk assessment of unregulated Endocrine Active Substances in surface waters: retinoids as a European case study
Environmental Sciences Europe volume 33, Article number: 20 (2021)
Regulatory hazard and risk assessment of endocrine-active substances currently specifies four modes of action: interference with sex hormone (oestrogen, androgen) pathways, steroidogenesis, and thyroid hormone signalling. This does not encompass the full complexity of the endocrine system and its extended interfaces with environmental pollutants that can potentially disrupt the carefully maintained balance. Here we take the retinoid signalling pathway as a European case study for both, under- and unregulated endocrine pathways and outline the different levels of interference, discuss their adversity, and indicate crosstalk to other signalling pathways. Retinoid compounds already exist in drinking water sources, occur naturally in cyanobacterial blooms and/or enter surface waters via wastewater discharge, where they pose a potential hazard to the environment and human health - a situation that can be expected to worsen due to water shortages induced by climate-change and population growth. We briefly review relevant aspects of current endocrine disruptor (ED) testing for regulatory purposes and then expand upon the needs for inclusion of disruption of retinoid signalling in (ED) regulatory safety assessment contributing to adverse health outcomes that include cognitive function and neurological disease. An overview of developmental effects of retinoid signalling disruption across species highlights critical processes and potential crosstalk with other signalling pathways. A focused weight of evidence-based evaluation of the biologically plausible associations between neurological disorders and altered retinoid signalling highlights the evidence gaps. We show that monitoring only a limited number of anthropogenic priority chemicals in water is insufficient to address the environmental risks of retinoid signalling disruption. To comprehensively assess impacts on the endpoints, processes, and pathways of the endocrine system that are most vulnerable to chemical interference we need further investigation of the true mixture composition in environmental matrices. On a weight of evidence-basis this information can then be integrated into a reliable, inclusive, quantitative approach that ultimately accommodates all the critical pathways. By focusing on the retinoid signalling pathway, we intend to improve the scope and relevance of an integrated approach for the risk assessment of endocrine disruptors.
Internationally, chemical substances are currently screened for endocrine activity in regulatory risk assessments (as for example in the European Union’s Biocides regulation [1, 2]), utilizing standard test methods that refer to chemical substances as endocrine active when interfering with sex hormone (oestrogen, androgen) receptors, steroidogenesis, or thyroid hormone signalling (EATS; the available tests are introduced in the “infobox” below) . It is recognized that the endocrine system, however, is a complex interplay of different, often evolutionary highly conserved, mechanisms that by far exceed the above-mentioned four modes of action. It includes all hormone signalling pathways, interlinking and regulating an extensive set of functions, including development, growth, reproduction and metabolism [4,5,6,7,8], and this is being actively examined at inter-governmental levels [8,9,10,11,12,13,14,15,16]. The endocrine system is highly sensitive and circulating hormone levels are in the pM–µM range, making it highly susceptible to interfering compounds [17, 18]. Interference of exogenous chemicals with the tightly regulated endocrine system may result in adverse health effects, that, especially when encountered during development, may have sustained and life-long [12 and references therein, 19] or even transgenerational impacts on individuals or contribute to non-communicable diseases like metabolic disorders and cancer [4, 18, 20,21,22,23,24,25,26,27,28,29].
To allow an assessment of risks related to chemicals in the environment, information on the ecological or human health hazard of these chemicals is needed [2, 3] together with information on exposure to these chemicals and/or mixtures, i.e. their levels and fate in the environment, to conclude as to whether there is a risk of adverse outcomes or not [30, 31].
Despite the progress in the development of test methods screening for endocrine disrupting activity, endocrine pathways other than EATS remain under-investigated. Whilst currently there are no specific test methods available with respect to other endocrine mechanisms, these are being actively explored at the European level (https://eurion-cluster.eu/), and internationally, for retinoids [13, reviewed in 14]. Such comprehensive reviews together with identification of relevant assays with reference and test chemicals are needed to address regulatory needs, prior to the development of the test method tools that can be included into legislative mechanisms.
In surface waters, endocrine disruption gained public attention when altered sex ratios, genital malformations, and reproductive impairment were discovered in aquatic vertebrates [6, 33,34,35,36,37,38]. Most strikingly, feminization of male fish occurred at oestrogen levels below the limit of detection by analytical methods available at that time and also led to the collapse of a fish population in a Canadian experimental lake . The oestrogen levels in the respective water bodies have been frequently attributed to poor treatment of communal wastewaters, containing high levels of human contraceptives . More recently progesterone has been detected in UK shores in molluscs at concentrations equivalent to those used in contraceptives and hormone replacement therapy . The striking impact of compounds interfering with the oestrogen hormone system has expanded the field of environmental endocrine disruption and enabled investigation of other endocrine pathways sensitive to environmental interference .
It is intended that this review provides a useful contribution to the discussion of under- and unregulated endocrine pathways, particularly in relation to the gap in hazard and risk assessment approaches to address anthropogenic and naturally occurring toxic retinoid substances for water quality. We focus on two key aspects of environmental chemicals’ potential to interfere with retinoid signalling: (1) with respect to the presence of chemicals that elicit retinoid-like activity via retinoid receptors, and (2) the potential of the endogenous retinoid system to be a target for an expanded range of chemicals which could disrupt this system. In addition to retinoid signalling pathway-related developmental and reproductive endpoints [reviewed in 13, 14], here we facilitate the addition of the less well studied endpoints of cognitive function and neurological disease. We thereby intend to contribute to the evidence base needed for the development of the tools and approaches to address endocrine adverse outcomes related to disruption of retinoid signalling pathway.
Hazard characterization of retinoid substances - from molecular interactions to developmental and neurological outcomes in vivo
Retinoid substances are chemically related to retinol (vitamin A). They are small organic molecules biosynthesized from isoprenoid precursors, mostly by photosynthetic organisms like phytoplankton and plants . Retinoids, generally obtained from the diet [70,71,72], particularly retinoic acid, play a pivotal role during early development, driving anterior–posterior patterning in developing embryos and development of the vertebrate brain [73,74,75,76,77]. At the same time, retinoic acids are classified as teratogenic, due to the pronounced dependence on the spatio-temporal distribution of retinoids in the tissues of developing organisms [73, 78,79,80,81]. The developmental processes in which retinoids are involved are further discussed in “Phenotypic patterns of interference with retinoid signalling during development” section. Besides the tissue distribution and metabolization of retinoid isomers, also the expression pattern of retinoic acid receptor (RAR) and retinoid X receptor (RXR) isoforms and variants in tissues determines retinoid effects [78, 82].
The endogenous ligand for RAR is all-trans retinoic acid (atRA; Fig. 1); for RXR it appears to be either 9,13-di-cis retinoic acid or 9-cis retinoic acid (9cRA; Fig. 1). Additional retinoids that have been shown to activate retinoid receptors include 9-cis didehydro retinoic acid, all-trans 5,6 epoxy retinoic acid, all-trans 4-oxo retinoic acid, and all-trans 4-oxo retinal [83,84,85,86,87,88]. In humans, the biologically active and most potent atRA is obtained by sequential oxidation from all-trans retinol (vitamin A; Fig. 1) via alcohol dehydrogenases (esp. retinol dehydrogenase 10)  and retinal dehydrogenases (RALDHs, mainly RALDH2 in mammals) [90, 91]. Retinol is stored in the liver as retinyl esters [92,93,94]. atRA cannot be synthetized de novo in vertebrates and requires nutritional sources, which can be in the easily metabolized precursor forms such as β-carotene [80, 94,95,96]. The Population Reference Intake ranges between 250 µg retinol equivalent/day in infants below the age of 1 year and up to 750 µg retinol equivalent/day in children and adults  and is within the same range as the daily vitamin A intake recommended by Public Health England .
Binding of retinoids, primarily atRA, to RAR results in their heterodimerization with RXR and subsequent transcriptional activation of retinoic acid-responsive elements (RAREs), which govern a number of crucial cellular processes, including inflammation, proliferation, differentiation and carcinogenesis [28, 98, 99]. RAR–RXR heterodimers furthermore can recruit co-repressor complexes and, depending on the presence of natural or synthetic ligands, modulate or suppress gene expression [100,101,102].
While RARs show a higher specificity towards retinoid compounds binding and are the main driver in retinoid-mediated patterning and teratogenicity [e.g. recently reviewed by 103], the role of RXRs is broader. One of the reasons is the molecular promiscuity of RXR. Type II nuclear receptors, characterized by forming heterodimers with RXR, govern the transcription of a large variety of target genes . They are involved in the biological responses to many endogenous ligands, anthropogenic and natural chemicals and therapeutic drugs. The affected functions include lipid metabolism (peroxisome-proliferator activated receptor, PPAR), steroidogenesis, xenobiotic response (pregnane X receptor, PXR; constitutive androstane receptor, CAR), vitamin D receptor (VDR), liver functions (FXR, LXR), orphan nuclear receptors (Nurs), and thyroid hormone signalling (thyroid hormone receptor, TR ; Fig. 2) [7, 85, 88, 105,106,107]. Whilst the receptors TR, VDR, and RAR form non-permissive heterodimers, the others (Fig. 2) form permissive heterodimers with RXR, where the transcriptional activity is regulated by a ligand binding to one of the dimerization partners [85, 104, 106]. Dimerization is achieved via the asymmetrical so-called identity box - a small region within the ligand binding domain, which, in the case of RXRα, consists of 40 amino acids [108, 109]. This subdomain shows a very high degree of conservation. Especially, the two amino acids A416 and R421 have been shown crucial for dimerization of RXRα with RAR [108, 109]. The high conservation of the RXR identity box even across animal phyla underlines the evolutionary importance of RXR [110, 111].
Molecular crosstalk in the RXR signalling pathway
The fact that nuclear receptors share the common heterodimerization partner, RXR, indicates the potential for molecular crosstalk between signalling pathways dependent on RXR heterodimerization. The sequestration of ligand-bound RXR from the pool of active RXR monomers with downstream modulating activities is indicated , and also direct ligand activation of, e.g. the PPAR family by retinoic acids [112, 113] has been reported in addition to activation of retinoid receptors. Additionally, there is evidence of crosstalk to the thyroid hormone signalling pathway by heterodimers of TR with RXR in vitro  and augmentation of thyroid hormone-related effects by RXR activation in vivo . Most often, the ubiquitous RXRα isoform is involved in heterodimerization and it is essential for xenobiotic metabolism [7, 13, 115]. Competitive decrease of effect due to RXRα sequestration by retinoic acid/RAR has been reported for CAR , LXR, FXR, PPARα , and PPARγ  and may be implied in the metabolization and detoxification capacity mediated via activation of, e.g. PPARs. The capacity of RXRs to form heterodimers with several dimerization partners allows integration of signals from simultaneous and independent signalling pathways that can be further modulated by transcription co-factors [13, reviewed in 87]. The importance of allosteric modulators has been also stressed in a recent study on nuclear receptor binding to DNA target sequences (direct repeats and half-sites), where in vitro binding was predictive of in vivo binding, but not of in vivo function .
The importance of co-evolution of nuclear receptors and overlapping cis-regulatory elements also becomes apparent at the intersection of RAR/RXR and ERα signalling pathways. RAR/RXR signalling has been demonstrated several times to antagonize ER binding to respective DNA target sequences [118,119,120,121]. Besides the therapeutic use of this observation particularly in ER-responsive breast cancer , ERs play a critical role in organogenesis and maturation processes that, thus, can be affected by dietary and environmental factors.
Steroidogenesis critically influences the production and subsequently the circulating amount of the prototype sex steroids oestrogen and testosterone . RAR/RXR play a pivotal role at the beginning of the steroidogenesis pathway, but RXR also as the essential dimerization partner for adjacent and subsequent steps interlinked with lipid metabolism (PPARs, LXR) and xenobiotic response (CAR, PXR) [13, 106]. At this interface, delivery of retinoic acid to the various nuclear receptors (RAR, PPAR or VDR) can have different consequences with respect to adiposity, such that, for example VDR activation in fibroblasts induces non-adipogenic gene transcription, whilst PPARγ/RXR heterodimers contribute to adipogenic processes [7, 122].
Whilst the therapeutic potential of the interdependency amongst many pathways and retinoid signalling via RXR has already been discovered and drugs specific to RXR, so-called “rexinoids” (e.g. bexarotene) are available to treat certain types of cancers , the implications of unintentional deregulation of retinoid signalling remain to be elucidated.
Phenotypic patterns of interference with retinoid signalling during development
Interference with retinoic acid signalling has the highest impact on humans during development and was first observed in vitamin A (retinol) deficiency. This has been understood since the early twentieth century from studies that investigated the teratogenic effects of both excess and a lack of retinoid activity [124,125,126,127,128,129,130]. To date, vitamin A deficiency is still a concern, especially in developing countries where one-third (33.3%) of pre-school age children and 15.3% of pregnant women have serum retinol levels below 0.7 µM , resulting in severe risk of vitamin A-preventable blindness that has a fatality rate in children of 50% within one year [131,132,133]. Without nutritional supplementation within the first year of life, this can be considered as irreversible retinoid disruption and interpreted as an example of an (irreversible) adverse outcome in humans justifying classification as an endocrine disruption pathway.
Retinoic acid gradients determine the dorso-ventral and anterior–posterior patterning of the embryo in the first trimester [73, 75, 78, 82]. Furthermore, the differential expression and activation of retinoid receptor variants and isoforms, together with the spatio-temporal regulation of RA synthesis and metabolism, drives organogenesis and elongation of the spinal axis [74, 76, 78, 134]. It also determines progenitor cells to the neural lineage, thus initiating the formation of the neural system including the spinal cord and the brain [73, 76, 82]. Notably, retinoid signalling drives the formation and segmentation of the hindbrain and neural network formation even before thyroid receptors are being expressed [73, 135, 136], and is involved in the correct development and positioning of other vital internal organs , including the heart [138,139,140], the lungs [139, 141,142,143], (male) genitals [13, 144,145,146,147], and the kidney [148, 149]. Overall, RA governs a multitude of developmental effects and also influences processes in adults, namely neuronal plasticity in the brain [150,151,152,153], peripheral neural regeneration [154,155,156], immune function [157,158,159], epithelial function [139, 160], and reproduction . An overview on the processes sensitive to or dependent on retinoic signalling is outlined in Table 1.
The most critical elements for interference in the retinoid signalling pathways, beyond RARs and RXRs, are the metabolizing enzymes of the cytochrome P450 subfamily 26 (CYP26) CYP26A1, CYP26B1, and CYP26C1 [94, 161, 162], the retinol-converting alcohol dehydrogenase (ADH), and retinal-oxidizing dehydrogenases (RALDHs) [90, 94, 163, 164]. Efforts to identify key players and switches in the hierarchical signalling network and sort them into adverse outcome pathways (AOPs) continue to be undertaken with respect to vertebrate axial and neural tube development [14, 165, 166], as well as mammalian reproduction [reviewed in 13].
Besides retinoids themselves, other environmental contaminants, such as pharmaceuticals (e.g. valproic acid), flame retardants (e.g. polybrominated diphenyl ethers), plasticizers (phthalate esters), and pesticides (triazole fungicides) have been reported to alter retinoid signalling biomarkers and induce retinoid-like teratogenic effects [111, 167,168,169,170] (see also Table 1). Exposure assessment of pharmaceuticals with the retinoid mode of action may require different regulatory approaches, depending upon the route of exposure, i.e. whether there is oral intake/dermal application, as opposed to their occurrence and potency in (waste)waters.
Contribution of retinoids to chronic neurological disorders
The contribution of endocrine disruptors to neurological disorders is receiving more attention, and increasing resources are being put into funding such research [e.g. 32, 171]. In addition to known adverse teratogenic effects during development, particularly, brain and neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease, or depression may be linked to altered retinoid signalling [172, 173].
While retinoid compounds are well described as early morphogens of the central nervous system (CNS) during development, their role in postnatal development of the brain is less investigated. Retinoid signalling is implied in neural plasticity, required for the formation of new memories and for learning [151, 174,175,176], in affective disorders , and in ageing - namely in Alzheimer’s disease and dementia .
To date, neurodegenerative diseases such as dementia, Parkinson’s, Alzheimer’s, and Huntington’s disease, are the 6th leading cause of deaths in adults in the US [179, 180]. Unlike mortality due to heart disease, stroke, or HIV, deaths linked to Alzheimer’s disease have more than doubled between 2000 and 2018 . Even more severe is the situation regarding neurological disorders in general, which are the second leading cause of death after heart disease and the leading cause of disability worldwide [181, 182]. To date, there is no cure for dementia and treatment focuses on ameliorating the symptoms of cognitive decline and increasing or maintaining quality of life .
While risk factors associated with dementia are mostly age, genetic predisposition (family history of dementia), or life-style related (high BMI, non-healthy diet, lack of physical and cognitive exercise) [179, 182], the contribution of environmental exposure has also been considered [183,184,185].
Most observations regarding retinoid signalling and adverse health outcomes in adolescents and adults have been derived from human intervention and clinical studies together with animal in vivo modelling. Of particular relevance are studies with pharmacological application of 13cRA for the treatment of acne or cancer [177, 186, 187].
Retinoic acid signalling is necessary for the differentiation and speciation of cell types, particularly in neurons . While the differentiation of neurons is often perceived as restricted to early developmental stages, in fact many postnatal processes, including memory and learning, are dependent on neural differentiation and speciation (also known as neural plasticity) throughout life [174, 188,189,190].
Cognitive function, memory, learning, and dementia
Postnatal disturbance of RAR/RXR signalling impairs cognitive functions, especially in the forebrain and hippocampus . Indeed the hippocampus region retains high postnatal RAR expression, and so is most susceptible to RA signalling interference [192,193,194]. One potential role of RA signalling in the adult brain is the modulation of synaptic plasticity, that is required for learning and the formation of memories [173, 174, 188]. In a mouse model, functional expression of retinoid receptors has been shown to be critical for long-term potentiation (RARβ) and long-term depression (RARβ and RXRγ) . The same study linked the decreased synaptic plasticity with a substantial performance loss in spatial learning and memory tasks in mice. While Chiang et al.  did not study the role of RARα, Aoto et al.  observed a rapid increase in synaptic strength upon treatment of primary rat neurons in vitro with 1 µM atRA or increased endogenous atRA synthesis due to decreased neuronal activity. The homeostatic modulation of synaptic strength was mediated by atRA via dendritic, i.e. non-nuclear, RARα and upregulated postsynaptic glutamate receptor 1 (GluR1) expression in a transcription-independent fashion . Membrane-bound RARα was also shown to be involved in the differentiation of spine neurons from the hippocampus , suggesting a non-transcriptional role of RARs and perhaps of RA as a paracrine signalling molecule.
Interestingly, the involvement of RA signalling in learning processes in vertebrates is not limited to mammals and may even play a role in invertebrate learning . It has been shown that RA is critical for learning and song maturation in songbirds (zebra finches) [198, 199]. Unlike vocalization in mice, song maturation involves a learning aspect similar to that in human speech . Convergent signalling mechanisms of forkhead box protein P2 and RA have been hypothesized to play a role in learned vocalization in both, birds and humans .
Involvement of RA signalling in these key cognitive functions raises the questions of its role in neurodegenerative diseases. Age-related cognitive decline with impaired spatial learning and memory is associated with decreased RA signalling in elderly vertebrates (human and mice) [201, 202]. In elderly mice with impaired cognitive function, the administration of 13cRA re-established RA signalling and hippocampal RARβ and RXRβ/γ expression and rescued the cognitive impairment [153, 201, 203].
As a specific form of dementia, Alzheimer’s disease (AD) is characterized by formation of amyloid-β plaques in the CNS, which leads to inflammation and subsequent neurodegeneration [179, 204]. Due to a reported decrease in RA signalling in AD patients’ brains, particularly in the hippocampus region responsible for the formation of memories [201, 202], retinoids, especially 13cRA, are proposed for AD treatment as neuroprotectants [123, 205,206,207,208,209]. Furthermore, specific synthetic agonists of RARα/β, such as tamibarotene, that are in use for cancer treatment, have been explored for AD treatment , but the clinical trials seem not to have progressed since . For AD, disruption of RA signalling was linked to increased amyloid-β deposition in rats , and RAR-agonism was effective to act both preventively and therapeutically to decrease amyloid-β-induced damage to human cell cultures in vitro and to mice in vivo [212,213,214,215,216,217,218]. Besides RARs, also RXRs are being explored for their pharmacological potential in neurodegenerative and inflammatory disease treatment, though the results are not conclusive so far [123, 219].
In contrast to the recovery of learning and memory abilities in elderly mice, longer-term (6 week) administration of 13cRA at a therapeutic dose (1 mg/kg/day, i.p.) during young adulthood decreased cell proliferation in the murine hippocampus and was associated with impaired learning and memory formation . The authors consider this result to be due to an insufficient growth factor supply to maintain a large differentiating neuron population, leading to premature neuronal death and longer-term decreased performance in RA-sensitive tasks. However, the impaired cognitive functions could also be linked to affective depression disorders, as reported in humans after extended periods of RA treatment .
Affective disorders - altered mood, depression, and suicide
RA was first linked to altered behaviour in rats in 1986 . Later a link between affective disorders and RA in humans was proposed after 13cRA was approved for medical use as a treatment of severe cystic and recalcitrant acne in 1982, leading to the inclusion of a warning on the label [221, 222]. A systematic review conducted by Marqueling and Zane  and an almost parallel review of studies by Strahan and Raimer  concluded that the current data available neither confirm nor disprove the association. The latter however noted that changes in mood can be accounted to 13cRA . Further case studies and reports on the involvement of retinoid exposure in affective disorders have been summarized by Bremner et al. .
Here, we briefly introduce mechanistic data generated from animal models, with respect to the involvement of RA signalling in the dopaminergic system, as this is of particular interest with respect to the development and manifestation of affective disorders, as well as schizophrenia.
In the late 1990s, mutation and knockout of RARβ, RXRβ, and RXRγ in mice were observed to be linked to impaired locomotion and decreased signalling via dopamine receptors 1 and 2 (D1R and D2R) [226, 227]. Also, the involvement of the orphan nuclear retinoid receptor 1 (Nurr1) in the differentiation and/or maturation of dopaminergic neurons was hypothesized [226, 228]. Consecutively, the involvement of RA signalling in the development of the dopaminergic system, particularly in the expression of D2R, was confirmed in mice  and rats [227, 230, 231]. Of interest are also studies of chronic 13cRA administration in mice that better reflect an extended exposure to retinoids. Administration of therapeutic doses (1 mg/kg/day) to young adult mice over 6 weeks did not alter general locomotor activity, but increased depression-like behaviour in the forced swim test and tail suspension test . A follow-up literature review to this study proposed alterations to the serotonin neurotransmitter system rather than dopamine . This is in line with an extended 13cRA exposure study in rats, which affected the serotonin rather than the dopamine neurotransmitter system . Interestingly, a parallel study with chronic exposure to 13cRA or atRA in rats did not confirm the observed behavioural despair (forced swim test) observed by O’Reilly et al. , indicating species differences in sensitivity to RA .
Another parallel between depression in (elderly) human and in mice was drawn rather recently, when Qi et al.  observed post-mortem a decrease in mRNA levels of brain-derived neurotropic factor (BDNF) and RA signalling pathway elements in the brain of depressed patients and were able to confirm this observation in mice (BDNF is a biomarker also considered for inclusion in AOPs for developmental neurotoxicity and learning impairment [236,237,238]). Additionally, they identified a RA-responsive element in the tropomyosin receptor kinase B (TrkB; receptor for BDNF) promoter region specifically targeted by RARα and thereby confirmed crosstalk between the RA and BDNF signalling pathways .
While the multifactorial aetiology of schizophrenia includes genetic and environmental risk factors, critical areas are early neurodevelopment, social behaviour and cognitive ability [239, 240]. In fact, genetic predisposition by itself is not necessary nor sufficient for the development of schizophrenia and the developmental cascade leading to the disease should include interactions with the environment . Whilst no discrete substance has been proven to cause schizophrenia, it has been hypothesized that the neurochemical processes affected by some recreational drugs play a role in the development of schizophrenia and psychoses [summarized in 241]. These processes are signal transduction via dopaminergic  and glutamergic synapses , the endocannabinoid system , and (neuro-)inflammation .
Twenty years ago retinoid signalling was postulated to be involved in the development of schizophrenia , and whilst further mechanistic evidence is present, it is not sufficient for confirmation. The link has been established based on a predisposition for schizophrenia in children with congenital anomalies similar to RA signalling disturbance, convergent gene loci of schizophrenia risk factors and the RA signalling cascade (esp. CYP26B1) [240, 247], and the already mentioned sensitivity of the dopamine neurotransmitter system, particularly D2R, to RA interference (see “Affective disorders - altered mood, depression, and suicide” section) [outlined in 246]. Besides the dopamine system, also γ-amino butyric acid (GABA)-ergic interneurons in the prefrontal cortex, whose aberrant development is associated with neurological disorders including schizophrenia, have been shown to be sensitive to RA .
Although a considerable number of studies address the biologically plausible link between retinoid signalling and neurological diseases, on balance, the evidence supporting the link is currently insufficient to attribute causation (see Table 2).
Whilst the causal link between aberrant retinoid signalling and neurological disease is currently weak, the biological plausibility of the association is high: RA is a morphogen during early development and is strongly involved in shaping the CNS, including differentiation and maturation of neurons. Despite the significant role during development, the role of RA signalling in the adult or postnatal brain is less clear. Still, the conserved mechanisms of RA signalling are most likely to act also in the adult brain, though the effects may be less evident due to the multitude of parallel processes and potential influencing factors. Also, it is difficult to simulate and assess the many hues of neurological disease in animal models that are distinctly different from humans and it is not possible to assess behavioural changes in in vitro systems.
The “Cognitive function, memory, learning, and dementia”–“Schizophrenia” sections introduced several neurological conditions that share common affected personality traits due to changed connections in the CNS and altered neural plasticity. While modified RA signalling is not the single cause of adverse psychological and neurological outcomes, it is a strong candidate for connecting environmental exposure to neurological and/or neurodegenerative disease by modulating neurotransmitter systems (i.e. the dopaminergic system) and altering the base-line population of (non-)differentiated cells in the CNS. The role of the retinoid signalling pathways is especially pronounced, because interference of environmental chemicals does not have to be mediated via the molecular initiating events of the nuclear receptors (RARs and RXRs) directly, but could interfere with the endogenous retinoid homeostasis, e.g. by altering RA degradation (via CYP26 enzymes) or its biosynthesis (via ALDH and/or RALDH).
Sources of retinoids in surface water - exposure
Whilst retinoids are an intrinsic part of the diet for terrestrial animals and humans, aquatic animals in particular may be susceptible to involuntary exposure to excess retinoids at critically sensitive early-life stages  due to the prevalence of retinoid sources, both natural - cyanobacteria (blue-green algae) in eutrophic (fresh)water ecosystems [249,250,251,252] - and/or anthropogenic - wastewater discharge .
Retinoid-like activities in environmental matrices mediated via RAR or RXR can be measured by in vitro receptor transactivation assays, similar to ER and AR (see “Infobox”). In fact, ligand binding to specific nuclear receptors that leads to the transcription of target genes which, in the case of reporter assays, govern the expression of an easily detectable (e.g. luciferase) product, has become the method-of-choice for recent screening programmes targeted at uncovering endocrine activities of chemicals in a high-throughput manner [254,255,256]. The signal reflecting the extent of receptor transactivation can be quantified relative to the reference ligand (atRA for RAR, 9cRA for RXR) [257,258,259]. Detected retinoid-like activity for the different types of samples is expressed as equivalent concentration of the reference ligand that would cause the same response. These retinoic acid equivalent concentrations integrate the potential of a given mixture to activate the transcriptional response of the receptor and are more informative than targeted analyses for a limited set of compounds.
An important source of retinoids to surface waters is cyanobacterial blooms in eutrophic freshwater ecosystems. Anthropogenic eutrophication of water bodies is driven by agricultural activities and insufficient removal of nutrients (mainly nitrogen and phosphorous) from communal wastewaters [260, 261]. The ability of cyanobacteria to fix dissolved carbon dioxide (HCO3−) by photosynthesis makes their occurrence independent of bioavailable carbon . Together with global climate change, these are the biggest factors enhancing cyanobacterial blooms in (fresh-)water environments [260, 263]. As a result, the main limiting nutrients are bioavailable inorganic nitrogen (nitrate, NO3−) and phosphorous (phosphate, PO43−) . These nutrients are further concentrated in long, dry warm periods in summer, that are increasing with, and exacerbated by, global climate change. Evaporation and increased abstraction from surface water bodies leads to increasing water temperatures especially in shallow surface waters, further fuelling the development of cyanobacterial blooms [264,265,266]. Greater abstraction will also be expected with the growth in human population. In addition, climate change increases the frequency and size of flooding events which, in turn, (a) increase sediment loss to surface water (which is a key mechanism via which phosphorus enters water ) and (b) promote resuspension of nutrient-laden benthic sediment, both of which further exacerbate cyanobacterial blooms . Besides being an integral part of the aquatic ecosystem, cyanobacteria produce a large variety of secondary metabolites, many of which show bioactive or even toxic properties [269, reviewed in 270]. Amongst others, cyanobacterial bloom biomass and affected waters were shown to contain retinoids, elicit retinoid-like activity in vitro, and to cause in vivo teratogenic effects in Xenopus laevis tadpoles and Danio rerio embryos, which implies relevance towards wildlife populations [79, 249, 251, 252, 271,272,273,274,275]. Although algae contain retinoids at comparable levels in their biomass to cyanobacteria [251, 271, 274], it is the latter that are major contributors to retinoids in surface waters due to their proliferation. While the occurrence of cyanobacteria themselves is natural, their hazardous massive blooming events are strongly driven by human actions making it an “anthropo-natural” phenomenon.
European and Asian environmental case examples
The chemical assessment of environmentally occurring retinoids or a quantification of retinoid-like activity is a monitoring data gap. However, the few studies systematically analysing water samples reveal highly concerning levels of retinoids or their activity.
Measured in Czech lake waters, retinoid-like activities reached up to 263 ng atRA equivalent (REQ) × L−1 . While this concentration does not exceed the nominal EC20 of atRA in zebrafish embryos, total bloom biomass extracts did cause teratogenic effects at these concentrations . This indicates that environmental retinoids extend beyond atRA and 9cRA. Indeed, a broad spectrum of retinoids has been detected in field samples of cyanobacterial blooms and their surrounding water, as well as in laboratory cultures and their exudates [84, 249, 251,252,253, 271, 275, 276]. Among the retinoids detected are retinoic acids (atRA, 9cRA, 11cRA, 13cRA), RA derivatives (5,6-epoxy atRA, 7-hydroxy atRA, 4-oxo atRA, 4-oxo 9cRA, 4-oxo 13cRA), retinal and its derivatives (all-trans retinal, all-trans 4-oxo retinal) [249, 251,252,253, 271, 272, 276]. However, the chemical analysis of retinoids could not entirely explain the retinoid-like bioactivity observed in the biological assays, hence it underestimates the endocrine active potential arising from these waters.
Besides occurring in cyanobacterial blooms, retinoids also enter the environment via wastewater effluents [reviewed in 253]. Humans, as well as animals, excrete retinoids most often as 4-oxo derivatives [277,278,279]. Even though retinoids are sensitive to oxidation and isomerization processes that significantly alter their bioactivity, in municipal wastewater treatment plants the treatment efficiency may not be sufficient for their complete removal and, consequently, retinoids can be released to the receiving water bodies at concentrations of up to 11.5 ng REQ × L−1 [253, 271, 280,281,282,283]. Amongst the detected isomers, oxidized (i.e. 4-oxo-) derivatives of retinoic acids dominate over the parent compounds. Besides dietary excreted retinoids, pharmaceutical retinoids (tretinoin (atRA), alitretinoin (9cRA), isotretinoin (13cRA), bexarotene, and others; pharmaceutical use: cancer, acne (≥ 0.5 mg isotretinoin/kg/days), eczema treatment [222, 284, 285]) and cosmetically used retinoids (retinol, retinyl palmitate, retinyl acetate; cosmetic use: body lotion (≤ 0.05% retinol equivalent), hand/face cream or rinse-off products (≤ 0.3% retinol equivalent) [279, 286]) can be excreted into wastewaters or washed-off after topical application. The use of retinoic acid in cosmetics is restricted within the EU and Norway [70, 286, 287], recommendations are provided by the European Medical Agency, with respect to oral use of the retinoid containing medicinal products in pregnancy, and also for those suffering from neuropsychiatric disorders . The potential contribution routes to retinoid compounds in surface waters are also summarized in Fig. 3.
Anthropogenic and natural endocrine-active substances
The presence of unregulated endocrine-active substances (EAS), like retinoids, in waters raises the questions: to what extent do they contribute to mixture effects? Do we need to update the assessment of water safety for human consumption? To date, EAS in the environment are managed by regulating their commercial release: the manufacturer is responsible for correct labelling of the product and has to assure an acceptable risk of the active ingredient, or the preparation, to the environment. While this management scheme covers anthropogenic releases of chemicals, it cannot capture natural sources that contribute to the cumulative effects observed in the environment in situ. Hence, it does not reflect the need to tackle mixture effects in the environment directly or just before release of complex mixtures like waste water effluents into the environment [288,289,290,291].
The European Union’s visionary concept of water legislation, encompassed in the Water Framework Directive (WFD, ), the Urban Waste Water Treatment Directive [288, 292], the Nitrates Directive , and the Drinking Water Directive [DWD, 294], aims to secure safe drinking water now and for future generations. However, the demand for water, for nutritional, recreational and agricultural purposes, increasingly challenges water supply managers and may require switching to less-favourable water sources to provide the consumers with the desired supply [295, 296].
To meet the high expectations for surface and drinking water safety, a holistic assessment at the point of abstraction for drinking water, including sub-acute and/or longer-term effects of EAS and putative endocrine disruptors, rather than managing only anthropogenic inputs of active substances (e.g. pesticides, fertilizers, pharmaceuticals) to the environment would be beneficial for risk assessment and more reflective of the true burden of EAS exposure via drinking water [44, 290, 297, 298]. The impact of substances such as pesticides, fertilizers, and pharmaceuticals upon the growth of cyanobacterial blooms causing increased “anthropo-natural” retinoid production is also a critical factor to include in the hazard and risk assessment process.
Discussion - implications for risk assessment
We have presented evidence here indicating that altered endogenous retinoid signalling is plausibly implicated in a variety of major public health areas of concern. In particular these include brain and neurodegenerative conditions such as Parkinson’s disease, dementia, schizophrenia, and depression (see sections “Contribution of retinoids to chronic neurological disorders”–“Schizophrenia”, Tables 1 and 2), as well as developmental effects. However, the available evidence causally linking these diseases with aberrant retinoid signalling is currently weak - particularly with respect to environmental exposure.
Retinoids in the form of vitamin A and its precursors are essential nutritional requirements, and it is well established that too little or too much can lead to adverse health outcomes. Whilst vitamin A dietary reference values are clearly specified [70, 72, 97], these are advisory and on the whole are not controlled by regulatory bodies, with the exception of fortified functional/novel foods, where fortification can impact upon vulnerable populations, as for example, with infant formula . Retinoid-based orally administered pharmaceuticals can also contribute to the daily exposure, while not being accounted for by nutritional reference values . Critical limitations in attributing altered retinoid signalling to environmental exposure are the lack of monitoring of retinoid compounds and virtual absence of effect-based screenings for retinoid-like activity, even though monitoring reports from the Czech Republic and Asia indicate significant (anthropo-)natural sources of retinoids [249,250,251,252, 271]. This data gap is aggravated by the retinoid signalling pathway not (yet) being included as a contributory pathway that can be adequately assessed by standardized test methods, as part of endocrine disruption hazard assessment and by the unknown hazards related to environmental mixtures of anthropogenic contaminants and (anthropo-)natural compounds adversely interfering with this pathway. Retinoid signalling is directly involved (via RAR) in a multitude of developmental, neurological and repair processes as well as indirectly via the universal heterodimerization partner RXR. This contributes to the non-linear intercommunication web of cause–effect relationships that are observed upon disturbed retinoid signalling and additionally allows pleiotropic effects through crosstalk with other pathways such as TR , or PPARβ/δ signalling  and steroidogenesis . In addition, the substantial evidence for the teratogenicity of retinoids is usually addressed under developmental toxicity hazard assessment, rather than endocrine disruption per se (see Table 1), whilst the proposed adverse outcomes in relation to spermatogenesis and male reproduction [summarized in 13], fall under reproductive toxicity, and the biologically plausible hypothesis of involvement in the development and manifestation of neurological disease, under (developmental) neurotoxicity (see Table 2). Furthermore, the elucidation of the link between neurological disease and altered RA signalling also requires more basic investigation into the role of retinoid signalling in the brain (using experimental models and clinical investigations) together with population-based studies - as has been done, e.g. for polychlorinated biphenyls [299, 300]. This would need a characterization of the exposure to compounds with potential retinoid signalling disruptive effects - as depicted in Table 2.
In addition to hazard assessment, the characterization and quantification of environmental levels of retinoid compounds and retinoid-like activity is key for the exposure evidence base needed to assess whether they are likely to pose a risk to the environment and human health. This needs to include a consideration of exceedance of vitamin A nutritional requirements and dietary sources of exposure. (Anthropo-)natural sources of EAS such as cyanobacterial blooms often exhibit pronounced cyclic recurrent (i.e. seasonal, non-continuous) patterns [270, 301]. Consequently, derived exposure limits should consider intermediate longer-term values in addition to lifetime-daily exposure, such as seasonal, monthly, or weekly exposure. This has been recently proposed and conducted by the WHO for a few selected cyanobacterial toxins . In surface waters, wastewater treatment effluents are a constant contributor of anthropogenic bioactive compounds including retinoids . To address transformation of pharmaceutically and cosmetically used retinoids, it is suggested that work being initiated at the OECD to develop a test guideline on anaerobic transformation of veterinary pharmaceuticals, organic compounds and biocides in liquid farmyard manure  could include retinoid-like monitoring endpoints. This would contribute to filling the assessment data gap of retinoid-like activity originating from farmyard manure and its fate in the environment. This could also be a tool of potential value in addressing subsequent monitoring of retinoid removal in urban wastewater effluents.
Besides recognizing the occurrence of endocrine disruptors in the environment, it is also critical to develop more accurate tools to assess their potential impact and hence any associated risk. In the case of interference with retinoid signalling, this means mainly to direct research efforts into the augmentation of already existing test guidelines and the validation of (non-animal alternative) methods for regulatory testing of retinoid signalling pathway disruption, which is already initiated at international intergovernmental levels (see “Introduction” section).
In addition to distinct test methods, AOPs are being developed with the intention of regulatory applications, to convey biologically plausible hierarchical structures of causes, effects, and outcomes from basic research to regulatory actions. It is important to refine and strengthen AOPs under development for retinoid signalling disturbance [13, 303]. Besides only linking the sequential “event-train”, recent efforts to define tipping points for transition between key events could make AOPs become quantitative, thus more useful for computational predictive approaches [21, 303, 304]. An analogous approach to AOPs has also been taken in exposure science with aggregate exposure pathways (AEPs). They aim to summarize exposure from different sources, and integrate target site exposure, e.g. at a receptor in the tissue . AEPs take into account potential environmental or metabolic transformation of a substance or cumulative effects of structurally similar substances in mixtures and are inclusive to substances of natural origin that may contribute to target site effects [305, 306]. The integration of exposure and effect assessment is also called for by European partnerships to achieve the ambitious goals laid out in the WFD .
Substances of emerging concern often show endocrine activity and/or are candidate endocrine disruptors [308, 309]. Although not intended, these substances often find their way into the environment, and, most importantly their environmental occurrence is augmented by human actions . For the sustainable development of society, we need to recognize our environmental impact and try to retain or re-establish the delicate balance of maintaining and protecting landscapes and ecosystems (see Fig. 3). Only then will we be able to achieve the visionary milestones identified and articulated, e.g. by the United Nations Organization as the “Sustainable Development Goals” [310, Goal 6: “Clean water and sanitation”], by the European Commission in water-related directives (e.g. WFD , DWD ) and, most recently, by the European Green Deal, which aims at ensuring a “toxic-free environment”, including a zero pollution approach and the development of an action plan regarding endocrine disruptors in the environment and circular economies . With respect to mixtures in the environment, it was recently proposed to combine all EU chemical-related legislation, independent of the use scenario, in order to allow an inclusive mixture impact assessment . A further proposal is to formulate “human health protection goals”, similar to the protection goals defined in the WFD for aquatic environments, with respect to involuntary and cumulative exposure to chemicals .
Here, we have presented the (anthropo-)natural occurrence of retinoids in freshwater environments as a case study example to highlight the importance of regulatory recognition of non-EATS endocrine disruption pathways, specifically the retinoid signalling pathway. Elaborating on diffuse and especially (anthropo-)natural sources of these teratogenic EAS, we highlight the necessity of including exposure to mixtures from different environmental media and evaluating environmental and human health impacts of compounds, irrespective of and independent to their initial use, e.g. biocide/plant protection product; environmental matrices like water or soil are indifferent to the use-case of a product.
The (anthropo-)natural occurrence and production of retinoids in water bodies in addition to anthropogenic sources suggests a human health hazard. However, due to insufficient data on environmental levels of retinoids, especially spatio-temporal screening data, an adequate risk assessment cannot be conducted to date. Future monitoring studies need to take into account both point sources such as wastewater treatment plants and diffuse (anthropo-)natural sources of EAS that include retinoids.
The retinoid signalling pathway is conserved at least across vertebrates and plays a pivotal role during prenatal development, such that its disturbance can cause teratogenic effects that range from mild malformations to lethality. Phenotypically similar developmental defects were observed in aquatic vertebrates exposed to environmental cyanobacterial bloom extracts with retinoid-like activity.
Postnatal roles of retinoids include epithelial integrity and spermatogenesis, and retinoid signalling disruption may play a role in the epidemic of neurological and neurodegenerative disease. A preliminary weight-of-evidence matrix for the association of disturbed retinoid signalling with neurological disease was presented to flag uncertainties in the experimental design or the biological link, however despite biological plausibility, the weight of evidence to date is insufficient to support the causality of retinoid signalling disturbance in neurological diseases.
Also, agonistic/antagonistic and additive actions that are not covered by the current assessment methods may occur due to the high degree of molecular crosstalk between different endocrine signalling pathways, as depicted for example for RXR.
To strengthen the retinoid relevant AOPs for regulatory applications, future toxicological studies need to further address and elucidate the toxicological tipping points from one key event to the next. Understanding the adaptive stress response in a concentration and time-dependent manner is crucial to derive not only acute and chronic (i.e. life-time daily) exposure limits, but also more realistic prolonged-short time exposure limits that, for example, reflect seasonal variations in exposure scenarios as recently conducted by WHO , although retinoids are not currently included in this proposed approach. It may also lead to a better understanding of life-stage and gender differences in toxic effects. The development of high-throughput methods and an increasing number of validated non-animal methods will enable more rapid and efficient understanding of these differences that could ultimately contribute to safer waters in the future - for humans and ecosystems.
Availability of data and materials
9-cis Retinoic acid, alitretinoin
13-cis Retinoic acid, isotretinoin
Aggregate exposure pathway
Adverse outcome pathway
All-trans retinoic acid, tretinoin
Brain-derived neurotropic factor
Constitutive androstane receptor
Central nervous system
Cytochrome P450 monooxygenase subfamily 26 (detoxifying enzyme)
- D1R, D2R:
Dopamine receptors 1 and 2
Drinking Water Directive
Sex hormone (oestrogen, androgen) receptors, steroidogenesis, and thyroid hormone signalling
Effective concentration affecting 20% of the tested population
γ-Amino butyric acid
Organisation for Economic Co-operation and Development
Peroxisome-proliferator activated receptor
Pregnane X receptor
Retinoic acid receptor
Retinoic acid-responsive element
Retinoid X receptor
Thyroid hormone receptor
Vitamin A (retinol) deficiency
Vitamin D receptor
Water Framework Directive
World Health Organization
European Commission (2018) Commission Regulation (EU) 2018/605 amending Annex II to Regulation (EC) No 1107/2009 by setting out scientific criteria for the determination of endocrine disrupting properties. https://doi.org/10.2903/j.efsa.2013.3132
EFSA, ECHA, with the technical support of the JRC, et al (2018) Guidance for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. EFSA J 16:e05311. https://doi.org/10.2903/j.efsa.2018.5311
OECD GD 150 (2018) Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption
La Merrill MA, Vandenberg LN, Smith MT et al (2020) Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat Rev Endocrinol 16:45–57. https://doi.org/10.1038/s41574-019-0273-8
Crain DA, Rooney AA, Orlando E, Guillette LJ (2000) Endocrine disrupting contaminants and hormone dynamics: lessons from wildlife. In: Guillette LJ, Crain DA (eds) Environmental endocrine disrupters: an evolutionary perspective. Taylor & Francis, New York, p 355
Schug TT, Johnson AF, Birnbaum LS et al (2016) Minireview: endocrine Disruptors: Past Lessons and Future Directions. Mol Endocrinol 30:833–847. https://doi.org/10.1210/me.2016-1096
Jacobs MN (2005) Nutrients and cell signaling. CRC Press, New York
OECD DRP 97 (2008) Detailed Review Paper on the use of metabolising systems for in vitro testing of endocrine disruptors. In: OECD Series on Testing and Assessment. OECD, p 213
OECD DRP 178 (2014) Detailed Review Paper on the state of the science on novel in vitro and in vivo screening and testing methods and endpoints for evaluating endocrine disruptors. In: OECD Series on Testing and Assessment. OECD
OECD (2017) New scoping document on in vitro and ex vivo assays for the identification of modulators of thyroid hormone signalling. In: OECD Series on Testing and Assessment, No. 207
Greally JM, Jacobs MN (2013) In vitro and in vivo testing methods of epigenomic endpoints for evaluating endocrine disruptors. Altex 30:445–471. https://doi.org/10.14573/altex.2013.4.445
Jacobs MN, Marczylo EL, Guerrero-Bosagna C, Uegg JR (2017) Marked for life: epigenetic effects of endocrine disrupting chemicals. Annu Rev Environ Resour 42:1–23. https://doi.org/10.1146/annurev-environ
Nilsson C (2020) Retinoids in Mammalian Reproduction, with an Initial Scoping Effort to Identify Regulatory Methods. TemaNord 2020:507. Nordic Council of Ministers
Grignard E, Hakansson H, Munn S (2020) Regulatory needs and activities to address the retinoid system in the context of endocrine disruption: the European viewpoint. Reprod Toxicol 93:250–258. https://doi.org/10.1016/j.reprotox.2020.03.002
Jacobs MN, Laws SC, Willett K, et al (2013) In vitro metabolism and bioavailability tests for endocrine active substances: What is needed next for regulatory purposes? Altex 30:331–351. https://doi.org/10.14573/altex.2013.3.331
Jacobs M, Janssens W, Bernauer U et al (2008) The use of metabolising systems for in vitro testing of endocrine disruptors. Curr Drug Metab 9:796–826. https://doi.org/10.2174/138920008786049294
Vandenberg LN, Colborn T, Hayes TB et al (2012) Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev 33:378–455
Bergman Å, Heindel JJ, Jobling S et al (2013) Endocrine disruptors and metabolic disorders. State Sci Endocr Disrupt Chem 2012:296
Marczylo EL, Jacobs MN, Gant TW (2016) Environmentally induced epigenetic toxicity: potential public health concerns. Crit Rev Toxicol 46:676–700
Legler J, Zalko D, Jourdan F et al (2020) The GOLIATH project: towards an internationally harmonised approach for testing metabolism disrupting compounds. Int J Mol Sci 21:3480. https://doi.org/10.3390/ijms21103480
Jacobs MN, Colacci A, Corvi R et al (2020) Chemical carcinogen safety testing: OECD expert group international consensus on the development of an integrated approach for the testing and assessment of chemical non-genotoxic carcinogens. Arch Toxicol 1:3. https://doi.org/10.1007/s00204-020-02784-5
Bergman Å, Heindel JJ, Kasten T et al (2013) The impact of endocrine disruption: a consensus statement on the state of the science. Environ Health Perspect. https://doi.org/10.1289/ehp.1205448
Schug TT, Janesick A, Blumberg B, Heindel JJ (2011) Endocrine disrupting chemicals and disease susceptibility. J Steroid Biochem Mol Biol 127:204–215
Li M, Sun Y, Guan X et al (2014) Advanced progress on the relationship between RA and its receptors and malignant tumors. Crit Rev Oncol Hematol 91:271–282
Stel J, Legler J (2015) The role of epigenetics in the latent effects of early life exposure to obesogenic endocrine disrupting chemicals. Endocrinology 156:3466–3472. https://doi.org/10.1210/en.2015-1434
Heindel JJ, Blumberg B, Cave M et al (2017) Metabolism disrupting chemicals and metabolic disorders. Reprod Toxicol 68:3–33. https://doi.org/10.1016/j.reprotox.2016.10.001
Trasande L, Blumberg B (2018) Endocrine disruptors as obesogens. In: Contemporary Endocrinology. Humana Press Inc., pp 243–253
Jacobs MN, Colacci A, Louekari K, et al (2016) International regulatory needs for development of an IATA for non-genotoxic carcinogenic chemical substances. Altex 33:359–392. https://doi.org/10.14573/altex.1601201
Murphy KA, Villano CM, Dorn R, White LA (2004) Interaction between the aryl hydrocarbon receptor and retinoic acid pathways increases matrix metalloproteinase-1 expression in keratinocytes. J Biol Chem 279:25284–25293. https://doi.org/10.1074/jbc.M402168200
Gormley Á, Pollard S, Rocks S, Black E (2011) Guidelines for Environmental Risk Assessment and Management - Green Leaves III
Scientific Committee EFSA, More SJ, Bampidis V et al (2019) Guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals. EFSA J 17:77. https://doi.org/10.2903/j.efsa.2019.5634
EURION (2018) Improving Identification of Endocrine Disruptors. https://eurion-cluster.eu/. Accessed 24 Feb 2020
Jobling S, Beresford N, Nolan M et al (2002) Altered Sexual Maturation and Gamete Production in Wild Roach (Rutilus rutilus) Living in Rivers That Receive Treated Sewage Effluents1. Biol Reprod 66:272–281. https://doi.org/10.1095/biolreprod66.2.272
Tyler CR, Jobling S, Sumpter JP (1998) Endocrine disruption in wildlife: a critical review of the evidence. Crit Rev Toxicol 28:319–361
Semenza JC, Tolbert PE, Rubin CH et al (1997) Reproductive toxins and alligator abnormalities at Lake Apopka, Florida. Environ Health Perspect 105:1030–1032
Purdom CE, Hardiman PA, Bye VJ et al (1994) Estrogenic Effects of Effluents from Sewage Treatment Works. Chemistry and Ecology 8:275–285. https://doi.org/10.1080/02757549408038554
Harris CA, Hamilton PB, Runnalls TJ et al (2011) The consequences of feminization in Breeding groups of wild fish. Environ Health Perspect 119:306–311. https://doi.org/10.1289/ehp.1002555
Jobling S, Nolan M, Tyler CR et al (1998) Widespread sexual disruption in wild fish. Environ Sci Technol 32:2498–2506. https://doi.org/10.1021/es9710870
Kidd KA, Blanchfield PJ, Mills KH et al (2007) Collapse of a fish population after exposure to a synthetic estrogen. Proc Natl Acad Sci USA 104:8897–8901. https://doi.org/10.1073/pnas.0609568104
Shore LS, Gurevitz M, Shemesh M (1993) Estrogen as an environmental pollutant. Bull Environ Contam Toxicol 51:361–366. https://doi.org/10.1007/BF00201753
Schwarz TI, Katsiadaki I, Maskrey BH, Scott AP (2018) Uptake and metabolism of water-borne progesterone by the mussel, Mytilus spp. (Mollusca). J Steroid Biochem Mol Biol 178:13–21. https://doi.org/10.1016/j.jsbmb.2017.10.016
Marty MS, Carney EW, Rowlands JC (2011) Endocrine disruption: historical perspectives and its impact on the future of toxicology testing. Toxicol Sci 120:S93–S108. https://doi.org/10.1093/toxsci/kfq329
WHO/UNEP (2013) State of the science of endocrine disrupting chemicals - 2012. An assessment of the state of the science of endocrine disruptors prepared by a group of experts for the United Nations Environment Programme (UNEP) and WHO. ISBN: 978 92 4 150503 1
Solecki R, Kortenkamp A, Bergman Å et al (2017) Scientific principles for the identification of endocrine-disrupting chemicals: a consensus statement. Arch Toxicol 91:1001–1006. https://doi.org/10.1007/s00204-016-1866-9
OECD (2015) Test No. 493: Performance-Based Test Guideline for Human Recombinant Estrogen Receptor (hrER) In Vitro Assays to Detect Chemicals with ER Binding Affinity, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. https://doi.org/10.1787/9789264242623-en
OECD (2015) Test No. 455: Performance-Based Test Guideline for Stably Transfected Transactivation In Vitro Assays to Detect Estrogen Receptor Agonists and Antagonists, OECD Publishing, Paris. https://doi.org/10.1787/9789264243040-en
OECD (2007) Test No. 440: Uterotrophic Bioassay in Rodents: A short-term screening test for oestrogenic properties, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. https://doi.org/10.1787/9789264067417-en
OECD (2007) Guidance Document on the uterotrophic bioassay - procedure to test for Antioestrogenicity. ENV/JM/MONO(2007)15. JT03230411. In: OECD Series on Testing and Assessment. OECD Publishing, Paris. http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2007)15&doclanguage=en
OECD (2020) Test No. 458: Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. https://doi.org/10.1787/9789264264366-en
OECD (2011) Guidance document on the androgenised female stickleback screen. JT03305970. ENV/JM/MONO(2011)29. In: OECD Series on Testing and Assessment: Testing for Endocrine Disrupters No. 148. OECD Publishing, Paris. http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=ENV/JM/MONO(2011)29&doclanguage=en
OECD (2009) Test No. 441: Hershberger Bioassay in Rats: A Short-term Screening Assay for (Anti)Androgenic Properties, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. https://doi.org/10.1787/9789264076334-en
OECD (2009) Test No. 230: 21-day Fish Assay: A Short-Term Screening for Oestrogenic and Androgenic Activity, and Aromatase Inhibition, OECD Guidelines for the Testing of Chemicals, Section 2, OECD Publishing, Paris. https://doi.org/10.1787/9789264076228-en
OECD (2010) Validation report on the 21-day androgenised female stickleback screening assay. In: Series on Testing and Assessment: Testing for Endocrine Disrupters No. 128. ENV/JM/MONO(2010)19. OECD Publishing, Paris. http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2010)19&doclanguage=en
Jolly C, Katsiadaki I, Morris S et al (2009) Detection of the anti-androgenic effect of endocrine disrupting environmental contaminants using in vivo and in vitro assays in the three-spined stickleback. Aquat Toxicol 92:228–239. https://doi.org/10.1016/j.aquatox.2009.02.006
Katsiadaki I, Morris S, Squires C et al (2006) Use of the three-spined stickleback (Gasterosteus aculeatus) as a sensitive in vivo test for detection of environmental antiandrogens. Environ Health Perspect 114:115–121. https://doi.org/10.1289/ehp.8063
Kurauchi K, Hirata T, Kinoshita M (2008) Characteristics of ChgH-GFP transgenic medaka lines, an in vivo estrogenic compound detection system. Mar Pollut Bull 57:441–444. https://doi.org/10.1016/j.marpolbul.2008.03.016
Kurauchi K, Nakaguchi Y, Tsutsumi M et al (2005) In vivo visual reporter system for detection of estrogen-like substances by transgenic medaka. Environ Sci Technol 39:2762–2768. https://doi.org/10.1021/es0486465
Spirhanzlova P, Leleu M, Sébillot A et al (2016) Oestrogen reporter transgenic medaka for non-invasive evaluation of aromatase activity. Comparative Biochem Physiol 179:64–71. https://doi.org/10.1016/j.cbpc.2015.08.011
Brion F (2017) Draft report of the phase 1 validation study of the EASZY assay. In: National Institute of Industrial Environment and Risks (INERIS) Chronic Risk Division. France. pp 1–12
Kiianitsa K, Maizels N (2013) A rapid and sensitive assay for DNA-protein covalent complexes in living cells. Nucleic Acids Res 41:e104. https://doi.org/10.1093/nar/gkt171
Sébillot A, Damdimopoulou P, Ogino Y et al (2014) Rapid fluorescent detection of (anti)androgens with spiggin-gfp medaka. Environ Sci Technol 48:10919–10928. https://doi.org/10.1021/es5030977
Browne P, Judson RS, Casey WM et al (2015) Screening chemicals for estrogen receptor bioactivity using a computational model. Environ Sci Technol 49:8804–8814. https://doi.org/10.1021/acs.est.5b02641
Kleinstreuer NC, Browne P, Chang X et al (2018) Evaluation of androgen assay results using a curated Hershberger database. Reprod Toxicol 81:272–280. https://doi.org/10.1016/j.reprotox.2018.08.017
OECD (2011) Test No. 456: H295R Steroidogenesis Assay, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. https://doi.org/10.1787/9789264122642-en
EURL ECVAM (2017) European drive to validate in vitro methods for the detection of thyroid disruptors| EU Science Hub. https://ec.europa.eu/jrc/en/science-update/vitro-methods-detection-thyroid-disruptors. Accessed 2 Jul 2020
JRC (2017) Thyroid receptor microarray assay for real-time Nuclear Receptor-coregulator interaction| EURL ECVAM - TSAR. https://tsar.jrc.ec.europa.eu/test-method/tm2017-02. Accessed 2 Jul 2020
OECD (2019) Test No. 248: Xenopus Eleutheroembryonic Thyroid Assay (XETA), OECD Guidelines for the Testing of Chemicals, Section 2, OECD Publishing, Paris. https://doi.org/10.1787/a13f80ee-en
Fini JB, Le Mevel S, Turque N et al (2007) An in vivo multiwell-based fluorescent screen for monitoring vertebrate thyroid hormone disruption. Environ Sci Technol 41:5908–5914. https://doi.org/10.1021/es0704129
IUPAC (1983) Nomenclature of retinoids. Pure Appl Chem 55:721–726
SCCS (2016) Opinion on vitamin A (retinol, retinyl acetate, retinyl palmitate). Final version of 6 October 2016, CORRIGENDUM on 23 December 2016. SCCS/1576/16 1–85. https://doi.org/10.2875/642264
COT (2014) Committee on toxicity of chemicals in food, consumer products and the environment: statement on the potential risks from high levels of vitamin A in the infant diet. COT Statement 2013(03):1–28
PHE (2016) Government dietary recommendations. Government recommendations for energy and nutrients for males and females aged 1-18 years and 19 + years. PHE publications; Nutrition Science TeamNutrition Science Team
Rhinn M, Dollé P, Dolle P (2012) Retinoic acid signalling during development. Development 139:843–858. https://doi.org/10.1242/dev.065938
Bryant SV, Gardiner DM (1992) Retinoic acid, local cell–cell interactions, and pattern formation in vertebrate limbs. Develop Biol 152:1–25. https://doi.org/10.1016/0012-1606(92)90152-7
Zieger E, Schubert M (2017) New insights into the roles of retinoic acid signaling in nervous system development and the establishment of neurotransmitter systems. In: International review of cell and molecular biology(330). pp 1–84
Maden M (2000) The role of retinoic acid in embryonic and post-embryonic development. Proc Nutr Soc 59:65–73
Maden M (1993) The effect of vitamin A (retinoids) on pattern formation implies a uniformity of developmental mechanisms throughout the animal kingdom. Acta Biotheor 41:425–445. https://doi.org/10.1007/BF00709375
Cunningham TJ, Duester G (2015) Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat Rev Mol Cell Biol 16:110–123. https://doi.org/10.1038/nrm3932
Gardiner D, Ndayibagira A, Grün F, Blumberg B (2003) Deformed frogs and environmental retinoids. In: Pure and Applied Chemistry. De Gruyter, pp 2263–2273
Tzimas G, Nau H (2001) The role of metabolism and toxicokinetics in retinoid teratogenesis. Curr Pharm Des 7:803–831. https://doi.org/10.2174/1381612013397708
Hendrickx AG, Peterson P, Hartmann D, Hummler H (2000) Vitamin A teratogenicity and risk assessment in the macaque retinoid model. Reprod Toxicol 14:311–323. https://doi.org/10.1016/s0890-6238(00)00091-5
Maden M (2007) Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci 8:755–765. https://doi.org/10.1038/nrn2212
Allenby G, Bocquel MT, Saunders M et al (1993) Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci USA 90:30–34. https://doi.org/10.1073/pnas.90.1.30
Priebojová J, Hilscherová K, Procházková T et al (2018) Intracellular and extracellular retinoid-like activity of widespread cyanobacterial species. Ecotoxicol Environ Saf 150:312–319. https://doi.org/10.1016/j.ecoenv.2017.12.048
De Lera ÁR, Krężel W, Rühl R (2016) An endogenous mammalian retinoid X receptor ligand, at Last! ChemMedChem 11:1027–1037. https://doi.org/10.1002/cmdc.201600105
Dawson MI, Xia Z (2012) The retinoid X receptors and their ligands. Biochem Biophys Acta 1821:21–56. https://doi.org/10.1016/j.bbalip.2011.09.014
Clark AK, Wilder JH, Grayson AW et al (2016) The Promiscuity of allosteric regulation of nuclear receptors by retinoid X Receptor. J Phys Chem B 120:8338–8345. https://doi.org/10.1021/acs.jpcb.6b02057
Krężel W, Rühl R, de Lera AR (2019) Alternative retinoid X receptor (RXR) ligands. Mol Cell Endocrinol 491:110436
Sandell LL, Lynn ML, Inman KE et al (2012) RDH10 oxidation of vitamin A is a critical control step in synthesis of retinoic acid during mouse embryogenesis. PLoS ONE 7:e30698. https://doi.org/10.1371/journal.pone.0030698
Ribes V, Wang Z, Dollé P, Niederreither K (2006) Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling. Development 133:351–361. https://doi.org/10.1242/dev.02204
Niederreither K, Vermot J, Schuhbaur B et al (2000) Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development 127:75–85
Lucek RW, Colburn WA (1985) Clinical pharmacokinetics of the retinoids. Clin Pharmacokinet 10:38–62. https://doi.org/10.2165/00003088-198510010-00002
Shirakami Y, Lee SA, Clugston RD, Blaner WS (2012) Hepatic metabolism of retinoids and disease associations. Biochem Biophys Acta 1821:124–136
Blomhoff R, Blomhoff HK (2006) Overview of retinoid metabolism and function. J Neurobiol 66:606–630. https://doi.org/10.1002/neu.20242
Rodriguez-Concepcion M, Avalos J, Bonet ML et al (2018) A global perspective on carotenoids: metabolism, biotechnology, and benefits for nutrition and health. Prog Lipid Res 70:62–93
Morriss-Kay GM, Wardt SJ (1999) Retinoids and mammalian development. Int Rev Cytol 188:73–131. https://doi.org/10.1016/s0074-7696(08)61566-1
EFSA NDA (2015) Scientific opinion on dietary reference values for vitamin A. EFSA panel on dietetic products, nutrition, and allergies (NDA) EFSA J 13:4028. https://doi.org/10.2903/j.efsa.2015.4028
Germain P, Chambon P, Eichele G et al (2006) International union of pharmacology. LX. Retinoic acid receptors. Pharmacol Rev 58:712–725
Das BC, Thapa P, Karki R et al (2014) Retinoic acid signaling pathways in development and diseases. Bioorg Med Chem 22:673–683. https://doi.org/10.1016/j.bmc.2013.11.025
Mouchon A, Delmotte M-H, Formstecher P, Lefebvre P (1999) Allosteric regulation of the discriminative responsiveness of retinoic acid receptor to natural and synthetic ligands by retinoid X receptor and DNA. Mol Cell Biol 19:3073–3085. https://doi.org/10.1128/mcb.19.4.3073
Vilhais-Neto GC, Pourquié O (2008) Retinoic acid. Curr Biol 18:R191–R192
le Maire T et al (2019) Regulation of RXR-RAR heterodimers by RXR- and RAR-specific ligands and their combinations. Cells 8:1392. https://doi.org/10.3390/cells8111392
Ghyselinck NB, Duester G (2019) Retinoic acid signaling pathways. Development (Cambridge). https://doi.org/10.1242/dev.167502
Penvose A, Keenan JL, Bray D et al (2019) Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity. Nature Communications 10:2514. https://doi.org/10.1038/s41467-019-10264-3
Szanto A, Narkar V, Shen Q et al (2004) Review retinoid x receptors: x-ploring their (patho)physiological functions. Cell Death Differ 11:S126–S143
Cai Y, Konishi T, Han G et al (2002) The role of hepatocyte RXRα in xenobiotic-sensing nuclear receptor-mediated pathways. Eur J Pharm Sci 15:89–96. https://doi.org/10.1016/S0928-0987(01)00211-1
Evans RM, Mangelsdorf DJ (2014) Nuclear receptors, RXR, and the big bang. Cell 157:255–266
Gampe RT, Montana VG, Lambert MH et al (2000) Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell 5:545–555. https://doi.org/10.1016/S1097-2765(00)80448-7
Lee S-K, Na S-Y, Kim H-J et al (1998) Identification of critical residues for heterodimerization within the ligand-binding domain of retinoid X receptor. Mol Endocrinol 12:325–332. https://doi.org/10.1210/mend.12.3.0072
Bourguet W, Vivat V, Wurtz JM et al (2000) Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell 5:289–298. https://doi.org/10.1016/S1097-2765(00)80424-4
André A, Ruivo R, Fonseca E et al (2019) The retinoic acid receptor (RAR) in molluscs: function, evolution and endocrine disruption insights. Aquat Toxicol 208:80–89. https://doi.org/10.1016/j.aquatox.2019.01.002
Al Tanoury Z, Piskunov A, Rochette-Egly C (2013) Vitamin a and retinoid signaling: genomic and nongenomic effects. J Lipid Res 54:1761–1775
Schug TT, Berry DC, Shaw NS et al (2007) Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 129:723–733. https://doi.org/10.1016/j.cell.2007.02.050
Paul-Friedman K, Martin M, Crofton KM et al (2019) Limited Chemical Structural Diversity Found to Modulate Thyroid Hormone Receptor in the Tox21 Chemical Library. Environ Health Perspect 127:097009. https://doi.org/10.1289/EHP5314
Pascussi J-M, Gerbal-Chaloin S, Duret C et al (2008) The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu Rev Pharmacol Toxicol 48:1–32. https://doi.org/10.1146/annurev.pharmtox.47.120505.105349
Kakizaki S, Karami S, Negishi M (2002) Retinoic acids repress constitutive active receptor-mediated induction by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene of the CYP2B10 gene in mouse primary hepatocytes. Drug Metab Dispos 30:208–211. https://doi.org/10.1124/dmd.30.2.208
Dubuquoy L, Dharancy S, Nutten S et al (2002) Role of peroxisome proliferator-activated receptor γ and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet 360:1410–1418
Hua S, Kittler R, White KP (2009) Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell 137:1259–1271. https://doi.org/10.1016/j.cell.2009.04.043
Segars JH, Marks MS, Hirschfeld S et al (1993) Inhibition of estrogen-responsive gene activation by the retinoid X receptor beta: evidence for multiple inhibitory pathways. Mol Cell Biol 13:2258–2268. https://doi.org/10.1128/mcb.13.4.2258
Rubin M, Fenig E, Rosenauer A et al (1994) 9-Cis retinoic acid inhibits growth of breast cancer cells and down-regulates estrogen receptor RNA and protein. Cancer Res 54:6549–6556
Rousseau C, Nichol JN, Pettersson F et al (2004) ERβ sensitizes breast cancer cells to retinoic acid: evidence of transcriptional crosstalk. Mol Cancer Res 2:523–531
Wang B, Yang Q, Harris CL et al (2016) Nutrigenomic regulation of adipose tissue development - role of retinoic acid: a review. Meat Sci 120:100–106. https://doi.org/10.1016/j.meatsci.2016.04.003
Schierle S, Merk D (2019) Therapeutic modulation of retinoid X receptors–SAR and therapeutic potential of RXR ligands and recent patents. Expert Opin Ther Pat 29:605–621. https://doi.org/10.1080/13543776.2019.1643322
Burt Wolbach S, Howe PR (1925) Tissue changes following deprivation of fat-soluble A vitamin. J Exp Med 42:753–778. https://doi.org/10.1084/jem.42.6.753
Hale F (1933) Pigs born without eye balls. J Hered 24:105–106. https://doi.org/10.1093/oxfordjournals.jhered.a103720
Green HN, Mellanby E (1928) Vitamin a as an anti-infective agent. BMJ 2:691–696. https://doi.org/10.1136/bmj.2.3537.691
Wilson JG, Roth CB, Warkany J (1953) An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin a at various times during gestation. Am J Anatomy 92:189–217. https://doi.org/10.1002/aja.1000920202
Thampson JN, Howell JM, Pitt GAJ, McLaughlin CI (1969) The biological activity of retinoic acid in the domestic fowl and the effects of vitamin A deficiency on the chick embryo. Br J Nutr 23:471–490. https://doi.org/10.1079/bjn19690056
Kalter H, Warkany J (1959) Experimental production of congenital malformations in mammals by metabolic procedure. Physiol Rev 39:69–115. https://doi.org/10.1152/physrev.19188.8.131.52
Kochhar DM (1973) Limb development in mouse embryos. I. Analysis of teratogenic effects of retinoic acid. Teratology 7:289–298. https://doi.org/10.1002/tera.1420070310
WHO (2009) Global prevalence of vitamin A deficiency in populations at risk 1995-2005 WHO Global Database on Vitamin A Deficiency. World Health Organization, Geneva
WHO (2013) Micronutrient deficiencies - Vitamin A deficiency. In: WHO. https://www.who.int/nutrition/topics/vad/en/. Accessed 24 Mar 2020
Sommer A, Djunaedi E, Loeden AA et al (1986) Impact of vitamin A supplementation on childhood mortality. A randomised controlled community trial. Lancet 1:1169–1173. https://doi.org/10.1016/S0140-6736(86)91157-8
Niederreither K, Dollé P (2008) Retinoic acid in development: towards an integrated view. Nat Rev Genet 9:541–553
Brent GA (2012) Mechanisms of thyroid hormone action. J Clin Investig 122:3035–3043. https://doi.org/10.1172/JCI60047
Kogai T, Liu Y-Y, Richter LL et al (2010) Retinoic acid induces expression of the thyroid hormone transporter, monocarboxylate transporter 8 (Mct8). J Biol Chem 285:27279–27288. https://doi.org/10.1074/jbc.M110.123158
Duester G (2008) Retinoic acid synthesis and signaling during early organogenesis. Cell 134:921–931. https://doi.org/10.1016/j.cell.2008.09.002
D’Aniello E, Waxman JS, D’Aniello E, Waxman JS (2015) Input overload: contributions of retinoic acid signaling feedback mechanisms to heart development and teratogenesis. Dev Dyn 244:513–523. https://doi.org/10.1002/dvdy.24232
Antipatis C, Ashworth CJ, Grant G et al (1998) Effects of maternal vitamin A status on fetal heart and lung: changes in expression of key developmental genes. Am J Physiol Lung Cell Mol Physiol. https://doi.org/10.1152/ajplung.1998.275.6.l1184
Stefanovic S, Zaffran S (2017) Mechanisms of retinoic acid signaling during cardiogenesis. Mech Dev 143:9–19. https://doi.org/10.1016/j.mod.2016.12.002
Malpel S, Mendelsohn C, Cardoso WV (2000) Regulation of retinoic acid signaling during lung morphogenesis. Development 127:3057–3067
Biesalski HK, Nohr D (2003) Importance of vitamin-A for lung function and development. Mol Aspects Med 24:431–440. https://doi.org/10.1016/S0098-2997(03)00039-6
Maden M, Hind M (2004) Retinoic acid in alveolar development, maintenance and regeneration. In: Philosophical Transactions of the Royal Society B: Biological Sciences. Roy Soc 359:799–808
Sternberg RM, Gooding MP, Hotchkiss AK, LeBlanc GA (2010) Environmental-endocrine control of reproductive maturation in gastropods: implications for the mechanism of tributyltin-induced imposex in prosobranchs. Ecotoxicology 19:4–23
Lufkin T, Lohnes D, Mark M et al (1993) High postnatal lethality and testis degeneration in retinoic acid receptor α mutant mice. Proc Natl Acad Sci USA 90:7225–7229. https://doi.org/10.1073/pnas.90.15.7225
Spiller CM, Bowles J (2015) Sex determination in mammalian germ cells. Asian J Androl 17:427–432. https://doi.org/10.4103/1008-682X.150037
Kastner P, Mark M, Leid M et al (1996) Abnormal spermatogenesis in RXRβ mutant mice. Genes Dev 10:80–92. https://doi.org/10.1101/gad.10.1.80
Kam RKT, Deng Y, Chen Y, Zhao H (2012) Retinoic acid synthesis and functions in early embryonic development. Cell and Bioscience 2:11. https://doi.org/10.1186/2045-3701-2-11
Li Y, Cheng CN, Verdun VA, Wingert RA (2014) Zebrafish nephrogenesis is regulated by interactions between retinoic acid, mecom, and Notch signaling. Develop Biol 386:111–122. https://doi.org/10.1016/j.ydbio.2013.11.021
Denisenko-Nehrbass NI, Mello CV (2001) Molecular targets of disulfiram action on song maturation in zebra finches. Mol Brain Res 87:246–250. https://doi.org/10.1016/S0169-328X(01)00002-X
Chiang MY, Misner D, Kempermann G et al (1998) An essential role for retinoid receptors RARβ and RXRγ in long-term potentiation and depression. Neuron 21:1353–1361. https://doi.org/10.1016/S0896-6273(00)80654-6
Cocco S, Diaz G, Stancampiano R et al (2002) Vitamin A deficiency produces spatial learning and memory impairment in rats. Neuroscience 115:475–482. https://doi.org/10.1016/S0306-4522(02)00423-2
Etchamendy N, Enderlin V, Marighetto A et al (2003) Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling. Behav Brain Res 145:37–49. https://doi.org/10.1016/S0166-4328(03)00099-8
Corcoran J, Maden M (1999) Nerve growth factor acts via retinoic acid synthesis to stimulate neurite outgrowth. Nat Neurosci 2:307–308
Zhelyaznik N, Schrage K, McCaffery P, Mey J (2003) Activation of retinoic acid signalling after sciatic nerve injury: up-regulation of cellular retinoid binding proteins. Eur J Neurosci 18:1033–1040. https://doi.org/10.1046/j.1460-9568.2003.02834.x
Zhelyaznik N, Mey J (2006) Regulation of retinoic acid receptors α, β and retinoid X receptor α after sciatic nerve injury. Neuroscience 141:1761–1774. https://doi.org/10.1016/j.neuroscience.2006.05.021
Ross AC (2012) Vitamin A and retinoic acid in T cell–related immunity. Am J Clin Nutr 96:1166S–1172S. https://doi.org/10.3945/ajcn.112.034637
Mey J, Schrage K, Wessels I, Vollpracht-Crijns I (2007) Effects of inflammatory cytokines IL-1β, IL-6, and TNFα on the intracellular localization of retinoid receptors in Schwann cells. GLIA 55:152–164. https://doi.org/10.1002/glia.20444
Wendland K, Niss K, Kotarsky K et al (2018) Retinoic acid signaling in thymic epithelial cells regulates thymopoiesis. J Immunol 201:524–532. https://doi.org/10.4049/jimmunol.1800418
Underwood BA (1984) Vitamin A in animal and human nutrition. In: The Retinoids. Elsevier, pp 281–392
Topletz AR, Tripathy S, Foti RS et al (2015) Induction of CYP26A1 by metabolites of retinoic acid: evidence that CYP26A1 is an important enzyme in the elimination of active retinoids. Mol Pharmacol 87:430–441. https://doi.org/10.1124/mol.114.096784
Samarut E, Fraher D, Laudet V, Gibert Y (2015) ZebRA: an overview of retinoic acid signaling during zebrafish development. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms 1849:73–83
Molotkova N, Molotkov A, Duester G (2007) Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone. Develop Biol 303:601–610. https://doi.org/10.1016/j.ydbio.2006.11.035
Rhinn M, Schuhbaur B, Niederreither K, Dollé P (2011) Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment. Proc Natl Acad Sci USA 108:16687–16692. https://doi.org/10.1073/pnas.1103877108
Tonk ECM, Pennings JLA, Piersma AH (2015) An adverse outcome pathway framework for neural tube and axial defects mediated by modulation of retinoic acid homeostasis. Reprod Toxicol 55:104–113. https://doi.org/10.1016/j.reprotox.2014.10.008
Robinson JF (2014) Retinoids and developmental neurotoxicity in vivo and in vitro. Available via OECD. https://www.oecd.org/chemicalsafety/testing/Retinoid CNSv2.pdf. Accessed 27 Apr 2020.
Piersma AH, Hessel EV, Staal YC (2017) Retinoic acid in developmental toxicology: teratogen, morphogen and biomarker. Reprod Toxicol 72:53–61. https://doi.org/10.1016/j.reprotox.2017.05.014
Chen Y, Reese DH (2016) Disruption of retinol (vitamin A) signaling by phthalate esters: SAR and mechanism studies. PLoS ONE 11:e0161167. https://doi.org/10.1371/journal.pone.0161167
Ellis-Hutchings RG, Cherr GN, Hanna LA, Keen CL (2009) The effects of marginal maternal vitamin A status on penta-brominated diphenyl ether mixture-induced alterations in maternal and conceptal vitamin A and fetal development in the Sprague Dawley rat. Birth Defects Res B 86:48–57. https://doi.org/10.1002/bdrb.20181
Haggard DE, Das SR, Tanguay RL (2017) Comparative toxicogenomic responses to the flame retardant mITP in developing Zebrafish. Chem Res Toxicol 30:508–515. https://doi.org/10.1021/acs.chemrestox.6b00423
ENDpoiNTs (2019) Novel Testing Strategies for Endocrine Disruptors in the Context of Developmental NeuroToxicity. ENDpoiNTs Project. https://cordis.europa.eu/project/id/825759. Accessed 2 Jun 2020
van Neerven S, Kampmann E, Mey J (2008) RAR/RXR and PPAR/RXR signaling in neurological and psychiatric diseases. Prog Neurobiol 85:433–451
Lane MA, Bailey SJ (2005) Role of retinoid signalling in the adult brain. Prog Neurobiol 75:275–293
Wondolowski J, Dickman D (2013) Emerging links between homeostatic synaptic plasticity and neurological disease. Front Cell Neurosci 7:223
Walters BJ, Josselyn SA (2019) Retinoic acid receptor plays both sides of homeostatic plasticity. Proc Natl Acad Sci USA 116:6528–6530
Hsu YT, Li J, Wu D et al (2019) Synaptic retinoic acid receptor signaling mediates mTOR-dependent metaplasticity that controls hippocampal learning. Proc Natl Acad Sci USA 116:7113–7122
Bremner JD, McCaffery P (2008) The neurobiology of retinoic acid in affective disorders. Prog Neuropsychopharmacol Biol Psychiatry 32:315–331. https://doi.org/10.1016/j.pnpbp.2007.07.001
Goodman AB (2006) Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease. J Cell Physiol 209:598–603
Alzheimer’s Association (2020) 2020 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia 16:391–460. https://doi.org/10.1002/alz.12068
Xu J, Murphy SL, Kochanek KD, Arias E (2020) Mortality in the United States, 2018. NCHS Data Brief No 355
Carroll WM (2019) The global burden of neurological disorders. Lancet Neurol 18:418–419
Nichols E, Szoeke CEI, Vollset SE et al (2019) Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18:88–106. https://doi.org/10.1016/S1474-4422(18)30403-4
Yegambaram M, Manivannan B, Beach T, Halden R (2015) Role of environmental contaminants in the etiology of Alzheimer’s Disease: a review. Curr Alzheimer Res 12:116–146. https://doi.org/10.2174/1567205012666150204121719
Gauthier E, Fortier I, Courchesne F et al (2001) Environmental pesticide exposure as a risk factor for Alzheimer’s disease: a case-control study. Environ Res 86:37–45. https://doi.org/10.1006/enrs.2001.4254
Killin LOJ, Starr JM, Shiue IJ, Russ TC (2016) Environmental risk factors for dementia: a systematic review. BMC Geriatrics 16:1–28. https://doi.org/10.1186/s12877-016-0342-y
Adams J (2010) The neurobehavioral teratology of retinoids: a 50-year history. Birth Defects Res A 88:895–905. https://doi.org/10.1002/bdra.20721
Ferguson SA, Cisneros FJ, Gough BJ, Ali SF (2005) Four weeks of oral isotretinoin treatment causes few signs of general toxicity in male and female Sprague-Dawley rats. Food Chem Toxicol 43:1289–1296. https://doi.org/10.1016/j.fct.2005.02.016
Olson CR, Mello CV (2010) Significance of vitamin A to brain function, behavior and learning. Mol Nutr Food Res 54:489–495
Galván A (2010) Neural plasticity of development and learning. Hum Brain Mapp 31:879–890. https://doi.org/10.1002/hbm.21029
McCaffery P, Zhang J, Crandall JE (2006) Retinoic acid signaling and function in the adult hippocampus. J Neurobiol 66:780–791
Nomoto M, Takeda Y, Uchida S et al (2012) Dysfunction of the RAR/RXR signaling pathway in the forebrain impairs hippocampal memory and synaptic plasticity. Mol Brain 5:8. https://doi.org/10.1186/1756-6606-5-8
Crandall J, Sakai Y, Zhang J et al (2004) 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. Proc Natl Acad Sci USA 101:5111–5116. https://doi.org/10.1073/pnas.0306336101
Wagner E, Luo T, Dräger UC (2002a) Retinoic acid synthesis in the postnatal mouse brain marks distinct developmental stages and functional systems. Cerebral cortex (New York, NY : 1991) 12:1244–53. https://doi.org/10.1093/cercor/12.12.1244
Fragoso YD, Shearer KD, Sementilli A et al (2012) High expression of retinoic acid receptors and synthetic enzymes in the human hippocampus. Brain Struct Functon 217:473–483. https://doi.org/10.1007/s00429-011-0359-0
Aoto J, Nam CI, Poon MM et al (2008) Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity. Neuron 60:308–320. https://doi.org/10.1016/j.neuron.2008.08.012
Chen N, Napoli JL (2008) All- trans -retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARα. FASEB J 22:236–245. https://doi.org/10.1096/fj.07-8739com
Rothwell CM, Spencer GE (2014) Retinoid signaling is necessary for, and promotes long-term memory formation following operant conditioning. Neurobiol Learn Mem 114:127–140. https://doi.org/10.1016/j.nlm.2014.05.010
Denisenko-Nehrbass NI, Jarvis E, Scharff C et al (2000) Site-specific retinoic acid production in the brain of adult songbirds. Neuron 27:359–370. https://doi.org/10.1016/S0896-6273(00)00043-X
Wood WE, Olson CR, Lovell PV, Mello CV (2008) Dietary retinoic acid affects song maturation and gene expression in the song system of the zebra finch. Develop Neurobiol 68:1213–1224. https://doi.org/10.1002/dneu.20642
Negwer M, Schubert D (2017) Talking convergence: growing evidence links FOXP2 and retinoic acid in shaping speech-related motor circuitry. Front Neurosci 11:19. https://doi.org/10.3389/fnins.2017.00019
Enderlin V, Alfos S, Pallet V et al (1997) Aging decreases the abundance of retinoic acid (RAR) and triiodothyronine (TR) nuclear receptor mRNA in rat brain: effect of the administration of retinoids. FEBS Lett 412:629–632. https://doi.org/10.1016/S0014-5793(97)00845-4
Khatib T, Chisholm DR, Whiting A et al (2020) Decay in retinoic acid signaling in varied models of Alzheimer’s Disease and in vitro test of novel retinoic acid receptor ligands (RAR-Ms) to regulate protective genes. J Alzheimer’s Dis 73:935–954. https://doi.org/10.3233/JAD-190931
Etchamendy N, Enderlin V, Marighetto A et al (2001) Alleviation of a selective age-related relational memory deficit in mice by pharmacologically induced normalization of brain retinoid signaling. J Neurosci 21:6423–6429. https://doi.org/10.1523/jneurosci.21-16-06423.2001
Mayeux R, Stern Y (2012) Epidemiology of Alzheimer disease. Cold Spring Harbor Perspect Med 2:a006239. https://doi.org/10.1101/cshperspect.a006239
Sahin M, Karauzum SB, Perry G et al (2005) Retinoic acid isomers protect hippocampal neurons from amyloid-beta induced neurodegeneration. Neurotox Res 7:243–250. https://doi.org/10.1007/bf03036453
Ono K, Yoshiike Y, Takashima A et al (2004) Vitamin A exhibits potent antiamyloidogenic and fibril-destabilizing effects in vitro. Exp Neurol 189:380–392. https://doi.org/10.1016/j.expneurol.2004.05.035
Lahiri DK, Nall C (1995) Promoter activity of the gene encoding the beta-amyloid precursor protein is up-regulated by growth factors, phorbol ester, retinoic acid and interleukin-1. Brain Res Mol Brain Res 32:233–240. https://doi.org/10.1016/0169-328x(95)00078-7
Steardo L, Signorile A, Scuderi C, Carratù MR (2016) How could retinoids fit into Alzheimer’s therapy? Drugs Fut 41:15–23
Fukasawa H, Nakagomi M, Yamagata N et al (2012) Tamibarotene: a candidate retinoid drug for Alzheimer’s disease. Biol Pharm Bull 35:1206–1212. https://doi.org/10.1248/bpb.b12-00314
ClinicalTrials.gov (2011) Efficacy and Safety of Tamibarotene (OAM80) for Alzheimer’s Disease. https://clinicaltrials.gov/ct2/show/study/NCT01120002.Accessed 13 May 2020
Corcoran JPT, Po LS, Maden M (2004) Disruption of the retinoid signalling pathway causes a deposition of amyloid β in the adult rat brain. Eur J Neurosci 20:896–902. https://doi.org/10.1111/j.1460-9568.2004.03563.x
Colas J, Chessel N, Ouared A et al (2020) Neuroprotection against amyloid-β-induced DNA double-strand breaks is mediated by multiple retinoic acid-dependent pathways. Neural Plasticity. ID 9369815. https://doi.org/10.1155/2020/9369815
Gruz-Gibelli E, Chessel N, Allioux C et al (2016) The Vitamin A derivative all-trans retinoic acid repairs amyloid-β-induced double-strand breaks in neural cells and in the murine neocortex. Neural Plasticity 2016:11. https://doi.org/10.1155/2016/3707406
Manzine PR, Ettcheto M, Cano A et al (2019) ADAM10 in Alzheimer’s disease: pharmacological modulation by natural compounds and its role as a peripheral marker. Biomed Pharmacother 113:108661
Goncalves MB, Clarke E, Hobbs C et al (2013) Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist. Eur J Neurosci 37:1182–1192. https://doi.org/10.1111/ejn.12142
Tippmann F, Hundt J, Schneider A et al (2009) Up-regulation of the α-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J 23:1643–1654. https://doi.org/10.1096/fj.08-121392
Endres K, Fahrenholz F, Lotz J et al (2014) Increased CSF APPs-a levels in patients with Alzheimer disease treated with acitretin. Neurology 83:1930–1935. https://doi.org/10.1212/WNL.0000000000001017
Jarvis CI, Goncalves MB, Clarke E et al (2010) Retinoic acid receptor-α signalling antagonizes both intracellular and extracellular amyloid-β production and prevents neuronal cell death caused by amyloid-β. Eur J Neurosci 32:1246–1255. https://doi.org/10.1111/j.1460-9568.2010.07426.x
Cummings JL, Zhong K, Kinney JW et al (2016) Double-blind, placebo-controlled, proof-of-concept trial of bexarotene in moderate Alzheimer’s disease. Alzheimer’s Res Ther 8:1–9. https://doi.org/10.1186/s13195-016-0173-2
Nolen GA (1986) The effects of prenatal retinoic acid on the viability and behavior of the offspring. Neurobehav Toxicol Teratol 8:643–654
US FDA (2005) Isotretinoin (marketed as Accutane) Capsule Information - FDA. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/isotretinoin-marketed-accutane-capsule-information. Accessed 13 May 2020
EMA (2018) Updated measures for pregnancy prevention during retinoid use. Warning on possible risk of neuropsychiatric disorders also to be included for oral retinoids. EMA/261767/2018. Committee for Medicinal Products for Human Use (CHMP) EMEA/H/A-3
Marqueling AL, Zane LT (2005) Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg 24:92–102. https://doi.org/10.1016/j.sder.2005.04.003
Strahan JE, Raimer S (2006) Isotretinoin and the controversy of psychiatric adverse effects. Int J Dermatol 45:789–799. https://doi.org/10.1111/j.1365-4632.2006.02660.x
Bremner JD, Shearer KD, McCaffery PJ (2012) Retinoic acid and affective disorders. J Clin Psychiatry 73:37–50. https://doi.org/10.4088/JCP.10r05993
Krężel W, Ghyselinck N, Samad TA et al (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279:863–867. https://doi.org/10.1126/science.279.5352.863
Samad TA, Krężel W, Chambon P, Borrelli E (1997) Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family. Proc Natl Acad Sci USA 94:14349–14354. https://doi.org/10.1073/pnas.94.26.14349
Zetterström RH, Solomin L, Jansson L et al (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250. https://doi.org/10.1126/science.276.5310.248
Krzyzosiak A, Szyszka-Niagolov M, Wietrzych M et al (2010) Retinoid X receptor gamma control of affective behaviors involves dopaminergic signaling in mice. Neuron 66:908–920. https://doi.org/10.1016/j.neuron.2010.05.004
Valdenaire O, Maus-Moatti M, Vincent J-D et al (2002) Retinoic acid regulates the developmental expression of dopamine D2 receptor in rat striatal primary cultures. J Neurochem 71:929–936. https://doi.org/10.1046/j.1471-4159.1998.71030929.x
Wang HF, Liu FC (2005) Regulation of multiple dopamine signal transduction molecules by retinoids in the developing striatum. Neuroscience 134:97–105. https://doi.org/10.1016/j.neuroscience.2005.04.008
O’Reilly KC, Shumake J, Gonzalez-Lima F et al (2006) Chronic administration of 13-cis-retinoic acid increases depression-related behavior in mice. Neuropsychopharmacology 31:1919–1927. https://doi.org/10.1038/sj.npp.1300998
O’Reilly K, Bailey SJ, Lane MA (2008) Retinoid-mediated regulation of mood: possible cellular mechanisms. Exp Biol Med 233:251–258. https://doi.org/10.3181/0706-MR-158
Ferguson SA, Cisneros FJ, Gough B et al (2005) Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats. Toxicol Sci 87:451–459. https://doi.org/10.1093/toxsci/kfi262
Qi XR, Zhao J, Liu J et al (2015) Abnormal retinoid and TrkB signaling in the prefrontal cortex in mood disorders. Cereb Cortex 25:75–83. https://doi.org/10.1093/cercor/bht203
Tschudi-Monnet F, FitzGerald R (2019) AOP 12: Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging. https://aopwiki.org/aops/12. Accessed 7 Jul 2020
Sachana M, Munn S, Bal-Price A (2019) AOP 13: Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities. https://aopwiki.org/aops/13. Accessed 7 Jul 2020
Rolaki A, Pistollato F, Munn S, Bal-Price A (2019) AOP 54: Inhibition of Na +/I- symporter (NIS) leads to learning and memory impairment. https://aopwiki.org/aops/54. Accessed 7 Jul 2020
Jablensky A (2000) Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci 250:274–285. https://doi.org/10.1007/s004060070002
Ripke S, Neale BM, Corvin A et al (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427. https://doi.org/10.1038/nature13595
Stilo SA, Murray RM (2019) Non-genetic factors in schizophrenia. Curr Psychiatry Rep 21:100. https://doi.org/10.1007/s11920-019-1091-3
Laruelle M, Abi-Dargham A (1999) Dopamine as the wind of the psychotic fire: New evidence from brain imaging studies. J Psychopharmacol 13:358–371
Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384
Fernandez-Espejo E, Viveros MP, Núñez L et al (2009) Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacology 206:531–549
Radhakrishnan R, Kaser M, Guloksuz S (2017) The Link between the Immune System, Environment, and Psychosis. Schizophr Bull 43:693–697. https://doi.org/10.1093/schbul/sbx057
Goodman AB (1998) Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci USA 95:7240–7244
Mistry M, Gillis J, Pavlidis P (2013) Genome-wide expression profiling of schizophrenia using a large combined cohort. Mol Psychiatry 18:215–225. https://doi.org/10.1038/mp.2011.172
Larsen R, Proue A, Scott EP, et al (2019) The thalamus regulates retinoic acid signaling and development of parvalbumin interneurons in postnatal mouse prefrontal cortex. eNeuro. 6:1–17. https://doi.org/10.1523/ENEURO.0018-19.2019
Sehnal L, Procházková T, Smutná M et al (2019) Widespread occurrence of retinoids in water bodies associated with cyanobacterial blooms dominated by diverse species. Water Res 156:136–147. https://doi.org/10.1016/j.watres.2019.03.009
Javůrek J, Sychrová E, Smutná M et al (2015) Retinoid compounds associated with water blooms dominated by Microcystis species. Harmful Algae 47:116–125. https://doi.org/10.1016/j.hal.2015.06.006
Wu X, Jiang J, Wan Y et al (2012) Cyanobacteria blooms produce teratogenic retinoic acids. Proc Natl Acad Sci 109:9477–9482. https://doi.org/10.1073/pnas.1200062109
Wu X, Jiang J, Hu J (2013) Determination and Occurrence of Retinoids in a Eutrophic Lake (Taihu Lake, China): cyanobacteria Blooms Produce Teratogenic Retinal. Environ Sci Technol 47:807–814. https://doi.org/10.1021/es303582u
Yeung KWY, Zhou G-J, Hilscherová K et al (2020) Current understanding of potential ecological risks of retinoic acids and their metabolites in aquatic environments. Environ Int 136:105464. https://doi.org/10.1016/j.envint.2020.105464
Vandenberg LN, Hunt PA, Gore AC (2019) Endocrine disruptors and the future of toxicology testing—lessons from CLARITY–BPA. Nat Rev Endocrinol 15:366–374
Wilson VS, LeBlanc GA, Kullman S et al (2016) Where do we go from here: challenges and the future of endocrine disrupting compound screening and testing. PeerJ Preprints 4:e2605v1. https://doi.org/10.7287/peerj.preprints.2605v1
Huang R, Sakamuru S, Martin MT et al (2014) Profiling of the Tox21 10 K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway. Scientific Reports 4:1–9. https://doi.org/10.1038/srep05664
Huang R, Xia M, Cho M-H et al (2011) Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect 119:1142–1148. https://doi.org/10.1289/ehp.1002952
Knudsen TB, Houck KA, Sipes NS et al (2011) Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets. Toxicology 282:1–15. https://doi.org/10.1016/j.tox.2010.12.010
Martin MT, Dix DJ, Judson RS et al (2010) Impact of environmental chemicals on key transcription regulators and correlation to toxicity end points within EPA’s toxcast program. Chem Res Toxicol 23:578–590. https://doi.org/10.1021/tx900325g
EC (2018) Proposal for a Directive of the European Parliament and of the Council on the quality of water intended for human consumption (recast). COM(2017) 753 final. https://eur-lex.europa.eu/legal-content/en/TXT/?uri=CELEX%3A52018DC0257
Huisman J, Codd GA, Paerl HW et al (2018) Cyanobacterial blooms. Nat Rev Microbiol 16:471–483. https://doi.org/10.1038/s41579-018-0040-1
Verspagen JMH, Van de Waal DB, Finke JF et al (2014) Rising CO2 levels will intensify phytoplankton blooms in eutrophic and hypertrophic lakes. PLoS ONE 9:e104325. https://doi.org/10.1371/journal.pone.0104325
Jankowiak J, Hattenrath-Lehmann T, Kramer BJ et al (2019) Deciphering the effects of nitrogen, phosphorus, and temperature on cyanobacterial bloom intensification, diversity, and toxicity in western Lake Erie. Limnol Oceanogr 64:1347–1370. https://doi.org/10.1002/lno.11120
Vinçon-Leite B, Casenave C (2019) Modelling eutrophication in lake ecosystems: a review. Sci Total Environ 651:2985–3001. https://doi.org/10.1016/j.scitotenv.2018.09.320
Havens KE, Ji G, Beaver JR et al (2019) Dynamics of cyanobacteria blooms are linked to the hydrology of shallow Florida lakes and provide insight into possible impacts of climate change. Hydrobiologia 829:43–59. https://doi.org/10.1007/s10750-017-3425-7
Meier HEM, Eilola K, Almroth-Rosell E et al (2019) Disentangling the impact of nutrient load and climate changes on Baltic Sea hypoxia and eutrophication since 1850. Clim Dyn 53:1–22. https://doi.org/10.1007/s00382-018-4296-y
Heathwaite AL, Dils RM (2000) Characterising phosphorus loss in surface and subsurface hydrological pathways. Sci Total Environ 251–252:523–538. https://doi.org/10.1016/S0048-9697(00)00393-4
Jeppesen E, Kronvang B, Meerhoff M et al (2009) Climate change effects on runoff, catchment phosphorus loading and lake ecological state, and potential adaptations. J Environ Qual 38:1930–1941. https://doi.org/10.2134/jeq2008.0113
Buratti FM, Manganelli M, Vichi S et al (2017) Cyanotoxins: producing organisms, occurrence, toxicity, mechanism of action and human health toxicological risk evaluation. Arch Toxicol 91:1049–1130. https://doi.org/10.1007/s00204-016-1913-6
Chorus I, Welker M (Eds) (2021) Toxic cyanobacteria in water: A Guide to Their Public Health Consequences, Monitoring and Management, 2nd edn. CRC Press, London. https://doi.org/10.1201/9781003081449
Wu X, Hu J, Jia A et al (2010) Determination and occurrence of retinoic acids and their 4-oxo metabolites in Liaodong Bay, China, and its adjacent rivers. Environ Toxicol Chem 29:2491–2497. https://doi.org/10.1002/etc.322
Pipal M, Priebojova J, Koci T et al (2020) Field cyanobacterial blooms producing retinoid compounds cause teratogenicity in zebrafish embryos. Chemosphere 241:125061. https://doi.org/10.1016/j.chemosphere.2019.125061
Smutná M, Priebojová J, Večerková J, Hilscherová K (2017) Retinoid-like compounds produced by phytoplankton affect embryonic development of Xenopus laevis. Ecotoxicol Environ Saf 138:32–38. https://doi.org/10.1016/j.ecoenv.2016.12.018
Jonas A, Scholz S, Fetter E et al (2015) Endocrine, teratogenic and neurotoxic effects of cyanobacteria detected by cellular in vitro and zebrafish embryos assays. Chemosphere 120:321–327. https://doi.org/10.1016/J.CHEMOSPHERE.2014.07.074
Jonas A, Buranova V, Scholz S et al (2014) Retinoid-like activity and teratogenic effects of cyanobacterial exudates. Aquat Toxicol 155:283–290. https://doi.org/10.1016/j.aquatox.2014.06.022
Kaya K, Shiraishi F, Uchida H, Sano T (2011) A novel retinoic acid analogue, 7-hydroxy retinoic acid, isolated from cyanobacteria. Biochim Biophys Acta Gen Subj 1810:414–419. https://doi.org/10.1016/j.bbagen.2010.11.009
Lambert WE, De Leenheer AP (1985) Demonstration of retinoic acid isomers in human urine under physiological conditions. Experientia 41:359–360. https://doi.org/10.1007/bf02004504
Nau H (1994) Retinoid teratogenesis: toxicokinetics and structure-specificity. In: Bolt HM, Hellman B, Dencker L (eds) Use of Mechanistic Information in Risk Assessment. Archives of Toxicology, Supplement 16, vol 16. Springer, Berlin, Heidelberg, pp 118–127
AGES (2007) Public Assessment Report - Scientific discussion: Cisderm 5 mg-capsules (Isotretinoin) AT/H/0165/01/DC
Zhen H, Wu X, Hu J et al (2009) Identification of retinoic acid receptor agonists in sewage treatment plants. Environ Sci Technol 43:6611–6616. https://doi.org/10.1021/es9000328
Sawada K, Inoue D, Wada Y et al (2012) Detection of retinoic acid receptor agonistic activity and identification of causative compounds in municipal wastewater treatment plants in Japan. Environ Toxicol Chem 31:307–315. https://doi.org/10.1002/etc.741
Inoue D, Sawada K, Wada Y et al (2013) Removal characteristics of retinoic acids and 4-oxo-retinoic acids in wastewater by activated sludge treatment. Water Sci Technol 67:2868–2874. https://doi.org/10.2166/wst.2013.214
Zhou GJ, Li XY, Leung KMY (2019) Retinoids and oestrogenic endocrine disrupting chemicals in saline sewage treatment plants: removal efficiencies and ecological risks to marine organisms. Environ Int 127:103–113. https://doi.org/10.1016/j.envint.2019.03.030
Layton A, Dreno B, Gollnick H, Zouboulis C (2006) A review of the European Directive for prescribing systemic isotretinoin for acne vulgaris. J Eur Acad Dermatol Venereol 20:773–776. https://doi.org/10.1111/j.1468-3083.2006.01671.x
de Almeida NR, Conda-Sheridan M (2019) A review of the molecular design and biological activities of RXR agonists. Med Res Rev 39:1372–1397
Bogen R, Lützow-Holm C, Lyche JL et al (2012) Risk assessment of vitamin A (retinol and retinyl esters) in cosmetics. Opinion of the panel on food additives, flavourings, processing aids, materials in contact with food and cosmetics of the norwegian scientific committee for food safety. VKM Report 1:74
EC (2019a) Database for information on cosmetic substances and ingredients (CosIng). https://ec.europa.eu/growth/tools-databases/cosing/pdf/COSING_AnnexII_v2.pdf. Accessed 2 Jun 2020
EC (2019b) Urban Waste Water Treatment Directive - Evaluation. https://ec.europa.eu/environment/water/water-urbanwaste/evaluation/index_en.htm. Accessed 11 Feb 2020
EC (2019c) European Union Strategic Approach to Pharmaceuticals in the Environment - COM(2019)-128. Brussels
Brack W, Dulio V, Ågerstrand M et al (2017) Towards the review of the European Union Water Framework Directive: recommendations for more efficient assessment and management of chemical contamination in European surface water resources. Sci Total Environ 576:720–737. https://doi.org/10.1016/J.SCITOTENV.2016.10.104
Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a framework for Community action in the field of water policy. Off J L 327:0001–0073. OJ L 327, 22.12.2000, p. 1–73. ELI: http://data.europa.eu/eli/dir/2000/60/oj
Council Directive 91/271/EEC of 21 May 1991 concerning urban waste-water treatment. OJ L 135, 30.5.1991, p. 40–52. ELI: http://data.europa.eu/eli/dir/1991/271/oj
Council Directive 91/676/EEC of 12 December 1991 concerning the protection of waters against pollution caused by nitrates from agricultural sources. OJ L 375, 31.12.1991, p. 1–8. ELI: http://data.europa.eu/eli/dir/1991/676/oj
Directive (EU) 2020/2184 of the European Parliament and of the Council of 16 December 2020 on the quality of water intended for human consumption (recast). Document 32020L2184. OJ L 435, 23.12.2020, p. 1–62. ELI: http://data.europa.eu/eli/dir/2020/2184/oj
Hervás-Gámez C, Delgado-Ramos F (2019) Drought management planning policy: from Europe to Spain. Sustainability 11:1862. https://doi.org/10.3390/su11071862
Stein U, Özerol G, Tröltzsch J, et al (2016) European drought and water scarcity policies. In: Governance for Drought Resilience: Land and Water Drought Management in Europe. Springer International Publishing, pp 17–44
Posthuma L, Munthe J, van Gils J et al (2019) A holistic approach is key to protect water quality and monitor, assess and manage chemical pollution of European surface waters. Environ Sci Eur. https://doi.org/10.1186/s12302-019-0243-8
Kortenkamp A, Faust M, Backhaus T et al (2019) Mixture risks threaten water quality: the European Collaborative Project SOLUTIONS recommends changes to the WFD and better coordination across all pieces of European chemicals legislation to improve protection from exposure of the aquatic environment to improve protection from exposure of the aquatic environment to multiple pollutants. Environ Sci Eur 31:69. https://doi.org/10.1186/s12302-019-0245-6
Jacobson JL, Jacobson SW (1996) Dose-response in perinatal exposure to polychlorinated biphenyls (PCBs): the Michigan and North Carolina cohort studies. Toxicol Ind Health 12:435–445. https://doi.org/10.1177/074823379601200315
Jacobson JL, Jacobson SW (1996) Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med 335:783–789. https://doi.org/10.1056/NEJM199609123351104
Urquhart EA, Schaeffer BA, Stumpf RP et al (2017) A method for examining temporal changes in cyanobacterial harmful algal bloom spatial extent using satellite remote sensing. Harmful Algae 67:144–152. https://doi.org/10.1016/j.hal.2017.06.001
Junker T, Atorf C, Berkner S et al (2020) Development of a test method for transformation of veterinary pharmaceuticals and biocides in anaerobic liquid manure. Environmental Sciences Europe 32:1–21. https://doi.org/10.1186/s12302-020-00323-8
Saili KS, Antonijevic T, Zurlinden TJ et al (2020) Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol 91:1–13. https://doi.org/10.1016/j.reprotox.2019.10.001
Sewell F, Gellatly N, Beaumont M et al (2018) The future trajectory of adverse outcome pathways: a commentary. Arch Toxicol 92:1657–1661. https://doi.org/10.1007/s00204-018-2183-2
Teeguarden JG, Tan YM, Edwards SW et al (2016) Completing the link between exposure science and toxicology for improved environmental health decision making: the Aggregate Exposure Pathway framework. Environ Sci Technol 50:4579–4586. https://doi.org/10.1021/acs.est.5b05311
Hines DE, Edwards SW, Conolly RB, Jarabek AM (2018) A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA). Environ Sci Technol 52:839–849. https://doi.org/10.1021/acs.est.7b04940
Altenburger R, Brack W, Burgess RM et al (2019) Future water quality monitoring: improving the balance between exposure and toxicity assessments of real-world pollutant mixtures. Environ Sci Eur 31:12. https://doi.org/10.1186/s12302-019-0193-1
US EPA (2008) SAB Advisory on Aquatic Life Water Quality Criteria for Contaminants of Emerging Concern. EPA-SAB-09-007. 63
Dulio V, van Bavel B, Brorström-Lundén E et al (2018) Emerging pollutants in the EU: 10 years of NORMAN in support of environmental policies and regulations. Environ Sci Eur 30:1–13
UN (2015) The Sustainable Development Goals| International Cooperation and Development. https://ec.europa.eu/europeaid/policies/sustainable-development-goals_en. Accessed 22 Feb 2019
EC (2019d) The European Green Deal| COM(2019) 640 final
Drakvik E, Altenburger R, Aoki Y et al (2020) Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment. Environ Int 134:105267. https://doi.org/10.1016/j.envint.2019.105267
Rydeen A, Voisin N, D’Aniello E et al (2015) Excessive feedback of Cyp26a1 promotes cell non-autonomous loss of retinoic acid signaling. Developmental Biology 405:47–55. https://doi.org/10.1016/j.ydbio.2015.06.008
Durston AJ (2019) What are the roles of retinoids, other morphogens, and Hox genes in setting up the vertebrate body axis? Genesis 57:e23296. https://doi.org/10.1002/dvg.23296