Agonism, Retinoic acid receptor

GO:0007612

GO learning

GO:0007613

GO memory

WIKI decreased

9606

NCBI Homo sapiens

WCS_9606

common toxicological species human

10116

NCBI rat

WCS_7227

common ecological species fruit fly

WCS_7955

common ecological species zebrafish

WCS_160004

common ecological species gastropods

10090

NCBI mouse

Agonism, Retinoic acid receptor

RAR agonism

Molecular

Biological state: Retinoic acid receptors (RARs) are nuclear receptors encoded by three distinct genes Rara, Rarb and Rarg (encoding RARα, RARβ, and RARγ, respectively). RARs are evolutionarily conserved in vertebrate taxa and mediate physiological processes during development and across the lifespan (reviewed in <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670431/">Mark et al., 2009</a>; <a href="https://www.sciencedirect.com/science/article/pii/S0925443910002358">Duong and Rochette-Egly 2011</a>). Functionally, RARs are ligand-activated transcription factors that require formation of heterodimers with retinoid X receptors (RXRs) α, β, and γ, and are activated by several retinoids, including all-trans-retinoic acid and its isomer, 9-cis-retinoic acid. Structurally, RARs include (1) a ligand-binding domain (LBD), (2) a DNA-binding domain (DBD) which can bind specific DNA sequences known as retinoic acid response elements (RAREs) and (3) a transcriptional activation domain (reviewed in <a href="https://faseb.onlinelibrary.wiley.com/doi/pdfdirect/10.1096/fasebj.10.9.8801176">Chambon 1996</a>, <a href="https://jme.bioscientifica.com/view/journals/jme/69/4/JME-22-0113.xml">Rastinejad 2022</a>). In the absence of ligand, the DNA-bound RAR/RXR heterodimers are associated with corepressors, such as nuclear receptor corepressor 1 and 2 (NCoR1 and NCoR2), and constitutively repress transcription (<a href="https://www.nature.com/articles/377451a0">Kurokawa et al., 1995</a>; <a href="https://www.nature.com/articles/nsmb.1855">le Maire et al., 2010</a>).   Biological compartments: The expression pattern of Rar genes during development has been studied in various species, with Rara having a widespread expression, while Rarb and Rarg show more complex, region-specific expression in both neural and non-neural tissues (reviewed in <a href="https://journals.sagepub.com/doi/epdf/10.1621/nrs.07006">Dollé 2009</a>). Rarg, although present in the embryo during neurulation, has not been detected at later prenatal and early postnatal stages of brain development in rodents (<a href="https://journals.biologists.com/dev/article/118/1/267/37781/Retinoic-acid-receptors-and-cellular-retinoid">Ruberte et al., 1993</a>; <a href="https://onlinelibrary.wiley.com/doi/full/10.1046/j.1460-9568.1999.00444.x">Zetterström et al., 1999</a>). Rara and Rarb are expressed early in the neural tube epithelium and are involved in the patterning of hindbrain rhombomere segmentation (<a href="https://journals.biologists.com/dev/article/111/1/45/36768/Retinoic-acid-receptors-and-cellular-retinoid">Ruberte et al., 1991</a>; <a href="https://journals.biologists.com/dev/article/126/22/5051/40550/Key-roles-of-retinoic-acid-receptors-alpha-and">Dup</a><a href="https://journals.sagepub.com/doi/epdf/10.1621/nrs.07006">é</a><a href="https://journals.biologists.com/dev/article/126/22/5051/40550/Key-roles-of-retinoic-acid-receptors-alpha-and"> et al., 1999a</a>). Later on during brain development, Rara and Rarb are co-expressed in the medulla oblongata, with Rarb showing localization in the somatic and visceral motor nuclei (<a href="https://journals.biologists.com/dev/article/118/1/267/37781/Retinoic-acid-receptors-and-cellular-retinoid">Ruberte et al., 1993</a>). Rara and Rarb are also co-expressed in the developing forebrain, particularly in the corpus striatum, hippocampus and cortex (<a href="https://journals.biologists.com/dev/article/118/1/267/37781/Retinoic-acid-receptors-and-cellular-retinoid">Ruberte et al., 1993</a>; <a href="https://www.sciencedirect.com/science/article/pii/0165380694901937?ref=pdf_download&fr=RR-2&rr=809b0f0f5c9895e4">Yamagata et al., 1994</a>). Rarb is additionally present in the olfactory tubercle, and in the choroid plexuses and meninges (<a href="https://journals.biologists.com/dev/article/118/1/267/37781/Retinoic-acid-receptors-and-cellular-retinoid">Ruberte et al., 1993</a>).    General role in biology: Retinoic acid receptors function as ligand-dependent transcriptional regulators of target genes involved in cellular differentiation, proliferation and apoptosis (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315372/">Gudas and Wagner 2011</a>; <a href="https://www.annualreviews.org/doi/abs/10.1146/annurev.nutr.28.061807.155509">Noy 2010</a>), and therefore play crucial roles in a multitude of biological processes, such as embryonic and fetal development, including cardiovascular, respiratory and CNS development, reproduction and immunity (reviewed in <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670431/">Mark et al., 2009</a>; <a href="https://www.sciencedirect.com/science/article/pii/S1359610100000022">McCaffery and Dräger 2000</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257687/#:~:text=It%20is%20now%20generally%20believed,as%20well%20as%20embryonic%20development.">Clagett-Dame and Knutson 2011</a>; <a href="https://www.sciencedirect.com/science/article/pii/S0890623818305811">Damdimoupoulou 2019</a>; <a href="https://www.cell.com/trends/immunology/pdf/S1471-4906(16)30223-X.pdf">Erkelens and Mebius 2017</a>).  RA signalling has been extensively studied for its role in early neurodevelopmental events such as patterning of hindbrain segmentation, and there is evidence from pharmacologic and genetic ablation studies also pointing toward a later role in forebrain development (<a href="https://journals.biologists.com/dev/article/139/5/843/45469/Retinoic-acid-signalling-during-development">Rhinn and Doll</a><a href="https://journals.sagepub.com/doi/epdf/10.1621/nrs.07006">é</a><a href="https://journals.biologists.com/dev/article/139/5/843/45469/Retinoic-acid-signalling-during-development"> 2012</a>; <a href="https://journals.biologists.com/dev/article/128/14/2755/41365/Local-retinoid-signaling-coordinates-forebrain-and">Schneider et al., 2001</a>; <a href="https://journals.biologists.com/dev/article/133/2/351/43186/Retinaldehyde-dehydrogenase-2-RALDH2-mediated">Ribes et al., 2006</a>; <a href="https://www.sciencedirect.com/science/article/pii/S0012160606013765?via%3Dihub">Halilagic et al., 2007</a>; <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1000609">Chatzi et al., 2011</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994967/#R19">Molotkova et al., 2007</a>; <a href="https://www.sciencedirect.com/science/article/pii/089662739390052S?via%3Dihub">LaMantia et al., 1993</a>).

There are yet no OECD methods available to measure RAR receptor agonism, although retinoic signalling has been acknowledged as one of the major endocrine pathways that can be subject to chemical perturbations (<a href="https://www.oecd-ilibrary.org/environment/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_9789264221352-en">OECD 2012</a>) and the need for its inclusion in future chemical testing strategies has been recently highlighted (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322530/#bib0105">Grignard et al., 2020</a>).  RAR receptor transactivation can be measured indirectly by using cell-based reporter gene assays. Expression of luciferase and β-galactosidase reporters driven by RARE-containing promoters have been employed (<a href="https://www.sciencedirect.com/science/article/pii/S0021925820699975?via%3Dihub">Idres et al., 2002</a>; <a href="https://molpharm.aspetjournals.org/content/76/6/1228">Moise et al., 2009</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570419/">Zolfaghari et al., 2019</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091987/">Ababon et al., 2016</a>) and RAR reporter assays are commercially available (e.g. INDIGO Biosciences).

High

During brain development

1.                         Mark M, Ghyselinck NB, Chambon P. Function of retinoic acid receptors during embryonic development. Nucl Recept Signal. 2009;7:e002. 2.                         Duong V, Rochette-Egly C. The molecular physiology of nuclear retinoic acid receptors. From health to disease. Biochim Biophys Acta. 2011;1812(8):1023-31. 3.                         Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J. 1996;10(9):940-54. 4.                         Rastinejad F. Retinoic acid receptor structures: the journey from single domains to full-length complex. J Mol Endocrinol. 2022;69(4):T25-T36. 5.                         Kurokawa R, Söderström M, Hörlein A, Halachmi S, Brown M, Rosenfeld MG, et al. Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature. 1995;377(6548):451-4. 6.                         le Maire A, Teyssier C, Erb C, Grimaldi M, Alvarez S, de Lera AR, et al. A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor. Nat Struct Mol Biol. 2010;17(7):801-7. 7.                         Dollé P. Developmental expression of retinoic acid receptors (RARs). Nucl Recept Signal. 2009;7:e006. 8.                         Ruberte E, Friederich V, Chambon P, Morriss-Kay G. Retinoic acid receptors and cellular retinoid binding proteins. III. Their differential transcript distribution during mouse nervous system development. Development. 1993;118(1):267-82. 9.                         Zetterström RH, Lindqvist E, Mata de Urquiza A, Tomac A, Eriksson U, Perlmann T, et al. Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid. Eur J Neurosci. 1999;11(2):407-16. 10.                       Ruberte E, Dolle P, Chambon P, Morriss-Kay G. Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development. 1991;111(1):45-60. 11.                       Dupé V, Ghyselinck NB, Wendling O, Chambon P, Mark M. Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse. Development. 1999;126(22):5051-9. 12.                       Yamagata T, Momoi MY, Yanagisawa M, Kumagai H, Yamakado M, Momoi T. Changes of the expression and distribution of retinoic acid receptors during neurogenesis in mouse embryos. Brain Res Dev Brain Res. 1994;77(2):163-76. 13.                       Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cell Physiol. 2011;226(2):322-30. 14.                       Noy N. Between death and survival: retinoic acid in regulation of apoptosis. Annu Rev Nutr. 2010;30:201-17. 15.                       McCaffery P, Dräger UC. Regulation of retinoic acid signaling in the embryonic nervous system: a master differentiation factor. Cytokine Growth Factor Rev. 2000;11(3):233-49. 16.                       Clagett-Dame M, Knutson D. Vitamin A in reproduction and development. Nutrients. 2011;3(4):385-428. 17.                       Damdimopoulou P, Chiang C, Flaws JA. Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis. Reprod Toxicol. 2019;87:32-41. 18.                       Erkelens MN, Mebius RE. Retinoic Acid and Immune Homeostasis: A Balancing Act. Trends Immunol. 2017;38(3):168-80. 19.                       Rhinn M, Dollé P. Retinoic acid signalling during development. Development. 2012;139(5):843-58. 20.                       Schneider RA, Hu D, Rubenstein JL, Maden M, Helms JA. Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH. Development. 2001;128(14):2755-67. 21.                       Ribes V, Wang Z, Dollé P, Niederreither K. Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling. Development. 2006;133(2):351-61. 22.                       Halilagic A, Ribes V, Ghyselinck NB, Zile MH, Dollé P, Studer M. Retinoids control anterior and dorsal properties in the developing forebrain. Dev Biol. 2007;303(1):362-75. 23.                       Chatzi C, Brade T, Duester G. Retinoic acid functions as a key GABAergic differentiation signal in the basal ganglia. PLoS Biol. 2011;9(4):e1000609. 24.                       Molotkova N, Molotkov A, Duester G. Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone. Dev Biol. 2007;303(2):601-10. 25.                       LaMantia AS, Colbert MC, Linney E. Retinoic acid induction and regional differentiation prefigure olfactory pathway formation in the mammalian forebrain. Neuron. 1993;10(6):1035-48. 26.                       OECD. 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 Disruptors2012. 27.                       Grignard E, Håkansson H, Munn S. Regulatory needs and activities to address the retinoid system in the context of endocrine disruption: The European viewpoint. Reprod Toxicol. 2020;93:250-8. 28.                       Idres N, Marill J, Flexor MA, Chabot GG. Activation of retinoic acid receptor-dependent transcription by all-trans-retinoic acid metabolites and isomers. J Biol Chem. 2002;277(35):31491-8. 29.                       Moise AR, Alvarez S, Domínguez M, Alvarez R, Golczak M, Lobo GP, et al. Activation of retinoic acid receptors by dihydroretinoids. Mol Pharmacol. 2009;76(6):1228-37. 30.                       Zolfaghari R, Mattie FJ, Wei CH, Chisholm DR, Whiting A, Ross AC. CYP26A1 gene promoter is a useful tool for reporting RAR-mediated retinoid activity. Anal Biochem. 2019;577:98-109. 31.                       Ababon MR, Li BI, Matteson PG, Millonig JH. Quantitative Measurement of Relative Retinoic Acid Levels in E8.5 Embryos and Neurosphere Cultures Using the F9 RARE-Lacz Cell-based Reporter Assay. J Vis Exp. 2016(115). AOPWiki 2024-01-14T10:08:44

2024-01-24T11:20:02

Altered expression of cell cycle genes

Molecular

The eukaryotic cell cycle is divided into phases, comprising the interphase (G1, S, and G2) and the mitotic (M) phase. Under certain conditions, cells can exit the cycle and reversibly enter a state of quiescence (the G0 phase), terminally differentiate or enter a senescent state (<a href="https://www.frontiersin.org/articles/10.3389/fcell.2021.645593/full#B243">Kumari and Jat 2021</a>). During cell division, the cells can progress through the cycle if they pass three major checkpoints (in G1-to-S, G2-to-M and M-to-G1), which ensure that the resulting daughter cells are healthy. The passage through successive phases is driven by cyclins and cyclin-dependent kinase (CDK) complexes (<a href="https://www.sciencedirect.com/science/article/pii/S0092867403010808?via%3Dihub">Murray, 2004</a>). Cyclins are divided into 4 groups (A-, B-, D-, and E-cyclins) and CDKs include at least 11 proteins (<a href="https://www.sciencedirect.com/science/article/pii/S0092867403010808?via%3Dihub">Murray, 2004</a>; <a href="https://www.nature.com/articles/nrm2510">Hochegger et al., 2008</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914104/">Malumbres, 2009</a>). However, there are two different perspectives as to how the cyclin-Cdk complexes temporally regulate events during the cell cycle (<a href="https://www.nature.com/articles/nrm2510">Hochegger et al., 2008</a>). One model asserts that the correct completion of the S and M phases is brought about through different biochemical activities of cyclin-cdk heterodimers associated with each phase. In this view, the various cyclin-CDK complexes appear in a specific temporal sequence and target different substrates to drive progression through the cell cycle (<a href="https://www.science.org/doi/10.1126/science.8266103">van den Heuvel and Harlow, 1993</a>; <a href="https://www.sciencedirect.com/science/article/pii/0092867493906365?via%3Dihub">Sherr, 1993</a>; <a href="https://www.cell.com/molecular-cell/fulltext/S1097-2765(11)00456-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276511004564%3Fshowall%3Dtrue">Pagliuca et al., 2011</a>). On the other hand, a second model proposes that it is the progressive increase in total CDK cell activity that drives the cell cycle, rather than CDK substrate specificity. In this view, substrates in the DNA replication phase are phosphorylated at a lower total CDK activity level than substrates in the mitotic phase (<a href="https://www.sciencedirect.com/science/article/pii/S0092867416316063?via%3Dihub">Swaffer et al., 2016</a>). Recently, Basu et al., have reconciled these two opposing perspectives into a unitary framework which proposes a quantitative view of core CDK cell cycle control with a minor qualitative element (<a href="https://www.nature.com/articles/s41586-022-04798-8">Basu et al., 2022</a>). Using phosphoproteomics to study in vivo CDK activity in fission yeast, the authors show that cyclin-CDK complexes are not completely specialised for either S or M phase, and that increasing the CDK activity of S phase dimers is sufficient to carry out mitosis (<a href="https://www.nature.com/articles/s41586-022-04798-8">Basu et al., 2022</a>).

How it is measured or detected Expression of cyclins and Cdks at various phases of the cell cycle can be performed at the transcript or protein level. The mRNA content of specific cyclins and Cdks can be measured using qPCR, or in the context of a more global analysis using microarray or RNAseq methods (see for e.g. <a href="https://www.sciencedirect.com/science/article/pii/S0012160603002744#aep-section-id30">Karsten et al., 2003</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665007/">Kowalczyk et al., 2015</a>; <a href="https://www.nature.com/articles/s41398-022-02279-0">Cheroni et al., 2022</a>). The protein amount of individual Cdks, cyclins, as well as their phosphorylated forms can be detected using immunodetection methods such as western blotting or enzyme-linked immunosorbent assays (ELISAs), as well as through mass spectrometric approaches (see for e.g. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740871/">Frisa and Jacobberger, 2009</a>; <a href="https://www.nature.com/articles/s41586-022-04798-8">Basu et al., 2022</a>).

1.                         Kumari R, Jat P. Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front Cell Dev Biol. 2021;9:645593. 2.                         Murray AW. Recycling the cell cycle: cyclins revisited. Cell. 2004;116(2):221-34. 3.                         Hochegger H, Takeda S, Hunt T. Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nat Rev Mol Cell Biol. 2008;9(11):910-6. 4.                         Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol. 2009;11(11):1275-6. 5.                         van den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993;262(5142):2050-4. 6.                         Sherr CJ. Mammalian G1 cyclins. Cell. 1993;73(6):1059-65. 7.                         Pagliuca FW, Collins MO, Lichawska A, Zegerman P, Choudhary JS, Pines J. Quantitative proteomics reveals the basis for the biochemical specificity of the cell-cycle machinery. Mol Cell. 2011;43(3):406-17. 8.                         Swaffer MP, Jones AW, Flynn HR, Snijders AP, Nurse P. CDK Substrate Phosphorylation and Ordering the Cell Cycle. Cell. 2016;167(7):1750-61.e16. 9.                         Basu S, Greenwood J, Jones AW, Nurse P. Core control principles of the eukaryotic cell cycle. Nature. 2022;607(7918):381-6. 10.                       Karsten SL, Kudo LC, Jackson R, Sabatti C, Kornblum HI, Geschwind DH. Global analysis of gene expression in neural progenitors reveals specific cell-cycle, signaling, and metabolic networks. Dev Biol. 2003;261(1):165-82. 11.                       Kowalczyk MS, Tirosh I, Heckl D, Rao TN, Dixit A, Haas BJ, et al. Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells. Genome Res. 2015;25(12):1860-72. 12.                       Cheroni C, Trattaro S, Caporale N, López-Tobón A, Tenderini E, Sebastiani S, et al. Benchmarking brain organoid recapitulation of fetal corticogenesis. Transl Psychiatry. 2022;12(1):520. 13.                       Frisa PS, Jacobberger JW. Cell cycle-related cyclin b1 quantification. PLoS One. 2009;4(9):e7064 AOPWiki 2024-01-14T10:15:42

2024-03-07T10:34:56

Decreased proliferation of cortical neural progenitor cells

Decreased proliferation of cortical NPCs

Cellular

Cell proliferation refers to the process of increasing the total number of cells through growth and division (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667397/">Homem et al., 2015</a>). In tissues, the rate of proliferation is influenced by multiple factors such as the initial pool of progenitor cells, the number and frequency of divisions they undergo, and the proportion of daughter cells that retain the proliferative potential (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667397/">Homem et al., 2015</a>). During brain development, the regulation of cell proliferation is important for the production of all cell types, including neurons which assemble into functional neural circuits (<a href="https://pubmed.ncbi.nlm.nih.gov/14556704/">Ohnuma and Harris, 2003</a>). Neurons in the brain originate from the neuroepithelial cell (NEC) population initially undergoing symmetric, self-renewing divisions at the luminal surface of the neural tube (<a href="https://link.springer.com/article/10.1007/s00441-007-0481-8">Malatesta et al., 2008</a>). NECs can be identified by expression of Sox2 and Nestin, or apical surface markers like Occludin and Zonula Occludens 1 (ZO-1) (<a href="https://pubmed.ncbi.nlm.nih.gov/16314867/">Götz and Huttner, 2005</a>). Subsequently, NECs undergo asymmetric divisions, generating radial glial cells (RGCs), a proliferative cell population which represents the main pool of neural progenitors for all regions of the developing brain (<a href="https://pubmed.ncbi.nlm.nih.gov/15046721/">Anthony et al., 2004</a>; <a href="https://link.springer.com/article/10.1007/s00441-007-0481-8">Malatesta et al., 2008</a>).  RGCs continue to express Nestin, and additionally express glial markers such as the glutamate transporter GLAST, glial fibrillary acidic protein (GFAP) and brain-lipid-binding protein (BLBP) (<a href="https://pubmed.ncbi.nlm.nih.gov/15046721/">Anthony et al., 2004</a>; <a href="https://www.nature.com/articles/nrm1739">Götz and Huttner, 2005</a>). During neocortical histogenesis, RGCs divide symmetrically and asymmetrically. The majority of asymmetric divisions are neurogenic, whereby RGC division yields a new RGC and a postmitotic neuron (<a href="https://www.nature.com/articles/nn1172">Noctor et al., 2004</a>). Other asymmetric divisions generate intermediate progenitors, which can then divide symmetrically to produce two neurons (<a href="https://www.nature.com/articles/nn1172">Noctor et al., 2004</a>). Following neurogenesis, a fraction of RGCs transition to gliogenesis to give rise to glial cells, including astrocytes and oligodendrocytes, whereas the remaining RGCs exit the cell cycle through a terminal neurogenic division (<a href="https://pubmed.ncbi.nlm.nih.gov/25417155/">Gao et al., 2014</a>).

Proliferation in neural progenitor cells can be measured using various experimental approaches. 1. Incorporation of thymidine analogues In preparation of cell division, eukaryotic cells duplicate their genetic material. During this process, the nucleoside subunits inserted into the newly synthesised DNA can be labelled and quantified, thus providing a means to measure cell proliferation. This is typically done by using various analogues of the nucleoside thymidine, such as tritiated thymidine (3H-thymidine), bromodeoxyuridine (BrdU) or 5-ethynyl-2'-deoxyuridine (EdU) (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264245/">Cavanagh et al., 2011</a>). These thymidine analogues can be detected by autoradiography or scintillation techniques (3H-thymidine), immunofluorescence (BrdU) and reaction with fluorescent azides (EdU) (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264245/">Cavanagh et al., 2011</a>). These approaches have been successfully applied to quantify NPC proliferation (<a href="https://www.frontiersin.org/articles/10.3389/ftox.2022.816370/full">Koch et al., 2022</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275325/">Liu et al., 2018</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679099/#R46">Wu et al., 2009</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724768/">Wang et al., 2005</a>). 2. Immunostaining or flow cytometric analysis of proteins associated with the cell cycle, such as cell cycle regulators or proteins with important functions during mitosis.  Examples:  <ul> <li dir="ltr"> Ki-67 is a nuclear protein expressed in actively dividing cells during all phases of the cell cycle, except for the resting phase (G0) (<a href="https://pubmed.ncbi.nlm.nih.gov/6206131/">Gerdes et al., 1984</a>). Immunofluorescent imaging of Ki-67 can be used to identify and quantify proliferating NPCs (<a href="https://www.nature.com/articles/s41467-020-17890-2">Zhou et al., 2020</a>). </li> <li dir="ltr"> Proliferating cell nuclear antigen (PCNA) is an important component for DNA replication and repair, and is present throughout the cell cycle (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091797/">Strzalka and Ziemienowicz, 2011</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1265825/">Essers et al., 2005</a>; <a href="https://www.sciencedirect.com/science/article/pii/0014482786905203?via%3Dihub">Kurki et al., 1986</a>). PCNA immunofluorescence can be used to assess proliferating NPCs (<a href="https://www.nature.com/articles/ncomms1155">Arai et al., 2011</a>). </li> <li dir="ltr"> Minichromosome maintenance protein 2 (MCM2) is part of the DNA replication initiation complex and is expressed throughout the cell cycle (<a href="https://www.sciencedirect.com/science/article/pii/S0167478198000335?via%3Dihub#BIB117">Kearsey and Labib, 1998</a>). MCM2 can be detected in developing and adult NPCs (<a href="https://www.frontiersin.org/articles/10.3389/fnana.2020.558435/full#B37">Fauser et al., 2020</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6725850/">Dougherty et al., 2005</a>; <a href="https://www.nature.com/articles/s41419-017-0019-2">Sun et al., 2018</a>). </li> <li dir="ltr"> Phosphohistone H3 (PH3) is present during the G2 and M phases of cell division (<a href="https://pubmed.ncbi.nlm.nih.gov/9362543/">Hendzel 1997</a>) and has been employed to measure NPC proliferation (<a href="https://www.cell.com/neuron/pdf/S0896-6273(20)30758-3.pdf">Xing et al., 2020</a>; <a href="https://www.jneurosci.org/content/jneuro/40/8/1766.full.pdf">Fietz et al., 2020</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051437/">Hashimoto-Torii et al., 2014</a>; <a href="https://jbiomedsci.biomedcentral.com/articles/10.1186/1423-0127-17-85">Kim et al., 2010</a>). </li> </ul> 3. In-situ hybridization (ISH) techniques can be applied to quantify mRNA transcripts of various markers of cycling NPCs (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784707/">Yeh et al., 2013</a>). 4. Time-lapse Imaging: Live-cell imaging techniques allow tracking of neural progenitor cells over time and assessment of their proliferation rates and patterns (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366109/">Bestman et al., 2012</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951355/">Keenan et al., 2010</a>).

Moderate 1.                         Homem CC, Repic M, Knoblich JA. Proliferation control in neural stem and progenitor cells. Nat Rev Neurosci. 2015;16(11):647-59. 2.                         Ohnuma S, Harris WA. Neurogenesis and the cell cycle. Neuron. 2003;40(2):199-208. 3.                         Malatesta P, Appolloni I, Calzolari F. Radial glia and neural stem cells. Cell Tissue Res. 2008;331(1):165-78. 4.                         Götz M, Huttner WB. The cell biology of neurogenesis. Nat Rev Mol Cell Biol. 2005;6(10):777-88. 5.                         Anthony TE, Klein C, Fishell G, Heintz N. Radial glia serve as neuronal progenitors in all regions of the central nervous system. Neuron. 2004;41(6):881-90. 6.                         Noctor SC, Martínez-Cerdeño V, Ivic L, Kriegstein AR. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci. 2004;7(2):136-44. 7.                         Gao P, Postiglione MP, Krieger TG, Hernandez L, Wang C, Han Z, et al. Deterministic progenitor behavior and unitary production of neurons in the neocortex. Cell. 2014;159(4):775-88. 8.                         Cavanagh BL, Walker T, Norazit A, Meedeniya AC. Thymidine analogues for tracking DNA synthesis. Molecules. 2011;16(9):7980-93. 9.                         Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133(4):1710-5. 10.                       Zhou X, Zhong S, Peng H, Liu J, Ding W, Sun L, et al. Cellular and molecular properties of neural progenitors in the developing mammalian hypothalamus. Nat Commun. 2020;11(1):4063. 11.                       Strzalka W, Ziemienowicz A. Proliferating cell nuclear antigen (PCNA): a key factor in DNA replication and cell cycle regulation. Ann Bot. 2011;107(7):1127-40. 12.                       Essers J, Theil AF, Baldeyron C, van Cappellen WA, Houtsmuller AB, Kanaar R, et al. Nuclear dynamics of PCNA in DNA replication and repair. Mol Cell Biol. 2005;25(21):9350-9. 13.                       Kurki P, Vanderlaan M, Dolbeare F, Gray J, Tan EM. Expression of proliferating cell nuclear antigen (PCNA)/cyclin during the cell cycle. Exp Cell Res. 1986;166(1):209-19. 14.                       Arai Y, Pulvers JN, Haffner C, Schilling B, Nüsslein I, Calegari F, et al. Neural stem and progenitor cells shorten S-phase on commitment to neuron production. Nat Commun. 2011;2:154. 15.                       Kearsey SE, Labib K. MCM proteins: evolution, properties, and role in DNA replication. Biochim Biophys Acta. 1998;1398(2):113-36. 16.                       Fauser M, Weselek G, Hauptmann C, Markert F, Gerlach M, Hermann A, et al. Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain. Front Neuroanat. 2020;14:558435. 17.                       Dougherty JD, Garcia AD, Nakano I, Livingstone M, Norris B, Polakiewicz R, et al. PBK/TOPK, a proliferating neural progenitor-specific mitogen-activated protein kinase kinase. J Neurosci. 2005;25(46):10773-85. 18.                       Sun D, Sun XD, Zhao L, Lee DH, Hu JX, Tang FL, et al. Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior. Cell Death Dis. 2018;9(1):8. 19.                       Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, et al. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma. 1997;106(6):348-60. 20.                       Xing L, Kalebic N, Namba T, Vaid S, Wimberger P, Huttner WB. Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex. Neuron. 2020;108(6):1113-29.e6. 21.                       Fietz SA, Namba T, Kirsten H, Huttner WB, Lachmann R. Signs of Reduced Basal Progenitor Levels and Cortical Neurogenesis in Human Fetuses with Open Spina Bifida at 11-15 Weeks of Gestation. J Neurosci. 2020;40(8):1766-77. 22.                       Hashimoto-Torii K, Torii M, Fujimoto M, Nakai A, El Fatimy R, Mezger V, et al. Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron. 2014;82(3):560-72. 23.                       Kim KC, Go HS, Bak HR, Choi CS, Choi I, Kim P, et al. Prenatal exposure of ethanol induces increased glutamatergic neuronal differentiation of neural progenitor cells. J Biomed Sci. 2010;17(1):85. 24.                       Yeh CW, Kao SH, Cheng YC, Hsu LS. Knockdown of cyclin-dependent kinase 10 (cdk10) gene impairs neural progenitor survival via modulation of raf1a gene expression. J Biol Chem. 2013;288(39):27927-39. 25.                       Bestman JE, Lee-Osbourne J, Cline HT. In vivo time-lapse imaging of cell proliferation and differentiation in the optic tectum of Xenopus laevis tadpoles. J Comp Neurol. 2012;520(2):401-33. 26.                       Keenan TM, Nelson AD, Grinager JR, Thelen JC, Svendsen CN. Real time imaging of human progenitor neurogenesis. PLoS One. 2010;5(10):e13187. AOPWiki 2024-01-14T10:20:05

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Altered brain morphology

Organ

AOPWiki 2024-01-14T10:21:53

2024-01-14T10:21:53

Impairment, Learning and memory

Individual

(Adapted from <a href="https://aopwiki.org/events/341" rel="noreferrer noopener" target="_blank">KE: 341</a> - in blue)  Learning can be defined as the process by which new information is acquired to establish knowledge by systematic study or by trial and error (Ono, 2009). Two types of learning are considered in neurobehavioral studies: a) associative learning and b) non- associative learning. Associative learning is based on making associations between different events. In associative learning, a subject learns the relationship among two different stimuli or between the stimulus and the subject’s behavior. On the other hand, non-associative learning can be defined as an alteration in the behavioral response that occurs over time in response to a single type of stimulus. Habituation and sensitization are some examples of non-associative learning.  The memory formation requires acquisition, retention and retrieval of information in the brain, which is characterized by the non- conscious recall of information (Ono, 2009). There are three main categories of memory, including sensory memory, short-term or working memory (up to a few hours) and long-term memory (up to several days or even much longer).  Learning and memory depend upon the coordinated action of different brain regions and neurotransmitter systems constituting functionally integrated neural networks (D’Hooge and DeDeyn, 2001). Among the many brain areas engaged in the acquisition of, or retrieval of, a learned event, the hippocampal-based memory systems have received the most study. For example, the hippocampus has been shown to be critical for spatial-temporal memory, visio-spatial memory, verbal and narrative memory, and episodic and autobiographical memory (Burgess et al., 2000; Vorhees and Williams, 2014). However, there is substantial evidence that fundamental learning and memory functions are not mediated by the hippocampus alone but require a network that includes, in addition to the hippocampus, anterior thalamic nuclei, mammillary bodies cortex, cerebellum and basal ganglia (Aggleton and Brown, 1999; Doya, 2000; Mitchell et al., 2002, Toscano and Guilarte, 2005; Gilbert et al., 2006, 2016). Thus, damage to variety of    brain structures can potentially lead to impairment of learning and memory. The main learning areas and pathways are similar in rodents and primates, including man (Eichenbaum, 2000; Stanton and Spear, 1990). While the prefrontal cortex and frontostriatal neural circuits have been identified as the primary sites of higher-order cognition in vertebrates, invertebrates utilize paired mushroom bodies, shown to contain ~300,000 neurons in honey bees (Menzel, 2012; Puig et al., 2014).  For the purposes of this KE (AO), impaired learning and memory is defined as an organism’s inability to establish new associative or non-associative relationships, or sensory, short-term or long-term memories which can be measured using different behavioral tests described below.

In laboratory animals: in rodents, a variety of tests of learning and memory have been used to probe the integrity of hippocampal function. These include tests of spatial learning like the radial arm maze (RAM), the Barnes maze, Hebb-Williams maze, passive avoidance and Spontaneous alternation and most commonly, the Morris water maze (MWM). Test of novelty such as novel object recognition, and fear based context learning are also sensitive to hippocampal disruption. Finally, trace fear conditioning which incorporates a temporal component upon traditional amygdala-based fear learning engages the hippocampus. A brief description of these tasks follows.  RAM, Barnes, MWM, Hebb-Williams maze are examples of spatial tasks, animals are required to learn the location of a food reward (RAM); an escape hole to enter a preferred dark tunnel from a brightly lit open field area (Barnes maze), or a hidden platform submerged below the surface of the water in a large tank of water (MWM) (Vorhees and Williams, 2014). The Hebb- Williams maze measures an animal’s problem solving abilities by providing no spatial cues to find the target (Pritchett & Mulder, 2004).  Novel Object recognition. This is a simpler task that can be used to probe recognition memory. Two objects are presented to animal in an open field on trial 1, and these are explored. On trial 2, one object is replaced with a novel object and time spent interacting with the novel object is taken evidence of memory retention – I have seen one of these objects before, but not this one (Cohen and Stackman, 2015).  Contextual Fear conditioning is a hippocampal based learning task in which animals are placed in a novel environment and allowed to explore for several minutes before delivery of an aversive stimulus, typically a mild foot shock. Upon reintroduction to this same environment in the future (typically 24-48 hours after original training), animals will limit their exploration, the context of this chamber being associated with an aversive event. The degree of suppression of activity after training is taken as evidence of retention, i.e., memory (Curzon et al., 2009).  Trace fear conditioning. Standard fear conditioning paradigms require animals to make an association between a neutral conditioning stimulus (CS, a light or a tone) and an aversive stimulus (US, a footshock). The unconditioned response (CR) that is elicited upon delivery of the footshock US is freezing behavior. With repetition of CS/US delivery, the previously neutral stimulus comes to elicit the freezing response. This type of learning is dependent on the amygdala, a brain region associated with, but distinct from the hippocampus. Introducing a brief delay between presentation of the neutral CS and the aversive US, a trace period, requires the engagement of the amygdala and the hippocampus (Shors et al., 2001).  Operant Responding. Performance on operant responding reflects the cortex’ ability to organize processes (Rabin et al., 2002).  In humans: A variety of standardized learning and memory tests have been developed for human neuropsychological testing, including children (Rohlman et al., 2008). These include episodic autobiographical memory, perceptual motor tests, short and long term memory tests, working memory tasks, word pair recognition memory; object location recognition memory. Some have been incorporated in general tests of intelligence (IQ) such as the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler.  Modifications have been made and norms developed for incorporating of tests of learning and memory in children. Examples of some of these tests include:  Rey Osterieth Complex Figure test (RCFT) which probes a variety of functions including as visuospatial abilities, memory, attention, planning, and working memory (Shin et al., 2006).  Children’s Auditory Verbal Learning Test (CAVLT) is a free recall of presented word lists that yields measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak 1994; Talley, 1986).  Continuous Visual Memory Test (CVMT) measures visual learning and memory. It is a free recall of presented pictures/objects rather than words but that yields similar measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak, 1984; 1994).  Story Recall from Wechsler Memory Scale (WMS) Logical Memory Test Battery, a standardized neurospychological test designed to measure memory functions (Lezak, 1994; Talley, 1986).  Autobiographical memory (AM) is the recollection of specific personal events in a multifaceted higher order cognitive process. It includes episodic memory- remembering of past events specific in time and place, in contrast to semantic autobiographical memory is the recollection of personal facts, traits, and general knowledge. Episodic AM is associated with greater activation of the hippocampus and a later and more gradual developmental trajectory. Absence of episodic memory in early life (infantile amnesia) is thought to reflect immature hippocampal function (Herold et al., 2015; Fivush, 2011).    Staged Autobiographical Memory Task. In this version of the AM test, children participate in a staged event involving a tour of the hospital, perform a series of tasks (counting footprints in the hall, identifying objects in wall display, buy lunch, watched a video). It is designed to contain unique event happenings, place, time, visual/sensory/perceptual details. Four to five months later, interviews are conducted using Children’s Autobiographical Interview and scored according to standardized scheme (Willoughby et al., 2014).  Attentional set-shifting (ATSET) task. Measures the ability to relearn cues over various schedules of reinforcement (Heisler et al., 2015).  In Honey Bees: For over 50 years an assay for evaluating olfactory conditioning of the proboscis extension reflex (PER) has been used as a reliable method for evaluating appetitive learning and memory in honey bees (Guirfa and Sandoz, 2012; LaLone et al., 2017). These experiments pair a conditioned stimulus (e.g., an odor) with an unconditioned stimulus (e.g., sucrose) provided immediately afterward, which elicits the proboscis extension (Menzel, 2012). After conditioning, the odor alone will lead to the conditioned PER. This methodology has aided in the elucidation of five types of olfactory memory phases in honey bee, which include early short-term memory, late short-term memory, mid-term memory, early long-term memory, and late long-term memory (Guirfa and Sandoz, 2012). These phases are dependent on the type of conditioned stimulus, the intensity of the unconditioned stimulus, the number of conditioning trials, and the time between trials. Where formation of short-term memory occurs minutes after conditioning and decays within minutes, memory consolidation or stabilization of a memory trace after initial acquisition leads to  mid-term memory, which lasts 1 d and is characterized by activity of the cAMP-dependent PKA (Guirfa and Sandoz, 2012). Multiple conditioning trials increase the duration of the memory after learning and coincide with increased Ca2+-calmodulin-dependent PKC activity (Guirfa and Sandoz, 2012). Early long-term memory, where a conditioned response can be evoked days to weeks after conditioning requires translation of existing mRNA, whereas late long-term memory requires de novo gene transcription and can last for weeks (Guirfa andSandoz, 2012)."

Basic forms of learning behavior such as habituation have been found in many taxa from worms to humans (Alexander, 1990). More complex cognitive processes such as executive function likely reside only in higher mammalian species such as non-human primates and humans. Recently, larval zebrafish has also been suggested as a model for the study of learning and memory (Roberts et al., 2013).  Life stage applicability: This key event is applicable to various life stages such as during brain development and maturity (Hladik & Tapio, 2016).  Sex applicability: This key event is not sex specific (Cekanaviciute et al., 2018), although sex-dependent cognitive outcomes have been recently ; Parihar et al., 2020).  Evidence for perturbation by a prototypic stressor: Current literature provides ample evidence of impaired learning and memory being induced by ionizing radiation (Cekanaviciute et al., 2018; Hladik & Tapio, 2016).

High Mixed

High

During brain development

High

Adult, reproductively mature

High High High High High High

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Test no. 426: Developmental neurotoxicity study. www.Oecd.Org/dataoecd/20/52/37622194.Pdf [accessed may 21, 2012].  OECD (2008) Nr 43 GUIDANCE DOCUMENT ON MAMMALIAN REPRODUCTIVE TOXICITY TESTING AND ASSESSMENT. ENV/JM/MONO(2008)16  Ono T. (2009) Learning and Memory. Encyclopedia of neuroscience. M D. Binder, N. Hirokawa and U. Windhorst (Eds). Springer- Verlag GmbH Berlin Heidelberg. pp 2129-2137.  Parihar, V. K. et al. (2020), "Sex-Specific Cognitive Deficits Following Space Radiation Exposure", Frontiers in Behavioral Neuroscience, Vol. 14, https://doi.org/10.3389/fnbeh.2020.535885.  Pritchett, K. and G. Mulder. (2004), "Hebb-Williams mazes.", Contemporary topics in laboratory animal science, Vol. 43/5, http://www.ncbi.nlm.nih.gov/pubmed/15461441.  Puig, M.V., Antzoulatos, E.G., Miller, E.K., 2014. Prefrontal dopamine in associative learning and memory. Neuroscience 282, 217– 229.  Rabin, B. M. et al. (2002), "Effects of Exposure to 56Fe Particles or Protons on Fixed-ratio Operant Responding in Rats", Journal of Radiation Research, Vol. 43/S, https://doi.org/10.1269/jrr.43.S225.  Roberts AC, Bill BR, Glanzman DL. (2013) Learning and memory in zebrafish larvae. Front Neural Circuits 7: 126.  Rohlman DS, Lucchini R, Anger WK, Bellinger DC, van Thriel C. (2008) Neurobehavioral testing in human risk assessment. Neurotoxicology. 29: 556-567.  Shin, MS, Park, SY, Park, SR, Oeol, SH and Kwon, JS. (2006). Clinical and empirical applications of the Rey-Osterieth complex figure test. Nature Protocols, 1: 892-899.    Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372-376.  Stanton ME, Spear LP (1990) Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group I report: comparability of measures of developmental neurotoxicity in humans and laboratory animals. Neurotoxicol Teratol 12:261-267.  Talley, JL. (1986). Memory in learning disabled children: Digit span and eh Rey Auditory verbal learning test. Archives of Clinical Neuropsychology, Elseiver.  Toscano CD, Guilarte TR. (2005) Lead neurotoxicity: From exposure to molecular effects. Brain Res Rev. 49: 529-554.  U.S.EPA. 1998. Health effects guidelines OPPTS 870.6300 developmental neurotoxicity study. EPA Document 712-C-98-239.Office of Prevention Pesticides and Toxic Substances.  Vorhees CV, Williams MT (2014) Assessing spatial learning and memory in rodents. ILAR J 55:310-332.  Willoughby KA, McAndrews MP, Rovet JF. Accuracy of episodic autobiographical memory in children with early thyroid hormone deficiency using a staged event. Dev Cogn Neurosci. 2014 Jul;9:1-11.     AOPWiki 2016-11-29T18:41:24

2024-07-26T09:54:11

<upstream-id>d1f459c9-04bf-4dd9-b09f-bfcff34a1850</upstream-id> <downstream-id>66d78e33-d2d2-48ad-9a2e-cb2c4aa4d0b3</downstream-id> Retinoic acid receptors (RARs) can function as ligand-dependent transcriptional regulators of target genes involved in cellular differentiation, proliferation and apoptosis (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315372/">Gudas and Wagner 2011</a>; <a href="https://www.annualreviews.org/doi/abs/10.1146/annurev.nutr.28.061807.155509">Noy 2010</a>), and therefore play crucial roles in a multitude of biological processes, such as embryonic and fetal development, including cardiovascular, respiratory and CNS development, reproduction and immunity (reviewed in <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670431/">Mark et al., 2009</a>; <a href="https://www.sciencedirect.com/science/article/pii/S1359610100000022">McCaffery and Dräger 2000</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257687/#:~:text=It%20is%20now%20generally%20believed,as%20well%20as%20embryonic%20development.">Clagett-Dame and Knutson 2011</a>; <a href="https://www.sciencedirect.com/science/article/pii/S0890623818305811">Damdimopoulou 2019</a>; <a href="https://www.cell.com/trends/immunology/pdf/S1471-4906(16)30223-X.pdf">Erkelens and Mebius 2017</a>).  The repertoire of target genes that can be regulated by RARs is cell-specific and additionally depends on the presence of receptor ligands (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798310/">Delacroix et al., 2010</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091300/#B9">Mahony et al., 2011</a>). Several genes regulated by RARs, including those within the retinoid pathway such as Rarb, Crbp1/2 (Rbp1/2), Crabp1/2, and Cyp26a1, have been identified (reviewed in <a href="https://www.sciencedirect.com/science/article/pii/S0022227520327541?via%3Dihub">Balmer and Blomhoff, 2002</a>). Additionally, members of the Hox gene family, such as Hoxa1, Hoxb1, Hoxb4, and Hoxd4, contain RAREs, with demonstrated in vivo functionality (reviewed in <a href="https://onlinelibrary.wiley.com/doi/10.1002/neu.20272">Glover et al., 2006</a>).  Retinoic acid (RA) regulation of the cell cycle and related genes has been studied in various cancer cells, where RA is able to induce cell cycle arrest and apoptosis (<a href="https://pubmed.ncbi.nlm.nih.gov/205660/">Lotan et al., 1978</a>; <a href="https://www.nature.com/articles/313404a0">Thiele et al., 1985</a>; <a href="https://www.nature.com/articles/bjc199832">Mangiarotti et al., 1998</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/10896783/">Hsu et al., 2000</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/11877298/">Dimberg et al., 2002</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843129/#:~:text=Retinoic%20acid%20may%20also%20regulate,and%20at%20the%20same%20time%2C">Chen and Ross, 2004</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/17234770/">Donato et al., 2007</a>; <a href="https://karger.com/cpb/article/33/6/1620/72826/All-Trans-Retinoic-Acid-Induces-DU145-Cell-Cycle">Lin et al., 2014</a>; <a href="https://academic.oup.com/ced/article-abstract/39/3/354/6621177?redirectedFrom=PDF">Zhang et al., 2014</a>). Likewise, RA has been shown to promote cell cycle exit and differentiation of mouse pluripotent (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666105/">Kim et al., 2009</a>), as well as various multipotent cells such as mouse embryonic palatal mesenchymal (MEPM) cells (<a href="https://academic.oup.com/toxsci/article/83/2/349/1713943">Yu et al., 2005</a>), mouse and human hemogenic endothelial cells (<a href="https://www.cell.com/cell-reports/pdf/S2211-1247(20)31454-6.pdf">Qiu et al., 2020</a>), mouse and human neural progenitor cells (<a href="https://pubmed.ncbi.nlm.nih.gov/9805273/">Wohl and Weiss, 1998</a>; Koch et al., manuscript in preparation; <a href="https://europepmc.org/article/med/22634143">Culbreth et al., 2012</a>).

Cell cycle genes regulated directly or indirectly by RA, the endogenous RAR agonist, include cyclins (e.g. cyclins A1, B1, B2, C, E, E1, E2, D1, D2, D3), cyclin-dependent kinases (e.g. CDK2, CDK4, CDK5, CDK6, CDK10, CDK14, CDK18, CDK19) and cyclin-dependent kinase inhibitors (e.g. CDKN1A, CDKN2A, CDKN1B, CDKN1C, CDKN2C)  (<a href="https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-017-0407-3">Duffy et al., 2017</a>; <a href="https://iovs.arvojournals.org/article.aspx?articleid=2124087">Li et al., 2003</a>; <a href="https://www.oncotarget.com/article/15441/text/">Wang et al., 2017</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/17234770/">Donato et al., 2007</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798310/">Delacroix et al., 2010</a>; <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0123380#pone.0123380.s013">Terranova et al., 2015</a>).

1.                   Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cell Physiol. 2011;226(2):322-30. 2.                   Noy N. Between death and survival: retinoic acid in regulation of apoptosis. Annu Rev Nutr. 2010;30:201-17. 3.                   Mark M, Ghyselinck NB, Chambon P. Function of retinoic acid receptors during embryonic development. Nucl Recept Signal. 2009;7:e002. 4.                   Clagett-Dame M, Knutson D. Vitamin A in reproduction and development. Nutrients. 2011;3(4):385-428. 5.                   Damdimopoulou P, Chiang C, Flaws JA. Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis. Reprod Toxicol. 2019;87:32-41. 6.                   Erkelens MN, Mebius RE. Retinoic Acid and Immune Homeostasis: A Balancing Act. Trends Immunol. 2017;38(3):168-80. 7.                   Delacroix L, Moutier E, Altobelli G, Legras S, Poch O, Choukrallah MA, et al. Cell-specific interaction of retinoic acid receptors with target genes in mouse embryonic fibroblasts and embryonic stem cells. Mol Cell Biol. 2010;30(1):231-44. 8.                   Mahony S, Mazzoni EO, McCuine S, Young RA, Wichterle H, Gifford DK. Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biol. 2011;12(1):R2. 9.                   Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res. 2002;43(11):1773-808. 10.                 Glover JC, Renaud JS, Rijli FM. Retinoic acid and hindbrain patterning. J Neurobiol. 2006;66(7):705-25. 11.                 Lotan R, Giotta G, Nork E, Nicolson GL. Characterization of the inhibitory effects of retinoids on the in vitro growth of two malignant murine melanomas. J Natl Cancer Inst. 1978;60(5):1035-41. 12.                 Thiele CJ, Reynolds CP, Israel MA. Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma. Nature. 1985;313(6001):404-6. 13.                 Mangiarotti R, Danova M, Alberici R, Pellicciari C. All-trans retinoic acid (ATRA)-induced apoptosis is preceded by G1 arrest in human MCF-7 breast cancer cells. Br J Cancer. 1998;77(2):186-91. 14.                 Hsu SL, Hsu JW, Liu MC, Chen LY, Chang CD. Retinoic acid-mediated G1 arrest is associated with induction of p27(Kip1) and inhibition of cyclin-dependent kinase 3 in human lung squamous carcinoma CH27 cells. Exp Cell Res. 2000;258(2):322-31. 15.                 Dimberg A, Bahram F, Karlberg I, Larsson LG, Nilsson K, Oberg F. Retinoic acid-induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and posttranscriptional up-regulation of p27(Kip1). Blood. 2002;99(6):2199-206. 16.                 Chen Q, Ross AC. Retinoic acid regulates cell cycle progression and cell differentiation in human monocytic THP-1 cells. Exp Cell Res. 2004;297(1):68-81. 17.                 Donato LJ, Suh JH, Noy N. Suppression of mammary carcinoma cell growth by retinoic acid: the cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling. Cancer Res. 2007;67(2):609-15. 18.                 Lin E, Chen MC, Huang CY, Hsu SL, Huang WJ, Lin MS, et al. All-trans retinoic acid induces DU145 cell cycle arrest through Cdk5 activation. Cell Physiol Biochem. 2014;33(6):1620-30. 19.                 Zhang ML, Tao Y, Zhou WQ, Ma PC, Cao YP, He CD, et al. All-trans retinoic acid induces cell-cycle arrest in human cutaneous squamous carcinoma cells by inhibiting the mitogen-activated protein kinase-activated protein 1 pathway. Clin Exp Dermatol. 2014;39(3):354-60. 20.                 Kim M, Habiba A, Doherty JM, Mills JC, Mercer RW, Huettner JE. Regulation of mouse embryonic stem cell neural differentiation by retinoic acid. Dev Biol. 2009;328(2):456-71. 21.                 Yu Z, Lin J, Xiao Y, Han J, Zhang X, Jia H, et al. Induction of cell-cycle arrest by all-trans retinoic acid in mouse embryonic palatal mesenchymal (MEPM) cells. Toxicol Sci. 2005;83(2):349-54. 22.                 Qiu J, Nordling S, Vasavada HH, Butcher EC, Hirschi KK. Retinoic Acid Promotes Endothelial Cell Cycle Early G1 State to Enable Human Hemogenic Endothelial Cell Specification. Cell Rep. 2020;33(9):108465. 23.                 Wohl CA, Weiss S. Retinoic acid enhances neuronal proliferation and astroglial differentiation in cultures of CNS stem cell-derived precursors. J Neurobiol. 1998;37(2):281-90. 24.                 Culbreth ME, Harrill JA, Freudenrich TM, Mundy WR, Shafer TJ. Comparison of chemical-induced changes in proliferation and apoptosis in human and mouse neuroprogenitor cells. Neurotoxicology. 2012;33(6):1499-510. 25.                 Duffy DJ, Krstic A, Halasz M, Schwarzl T, Konietzny A, Iljin K, et al. Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance. Genome Med. 2017;9(1):15. 26.                 Li A, Zhu X, Brown B, Craft CM. Gene expression networks underlying retinoic acid-induced differentiation of human retinoblastoma cells. Invest Ophthalmol Vis Sci. 2003;44(3):996-1007. 27.                 Wang X, Dasari S, Nowakowski GS, Lazaridis KN, Wieben ED, Kadin ME, et al. Retinoic acid receptor alpha drives cell cycle progression and is associated with increased sensitivity to retinoids in T-cell lymphoma. Oncotarget. 2017;8(16):26245-55. 28.                 Terranova C, Narla ST, Lee YW, Bard J, Parikh A, Stachowiak EK, et al. Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1). PLoS One. 2015;10(4):e0123380. AOPWiki 2024-01-14T10:23:52

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A systematic search was performed in PubMed database. Search and acquisition dates: July 2023 Search terms: neuronal progenitor AND proliferation AND retinoic acid; Search returned 121 results, Screened abstracts: 63 Exclusion criteria: proliferation at any postnatal stage, proliferation in carcinoma-derived cells (dysregulated cell cycle), proliferation of neuroblastoma cells (are carcinomas and often <a href="https://www.nature.com/articles/nrdp201678">extracranial in origin</a>), proliferation of non-neuronal progenitors

Rara and Rarb are co-expressed in the developing mouse telencephalon, particularly in the corpus striatum, hippocampus and cortex (<a href="https://journals.biologists.com/dev/article/118/1/267/37781/Retinoic-acid-receptors-and-cellular-retinoid" style="color:blue; text-decoration:underline">Ruberte et al., 1993</a>; <a href="https://www.sciencedirect.com/science/article/pii/0165380694901937?ref=pdf_download&fr=RR-2&rr=809b0f0f5c9895e4" style="color:blue; text-decoration:underline">Yamagata et al., 1994</a>), and exposure to retinoids during prenatal development can lead to microcephaly in humans (<a href="https://pubmed.ncbi.nlm.nih.gov/3162101/" style="color:blue; text-decoration:underline">Lammer et al., 1985</a>), rodents (<a href="https://link.springer.com/article/10.1007/s10735-004-1683-y" style="color:blue; text-decoration:underline">Colakoğlu and Kükner, 2004</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/5014447/" style="color:blue; text-decoration:underline">Shenefelt, 1972</a>; <a href="https://onlinelibrary.wiley.com/doi/epdf/10.1002/tera.1420340203" style="color:blue; text-decoration:underline">Irving et al., 1986</a>), zebrafish (<a href="https://www.sciencedirect.com/science/article/pii/088723339500012W?via%3Dihub" style="color:blue; text-decoration:underline">Herrmann, 1995</a>) and Xenopus (<a href="https://www.nature.com/articles/340140a0" style="color:blue; text-decoration:underline">Durston et al., 1989</a>). Furthermore, active transcriptional repression mediated by unligated RARs is necessary for correct specification of anterior structures, including the forebrain (<a href="https://www.nature.com/articles/nrg2340" style="color:blue; text-decoration:underline">Niederreither and Dollé, 2008</a>). As evidenced by studies in Xenopus laevis, RAR activation during early neurodevelopment leads to anterior truncations. Expressing a dominant-negative co-repressor, which inhibits RAR-mediated transcriptional repression, or reducing RARα protein with morpholino antisense oligonucleotides, results in neurodevelopmental defects that parallel those caused by excess RA (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC312762/" style="color:blue; text-decoration:underline">Koide et al., 2001</a>). Later on, active RAR signalling instructs corticogenesis, through an atRA gradient secreted from the meninges (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772834/" style="color:blue; text-decoration:underline">Siegenthaler et al., 2009</a>).

Current evidence suggests that activation of RAR reduces proliferation of human cortical NPCs (Koch et al., manuscript in preparation; <a href="https://europepmc.org/article/med/22634143" style="color:blue; text-decoration:underline">Culbreth et al., 2012</a>). Data regarding the effects of RAR agonism on cortical NPC proliferation in other species is lacking, although a few studies suggest that proliferation of various populations of neural progenitors may also be negatively affected by exposure to RAR agonists in rat (<a href="https://www.sciencedirect.com/science/article/pii/S0012160608013857?via%3Dihub#bib54" style="color:blue; text-decoration:underline">Goncalves et al, 2009</a>), mouse (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666105/" style="color:blue; text-decoration:underline">Kim et al., 2009</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/9805273/" style="color:blue; text-decoration:underline">Wohl and Weiss, 1998</a>), chicken (<a href="https://pubmed.ncbi.nlm.nih.gov/9332497/" style="color:blue; text-decoration:underline">Salvarezza and Rovasio, 1997</a>), zebrafish (<a href="https://pubmed.ncbi.nlm.nih.gov/24326414/" style="color:blue; text-decoration:underline">Kinikoglu et al., 2014</a>), and xenopus (<a href="https://pubmed.ncbi.nlm.nih.gov/23824578/" style="color:blue; text-decoration:underline">Janesick et al., 2013</a>).  RAR activation using atRA reduces human cortical NPC proliferation in cultured NPCs (Nestin and Sox2-positive) derived from cortices of 16- to 19-week old fetuses (Koch et al., manuscript in preparation). This Neurosphere Assay for the assessment of NPC proliferation through BrdU incorporation (called NPC1) was developed and scientifically validated at the Leibniz Research Institute for Environmental Medicine (<a href="https://www.frontiersin.org/articles/10.3389/ftox.2022.816370/full" style="color:blue; text-decoration:underline">Koch et al., 2022</a>). The NPC1 assay is part of the developmental neurotoxicity in vitro test battery under consideration by the OECD and EFSA (<a href="https://www.altex.org/index.php/altex/article/view/61" style="color:blue; text-decoration:underline">Fritsche et al., 2017</a>; <a href="https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/sp.efsa.2020.EN-1938" style="color:blue; text-decoration:underline">Masjosthusmann et al., 2020</a>; <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912397/" style="color:blue; text-decoration:underline">Sachana et al., 2021</a>). Another study showing decreased proliferation upon exposure to atRA of human NPC cells has used the ReNcell CX (ReN CX) model (<a href="https://europepmc.org/article/med/22634143" style="color:blue; text-decoration:underline">Culbreth et al., 2012</a>). Nestin- and Sox2-positive ReN CX cells, which are immortalised human neural progenitors obtained from 14-week fetal cortex (<a href="https://pubmed.ncbi.nlm.nih.gov/17531091/" style="color:blue; text-decoration:underline">Donato et al., 2007</a>), were exposed to 1-30 μM atRA for 24 hours and proliferation was assessed through a BrdU incorporation assay. The authors reported that 30 μM atRA was the threshold concentration observed to induce at least a 50% decrease in BrdU incorporation (<a href="https://europepmc.org/article/med/22634143" style="color:blue; text-decoration:underline">Culbreth et al., 2012</a>).  It is not yet established which RAR isotype is responsible for mediating the reduction in cortical NPC proliferation, but there is some indication that RARα mediates this effect in forebrain progenitors. Goncalves et al., showed that selective activation of RARα in cultured rat fetal forebrain NPCs decreases proliferation, whereas activation of RARβ increases NPC proliferation, as assessed using ki67 staining (<a href="https://www.sciencedirect.com/science/article/pii/S0012160608013857?via%3Dihub#bib54" style="color:blue; text-decoration:underline">Goncalves et al, 2009</a>).

High

During brain development

Moderate

1.                         Ruberte E, Friederich V, Chambon P, Morriss-Kay G. Retinoic acid receptors and cellular retinoid binding proteins. III. Their differential transcript distribution during mouse nervous system development. Development. 1993;118(1):267-82. 2.                         Yamagata T, Momoi MY, Yanagisawa M, Kumagai H, Yamakado M, Momoi T. Changes of the expression and distribution of retinoic acid receptors during neurogenesis in mouse embryos. Brain Res Dev Brain Res. 1994;77(2):163-76. 3.                         Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313(14):837-41. 4.                         Colakoğlu N, Kükner A. Teratogenicity of retinoic acid and its effects on TGF-beta2 expression in the developing cerebral cortex of the rat. J Mol Histol. 2004;35(8-9):823-7. 5.                         Shenefelt RE. Morphogenesis of malformations in hamsters caused by retinoic acid: relation to dose and stage at treatment. Teratology. 1972;5(1):103-18. 6.                         Irving DW, Willhite CC, Burk DT. Morphogenesis of isotretinoin-induced microcephaly and micrognathia studied by scanning electron microscopy. Teratology. 1986;34(2):141-53. 7.                         Herrmann K. Teratogenic effects of retinoic acid and related substances on the early development of the zebrafish (Brachydanio rerio) as assessed by a novel scoring system. Toxicol In Vitro. 1995;9(3):267-83. 8.                         Durston AJ, Timmermans JP, Hage WJ, Hendriks HF, de Vries NJ, Heideveld M, et al. Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature. 1989;340(6229):140-4. 9.                         Niederreither K, Dollé P. Retinoic acid in development: towards an integrated view. Nat Rev Genet. 2008;9(7):541-53. 10.                       Koide T, Downes M, Chandraratna RA, Blumberg B, Umesono K. Active repression of RAR signaling is required for head formation. Genes Dev. 2001;15(16):2111-21. 11.                       Siegenthaler JA, Ashique AM, Zarbalis K, Patterson KP, Hecht JH, Kane MA, et al. Retinoic acid from the meninges regulates cortical neuron generation. Cell. 2009;139(3):597-609. 12.                       Culbreth ME, Harrill JA, Freudenrich TM, Mundy WR, Shafer TJ. Comparison of chemical-induced changes in proliferation and apoptosis in human and mouse neuroprogenitor cells. Neurotoxicology. 2012;33(6):1499-510. 13.                       Goncalves MB, Agudo M, Connor S, McMahon S, Minger SL, Maden M, et al. Sequential RARbeta and alpha signalling in vivo can induce adult forebrain neural progenitor cells to differentiate into neurons through Shh and FGF signalling pathways. Dev Biol. 2009;326(2):305-13. 14.                       Kim M, Habiba A, Doherty JM, Mills JC, Mercer RW, Huettner JE. Regulation of mouse embryonic stem cell neural differentiation by retinoic acid. Dev Biol. 2009;328(2):456-71. 15.                       Wohl CA, Weiss S. Retinoic acid enhances neuronal proliferation and astroglial differentiation in cultures of CNS stem cell-derived precursors. J Neurobiol. 1998;37(2):281-90. 16.                       Salvarezza SB, Rovasio RA. Exogenous retinoic acid decreases in vivo and in vitro proliferative activity during the early migratory stage of neural crest cells. Cell Prolif. 1997;30(2):71-80. 17.                       Kinikoglu B, Kong Y, Liao EC. Characterization of cultured multipotent zebrafish neural crest cells. Exp Biol Med (Maywood). 2014;239(2):159-68. 18.                       Janesick A, Abbey R, Chung C, Liu S, Taketani M, Blumberg B. ERF and ETV3L are retinoic acid-inducible repressors required for primary neurogenesis. Development. 2013;140(15):3095-106. 19.                       Koch K, Bartmann K, Hartmann J, Kapr J, Klose J, Kuchovská E, et al. Scientific Validation of Human Neurosphere Assays for Developmental Neurotoxicity Evaluation. Front Toxicol. 2022;4:816370. 20.                       Fritsche E, Crofton KM, Hernandez AF, Hougaard Bennekou S, Leist M, Bal-Price A, et al. OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes. ALTEX. 2017;34(2):311-5. 21.                       Masjosthusmann S, Blum J, Bartmann K, Dolde X, Holzer A-K, Stürzl L-C, et al. Establishment of an a priori protocol for the implementation and interpretation of an in-vitro testing battery for the assessment of developmental neurotoxicity. EFSA Supporting Publications. 2020;17(10):1938E. 22.                       Sachana M, Shafer TJ, Terron A. Toward a Better Testing Paradigm for Developmental Neurotoxicity: OECD Efforts and Regulatory Considerations. Biology (Basel). 2021;10(2). 23.                       Donato R, Miljan EA, Hines SJ, Aouabdi S, Pollock K, Patel S, et al. Differential development of neuronal physiological responsiveness in two human neural stem cell lines. BMC Neurosci. 2007;8:36. AOPWiki 2024-01-14T10:27:02

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Retinoic acid receptor agonism during neurodevelopment leading to impaired learning and memory

RAR agonism during neurodevelopment leading to impaired learning and memory

Diana Lupu

Open for adoption

2.6

A prime example of impairments in learning and memory as the adverse outcome for regulatory action is developmental lead exposure and IQ function in children (Bellinger, 2012). Most methods are well established in the published literature and many have been engaged to evaluate the effects of developmental thyroid disruption. The US EPA and OECD Developmental Neurotoxicity (DNT) Guidelines (OCSPP 870.6300 or OECD TG 426) as well as OECD TG 443 (OECD, 2018) both require testing of learning and memory (USEPA, 1998; OECD, 2007) advising to use the following tests passive avoidance, delayed-matching-to-position for the adult rat and for the infant rat, olfactory conditioning, Morris water maze, Biel or Cincinnati maze, radial arm maze, T-maze, and acquisition and retention of schedule-controlled behavior. These DNT Guidelines have been deemed valid to identify developmental neurotoxicity and adverse neurodevelopmental outcomes (Makris et al., 2009).  Also, in the frame of the OECD GD 43 (2008) on reproductive toxicity, learning and memory testing may have potential to be applied in the context of developmental neurotoxicity studies. However, many of the learning and memory tasks used in guideline studies may not readily detect subtle impairments in cognitive function associated with modest degrees of developmental thyroid disruption (Gilbert et al., 2012).

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During brain development

Moderate High High

AOPWiki 2024-01-14T09:50:34

2024-02-02T04:46:38