Immunohistochemistry of aberrant neuronal development induced by 6-propyl-2-thiouracil in rats

Shiraki, Ayako; Tanaka, Takeshi; Watanabe, Yousuke; Saito, Fumiyo; Akahori, Yumi; Imatanaka, Nobuya; Yoshida, Toshinori; Shibutani, Makoto

doi:10.1016/j.toxlet.2016.08.019

Cited by 14 publications

(33 citation statements)

References 51 publications

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“…With regard to the GABAergic interneurons, hypothyroidism also strongly affects these cell populations (Moog et al, 2017). In the present study, developmental exposure to PTU at 10 ppm decreased the number of PVALB + cells and increased SST + cells and CALB2 + cells in the hilar region at the adult stage, similar to the previous studies (Shiraki et al, 2016;Uchida et al, 2014;Wallis et al, 2008). With regard to synaptic plasticity-related neuronal cell populations, the present study revealed decrease of FOS + granule cells by 10 ppm PTU at the adult stage, similar to the previous study of developmental hypothyroidism (Dong et al, 2005).…”

Section: Discussionsupporting

confidence: 91%

“…Developmental hypothyroidism causes sustained disruption of hippocampal neurogenesis in rats Shiraki et al, 2016). We previously found that PTU at 10 ppm affects differentiation and cell survival of granule cell lineages that involve type-1 stem cells on PND 21, and most of the changes in neurogenesis were reversed on PND 77 (Shiraki et al, 2016). In the present study, we observed decreased number of DCX + cells and NeuN + cells, suggestive of type-2b and type-3 progenitor cells and immature and mature granule cells, by 10 ppm PTU at the adult stage.…”

Section: Discussionmentioning

confidence: 99%

“…2). Concentration of PTU was determined in accordance with the previous study revealing hypothyroidism in both dams and offspring (Shiraki et al, 2016). On PND 4, the litters were culled randomly to preserve six male and two female pups per litter.…”

Section: Experimental Designmentioning

confidence: 99%

“…Experimental induction of developmental hypothyroidism in rats causes aberrant brain growth involving diverse cellular populations and also impairs inherent brain structures and functions (Moog et al, 2017). Developmental hypothyroidism impairs neuronal migration and results in subcortical band heterotopia in the corpus callosum, affects postnatal neurogenesis in the hippocampus (Moog et al, 2017;Shiraki et al, 2016), and causes white matter hypoplasia with suppression of both axonal myelination and oligodendrocytic accumulation (Schoonover et al, 2004). It has been considered that maternal hypothyroidism is associated with autism spectrum disorders (ASD; Moog et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats

et al. 2019

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Developmental hypothyroidism as a model of autism spectrum disorders disrupts hippocampal neurogenesis through the adult stage. The present study investigated the ameliorating effect of postweaning exposure to antioxidant on the hypothyroidism-induced disruptive neurogenesis. Mated female Sprague-Dawley rats were treated with 0 or 10 ppm 6-propyl-2-thiouracil (PTU) as an anti-thyroid agent in drinking water from gestational day 6 to postnatal day (PND) 21 on weaning. PTU-exposed male offspring were fed either basal diet, diet containing α-glycosyl isoquercitrin (AGIQ) at 5,000 ppm or α-lipoic acid (ALA) at 1,000 ppm as an antioxidant from PND 21 to PND 77. PTU-exposure decreased DCX + and NeuN + granule cell lineage subpopulations, synaptic plasticity-related FOS + granule cells, and hilar PVALB + and GAD67 + GABAergic interneurons, increased hilar SST + and CALB2 + interneurons, and upregulated Gria3, Otx2, and antioxidant enzyme genes in the dentate gyrus on PND 77. These results suggest disruption of neurogenesis remained in relation with increase of oxidative stress and compensatory responses to the disruption at the adult stage. AGIQ recovered expression of some antioxidant enzyme genes and was effective for restoration of NeuN + postmitotic granule cells and PVALB + and SST + interneurons. In contrast, ALA was effective for restoration of all interneuron subpopulations, as well as postmitotic granule cells, and upregulated Grin2a that may play a role for the restoration. Both antioxidants recovered expression of Otx2 and AGIQ-alone recovered Gria3, suggesting a reversal of disruptive neurogenesis by compensatory responses. Thus, postweaning antioxidant exposure may be effective for ameliorating developmental hypothyroidism-induced disruptive neurogenesis by restoring the function of regulatory system.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats

et al. 2019

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“…Animal studies that showed delays in reflexes and physical development (e.g., hair growth and tooth eruption) were noted (Mallela et al, 2014;Zhou et al, 2016). Changes in neurodevelopment were also described (Shiraki et al, 2016).…”

Section: Propylthioruacilmentioning

confidence: 99%

Teratogen update: Antithyroid medications

Romeo

Običan

2020

Birth Defects Research

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Objective Thyroid disorders including hyperthyroidism are common during pregnancy. Untreated hyperthyroidism can result in adverse outcomes for pregnancy. Methods Iodine, propylthiouracil (PTU), carbimazole (CMZ), and methimazole (MMI) are common medications for hyperthyroidism treatment. The literature regarding antithyroid medication use in pregnancy and breastfeeding is reviewed. Results Animal studies for PTU have suggested congenital anomalies while animal studies for MMI have only indicated adverse outcomes at higher doses than used in humans. Epidemiological studies have noted an increased risk of congenital anomalies for PTU less often than CMZ or MMI but the epidemiological evidence remains mixed. A pattern of anomalies has been described for CMZ and MMI, from both case and epidemiological studies, including choanal atresia, aplasia cutis congenita, and other facial, heart, gastrointestinal, and skin anomalies. Closer examination of cases indicates that a few cases of the anomalies have occurred without exposure to CMZ or MMI and outside of the proposed critical period. PTU has a small risk of hepatotoxicity which rarely results in liver transplantation and death. Some authors have suggested that PTU be prescribed in early pregnancy and switched to MMI in late pregnancy. Untreated hyperthyroidism, from either a lack of medications or switching medications during the first trimester, may also increase the chance of congenital anomalies. Multiple case studies and larger epidemiological studies have failed to provide clear, consistent outcomes for the use of PTU, CMZ, and MMI in pregnancy. MMI and PTU both enter the breastmilk in small amounts. Conclusion Additional research is needed to assist in the medical management and exposure counseling of pregnant and breastfeeding women with hyperthyroidism.

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Identification of gene targets of developmental neurotoxicity focusing on DNA hypermethylation involved in irreversible disruption of hippocampal neurogenesis in rats

Kikuchi

Takahashi

Ojiro

et al. 2020

J of Applied Toxicology

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We have previously found that maternal exposure to 6‐propyl‐2‐thiouracil (PTU), valproic acid (VPA), or glycidol (GLY) has a sustained or late effect on hippocampal neurogenesis at the adult stage in rat offspring. Herein, we searched for genes with hypermethylated promoter region and downregulated transcript level to reveal irreversible markers of developmental neurotoxicity. The hippocampal dentate gyrus of male rat offspring exposed maternally to PTU, VPA, or GLY was subjected to Methyl‐Seq and RNA‐Seq analyses on postnatal day (PND) 21. Among the genes identified, 170 were selected for further validation analysis of gene expression on PND 21 and PND 77 by real‐time reverse transcription‐PCR. PTU and GLY downregulated many genes on PND 21, reflecting diverse effects on neurogenesis. Furthermore, genes showing sustained downregulation were found after PTU or VPA exposure, reflecting a sustained or late effect on neurogenesis by these compounds. In contrast, such genes were not observed with GLY, probably because of the reversible nature of the effects. Among the genes showing sustained downregulation, Creb, Arc, and Hes5 were concurrently downregulated by PTU, suggesting an association with neuronal mismigration, suppressed synaptic plasticity, and reduction in neural stem and progenitor cells. Epha7 and Pvalb were also concurrently downregulated by PTU, suggesting an association with the reduction in late‐stage progenitor cells. VPA induced sustained downregulation of Vgf and Dpysl4, which may be related to the aberrations in synaptic plasticity. The genes showing sustained downregulation may be irreversible markers of developmental neurotoxicity.

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Immunohistochemistry of aberrant neuronal development induced by 6-propyl-2-thiouracil in rats

Cited by 14 publications

References 51 publications

Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats

Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats

Teratogen update: Antithyroid medications

Identification of gene targets of developmental neurotoxicity focusing on DNA hypermethylation involved in irreversible disruption of hippocampal neurogenesis in rats

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