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

Abstract

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.

• Authors: Takaharu Tanaka, Yasunori Masubuchi, Rena Okada, Kota Nakajima, Kazuki Nakamura, Sosuke Masuda, Junta Nakahara, Robert R Maronpot, Toshinori Yoshida, Mihoko Koyanagi, Shim-Mo Hayashi, Makoto Shibutani
• Journal: The Journal of toxicological sciences (J Toxicol Sci) Vol. 44 Issue 5 Pg. 357-372 ( 2019) ISSN: 1880-3989 [Electronic] Japan
• PMID: 31068541 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Dcx protein, rat
• Doublecortin Protein
• isoquercitrin
• Propylthiouracil
• Thioctic Acid
• Quercetin

Topics

• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Doublecortin Protein
• Female
• Gene Expression Regulation, Developmental (drug effects)
• Hippocampus (drug effects, growth & development)
• Hypothyroidism (chemically induced, genetics, physiopathology)
• Male
• Neurogenesis (drug effects)
• Pregnancy
• Propylthiouracil
• Quercetin (analogs & derivatives, pharmacology)
• Rats, Sprague-Dawley
• Thioctic Acid (pharmacology)