Apical Effect/Key mechanism/Endpoint | Morphological alteration level | Developmental stage | Test system (species) | Main relevant and related pathways, genes, enzymes | Endpoint/hallmark affected cross-reactions | Substances associated with key mechanism/adverse outcome | Associated human pathology | Reference(s) |
---|---|---|---|---|---|---|---|---|
Axial development, Anterior-posterior patterning, osteogenesis | Tissue | Embryo, larvae | Branchiostoma floridae (amphioxus), zebrafish (stocksteif mutant), chicken, mouse | ADH/ RALDH, Cyp26b1, Cyp26a1, RARα, RARβ, RARγ, Wnt, FGF, Hox (esp. 1&3), BMP | RA acts as an early developmental morphogen along the anterior-posterior axis; it coordinates the position of endoderm-derived organs along the anterior-posterior axis. Cyp26/ RA concentration drives the osteogenesis in the vertebral column (in osteoblasts); posteriorization of gills and mouth in invertebrate chordates. Hyperactive RAR induces higher expression levels of RA-metabolizing Cyp26a1 and acts in a paracrine way | RA, retinol | ||
Symmetric somite development is mediated by RA | ||||||||
Human, zebrafish, rat, mouse | Dhrs3, Cyp26(a1) | Axial skeletal and craniofacial defects upon exposure | Triazole fungicides (flusilazole, triadimefon) | |||||
Neural tube formation | Organ/organism | Embryo | Quail | FGF and Wnt gradients/signaling, CYP26A1, RALDH activity | Mesodermal segmentation, somite formation, and neurogenesis in caudal neural tube (future spinal cord) are RA dependent | RA | ||
Human, zebrafish, rat | Dhrs3, Cyp26(a1) | Neural tube (and axial) defects; proposed Adverse Outcome Pathway: “for neural tube and axial defects mediated by modulation of retinoic acid homeostasis” | Triazole fungicides (flusilazole) | [165] | ||||
Neural differentiation and spinal cord formation | Tissue/organ | Embryo, (adult) | Mouse, zebrafish, Xenopus | FGF and Wnt, CYP26A1, RALDH, RARβ, RARα, Hox | The nervous system develops sequentially along this axis, starting anteriorly (CNS/brain), continuing via hindbrain to spinal cord. Determination of cell fate and differentiation of ventral neuronal cell types in developing spinal cord. Neurite outgrowth in embryos and adults is dependent on RARβ expression; RARα knockdown abolishes atRA-mediated dendritic growth | RA (endogenous) | ||
Early neural differentiation | Tissue/organ system | Embryo | Mouse | RAR, TR, MCT8 | Organization of the (central) nervous system; RA signalling precedes TRα expression/TR signaling; RA induces MCT8 expression in the developing brain allowing TH transport | RA, TH | ||
Zebrafish | RA co-administration (1 nM) prevents adverse effects (behavioural and histological) of ethanol (150 mM) exposure during gastrulation | RA, ethanol | [337] | |||||
Hindbrain segmentation, Ear development and hearing recovery | Tissue/organ | Embryo, adult | Mouse, rat, zebrafish, VAD quail model, chicken, Xenopus | RARα, RARβ, (CRABP), SHH, Wnt, FGF, Hox; CYP26A1, CYP26C1, RALDH activity | RA guides the formation of 8 segments (rhombomeres) that give rise to e.g. otic vesicle, sensory tract. RA determines the forebrain-hindbrain and hindbrain-spinal cord boundary (excess leads to posteriorization); midbrain-hindbrain boundary is unaffected (in mouse and Xenopus). RA directly influences the differentiation of branchiomotor neurons (zebrafish) | RA | [91, 124, 148, 321, 331, 340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359] | |
Mouse, zebrafish | Development of the olfactory region requires RA. RA stimulates regeneration of auditory hair cells | |||||||
Fetal alcohol syndrome; cerebellar maldevelopment | ||||||||
Head and forebrain development; Eye development | Tissue/organ | Embryo | Mouse, VAD quail model, pig, rabbit, cattle, sheep, rat, zebrafish | Formation of optic vesicle (retina precursor; invagination of neuroepithelium); micro-/anophthalmia in absence of RA. However: head development in general requires absence of RA [76] | RA | |||
Rat, human | RALDH, CYP26, AhR | Craniofacial malformations are linked to RA deregulation | atRA, 13cRA | Cleft palate and lip | ||||
Telencephalon differentiation | Tissue | Embryo | Mouse | Changed population of ganglia; altered precursor population; RA stimulates production of dopaminergic neurons | RA | |||
Cerebral cortex | Tissue | Embryo, postnatal | Mouse | RAR | Influence on neurogenesis/migration/ differentiation in other brain regions/ at other developmental stages. Sensitivity to RA is retained in the mature cortex | RA (endogenous), 13cRA | Affective liability and behavioural disinhibition upon 13cRA treatment, depression [177] | |
Hippocampus, neuronal plasticity | Cell/ tissue | Adult | Mouse, rat, zebra finch | RAR/RXR, esp. RARβ, RXRγ | Defects in spatial learning and memory, and recognition working memory (RXRγ) upon vitamin A deprivation; restoration of cognitive impairment with vitamin A supply; cognitive impairment also in excess RA scenario (13cRA). Decreased ability to learn mating song in zebra finches | RA, vitamin A | Learning and memory impairment, depression | |
Hippocampus | Tissue/organ | Adult | Rat, human (Alzheimer’s disease patients), mouse | Calbindin D28K, neurogranin, somatostatin, CHAT; RARα, RARβ, RXRγ, amyloid pathway, RBP4, CYP26, RALDH2 (in adjacent meninges) | Regulation of memory and spatial learning; RA acts as a proamnesic molecule Deprivation leads to amyloid-β accumulation, RARα downregulation, CHAT expression loss in forebrain cortical neurons RA regulates proteins linked to protection from Alzheimer’s disease | Vitamin A | Alzheimer’s disease, ageing | [82, 151, 178, 192, 205, 211, 384,385,386,387,388,389,390,391,392] |
Hippocampus | Organ | Postnatal | Mouse, rat | RARs (esp. RARα), RXRs, GR, somatostatin, RALDH2 (in adjacent meninges) | RARβ-/- and RXRγ-/-: deficiency in spatial learning and memory, like VAD rats (rescue by RA treatment). Degradation of hippocampal function in aging mice via proliferation/differentiation of hippocampal stem cells VAD increases GR binding capacity and modulates the somatostatinergic and acetylcholinergic hippocampal system | Vitamin A, atRA, 13cRA | Memory/learning impairment, dementia, Alzheimer’s disease, depression | [73, 151,152,153, 173, 188, 192, 193, 203, 374, 381, 391, 393,394,395,396,397,398] |
Rat | Hippocampal volume is reduced after 3 weeks of 13cRA treatment | [190] | ||||||
Learning | Organism | Embryo | Rat | RALDH, PC2 | Exposure during gestation (day 11–13 in rat) impaired amphetamine-stimulated activity and avoidance learning, but not performance in complex spatial maze or auditory startle response in offspring. A signalling decline is observed in aging and associated with cognitive impairment, decreased acquisition of new memories; reversible by RA administration | atRA, 13cRA, 9cRA | Possibly: affective disorders, neurodegenerative disorders, schizophrenia, autism | |
Postnatal | Rat, Mouse | RARβ, RXRγ | Vitamin A deprivation and RARβ-/- mutants show spatial learning and memory impairment | |||||
Behavioural changes | Organism | Adult | Mouse, rat | Extended low-dose exposure in mice induced depression-like behaviour. This was partially confirmed in 91 days-old rats, but not in older rats. | 13cRA | Depression | ||
Human | D2, (D1), Ser1A | 13cRA use/treatment is associated with depression and suicidal behaviour with longer onset (~4–8 weeks; long-term effect). | Case studies are reviewed in the reference | [177] | ||||
Striatum | Tissue/organ | Adult | Mouse, rat, human | D2, RAR(α)β/RXRβγ; Nurr1/RXR, RALDH1, RALDH3, neurogranin, GAP43 | The striatum shows the highest endogenous RA concentrations in the adult brain. Dopaminergic neurons; autocrine action on neurotransmission, paracrine action on striatal cells; locomotor impairment in RAR/RXR and Nurr1/RXR mutant mice. RXRγ-/- mutants: increased despair behaviour, anhedonia (reversible by re-expression of RXRγ). Induction of Parkinsonism and catatonia by lesions in basal ganglia | RA (endogenous), disulphirama | Depression, (potentially: Parkinson’s and Huntington’s disease), mood disorders | |
Extended 13cRA dose (in rat) increases dopamine and serotonin metabolites | [187] | |||||||
GABAergic (inter-)neurons | Cell/ tissue | Embryo/foetus | Mouse | Raldh3 | Enhanced differentiation; migration to olfactory bulb and cortex. Raldh3 activity is required for efficient differentiation of GABAergic interneurons, while Raldh2 is not | RA (endogenous) | ||
Adult | GABAergic interneurons of the olfactory bulb are RA sensitive | [405] | ||||||
Branchial arches | Tissue/organ | Embryo | Mouse | RAR, Hoxa1, Hoxb1, Pax1/9 | 3rd–6th arch are RA responsive, give rise to: endodermal pouches, thymus, parathyroid glands, aorta and associated large blood vessels, nerves etc. Linked to rhombomeric (hindbrain) origin of mesenchyme/neural crest cells | RA | DiGeorge syndrome, CATCH22 syndrome | |
Heart development | Organ | Embryo | Mouse, chicken, zebrafish | RARs, RXRs (esp. RXRα), Hoxb1, Hoxb5b, Tbx1, RALDH2, STRA6, CYP26A1, FGF8, NR2F5 | Congenital heart disease, incl. conotruncal and aortic arch artery malformations (patterning defects); defects in RA synthesis can be, in some cases, partly rescued by maternal RA levels/RA supplementation. STRA6 mutations (vitamin A transport/ cellular uptake) may result in developmental defects in atrial and venous vessels. Later in development, RA is cardiotoxic (in zebrafish) | RA | Rarely observed/undocumented, maybe due to embryonic death. Matthew-Wood syndrome (STRA6 mutation) [411, 412], DiGeorge syndrome [413] | [89, 138, 140, 164, 196, 369, 414,415,416,417,418,419,420,421,422,423,424,425] |
Zebrafish, rat | RARα, SHH, AhR | Flame retardants (miTP, TPP, PBDE), TCDD | ||||||
Lung development and regeneration | Tissue/organ | Embryo, adult | Mouse; embryonic explants, rat | RALDH2, Wnt, TGF-β, FGF10, BMP, SHH | Lack of RA/RAR activity prevents induction and growth of primary lung buds; RA induces regeneration of alveoli in rat and rescues lung functionality in experimental hypoplasia. RA is not required for endodermal lung cell fate, but essential for primordial lung bud formation | RA | ||
VEGF, FGF18 | RA regulates angiogenesis and elastin production in the maturing lung | [434] | ||||||
Pancreas formation | Tissue/organ | Embryo | Zebrafish, Xenopus, mouse | Cyp26a1, Cdx4, RALDH | Formation of dorsal pancreatic bud (pancreatic and hepatic endoderm); specification of pancreatic endocrine cell lineages. RA is required for ventral pancreas patterning. In mouse and human pancreas, β-cell differentiation may be influenced by RA | RA | ||
Kidney formation | Organ | Embryo | Xenopus, zebrafish, mouse | RARα, RARβ, RALDH2, Notch signalling, mecom | Inactivation of RARα and RARβ results in renal malformation (mouse); ureteric bud cell signalling depends mainly on RALDH2-generated atRA. Specification of renal progenitor cells depends on RA signaling (Xenopus, zebrafish) | RA | ||
Competition for RALDH2 | Ethanol | |||||||
Limb (and tail) development and regeneration | Organ | Embryo, postnatal | Amphibians, chicken, mouse, zebrafish | FGF8, SHH, FGF4, RALDH2, Cyp26(b1), Hoxb8 | RA can induce development (embryonic) or regeneration (postnatal) of supernumerary limbs or digits, when locally applied to the limb bud. In mice, RA exposure on gestational day 12 (33–41 somite pairs) affected rather forelimbs, on gestational day 13 (40–51 somite pairs) rather hindlimbs. Also, tail and tail vertebrae development is impaired by RA exposure | RA, 9cRA | ||
Gene expression repression by unliganded receptors (RARs) | Cellular | Embryo | Xenopus, mouse | RAR, NCoR-1/2, SMRT, CYP26. (further: Fgf, Wnt, Hox genes) | Head development in Xenopus and skeletal development in mice requires gene repression by unliganded RAR (otherwise: malformation of the head, anterior/posterior shift) | RA | ||
Acute promyelocytic leukemia | [462] | |||||||
Invertebrate development | Organ/organism | Chordata, Arthropoda, Mollusca, Porifera | RAR, RXR, CYP26, RALDH | Conservation of the retinoid signalling pathway and involvement in invertebrate development; incl.: all body, digestive glands, gonads, limb buds, regeneration of body parts | RA, retinol | Reviewed in [322] | ||
Crustacea, Drosophila | EcR, USP | Ecdysone is the driver of invertebrate molting. EcR dimerizes with USP (RXR-homolog), which increases dimer stability and affinity towards target DNA sequences | Ecdysone, tributyltin | |||||
Organ | Mollusca, Gastropoda | RXR | Imposex (gastropods), shell thickening, reproduction perturbation (Crassostrea gigas); RAR/RXR heterodimers have a repressive function (instead of activating) | Tributyltin, HX630 (only linked to imposex in gastropods), 9cRA | ||||
Reproductive tract development | Organ | Molluscs | RXR; potential crosstalk with PPARγ | Induction of outgrowth of male reproductive structures (T. clavigera), regulation of male/female seasonality (reproductive tract recrudescence; Ilyanassa obsolete) | 9cRA | |||
Reproductive organ development, testes; male fertility | Organ/organism | Embryo, adult | Mouse | RARα, RARγ, RXRβ, RALDH2, Cyp26b1, SHH, BMP4, STRA8 | Degeneration of testes after knockout of all RARα isoforms; sterility of male mice after knockout of RARγ; male sterility in RXRβ knockout mice. RA is required for spermatogenesis | RA | ||
Mouse, in vitro (P19 and C3H10T1/2), human | RALDH, Cyp26 Hoxa1, HDAC-I, AR (via SHH) | Phthalate esters (esp. containing aryl and cyclohexane groups), valproic acid | ||||||
Peripheral nervous system, regeneration | Organ system | Adult | Human | RARα, RARβ, RBP | Regeneration of spinal cord motor neurons depends on RA-induced RARβ(2) expression; RA peaks 4-7 days after encountering the injury | RA, 9cRA | ||
Nervous system | Organ system | Adult | Human | RARα, RALDH2, RBP(1) | Motor neurons: neurofilament accumulation, astrocytosis, decrease in neuron number, elimination of RARα and reduction of RALDH2 expression, reduction in retinol binding protein levels in spinal cord | Vitamin A, RA | Amyotrophic lateral sclerosis (ALS) | |
Embryo | Rat | Gestational exposure (day 11–13) led to difficulty to swallow milk (motor control); delayed righting reflex at 35 days. Decreased locomotor activity, motor coordination, and learning (90 days) | Depression, suicidal behaviour [223] | |||||
Vision | Pregnancy | Human (pregnant women) | Vitamin A | Night blindness; associated with miscarriage | [131] | |||
Pre-school age children, adult | Human | Retinal is required in the retina | Vitamin A, RA | Blindness; 50% fatal in children within 1 year if untreated; impaired vision | ||||
Keratinization of epithelia | Tissue | Adult, embryo | Human, rat | Mucous epithelia (as with the trachea/respiratory/gastrointestinal tract) become keratinized in absence of RA; RA is required for continuous renewal of skin epithelia. Treatment of cystic and nodular acne with “Accutane” (13cRA) | RA, 13cRA | |||
Human (in vitro) | AhR, RA-signaling | TCDD alters matrix protein (esp. collagen) deposition; atRA shows an additive effect. The increased protein deposition is due to promoter activation and increased mRNA stability | TCDD, atRA | [29] | ||||
Immune function | Organ system | Adult | Human, mouse | RARα | Immune function severely compromised in absence of RA. RA is required for (CD4+) T cells in the thymus | RA |