YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
総説
ダイオキシンによる出生児の性未成熟の分子機構
武田 知起
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ジャーナル フリー

2017 年 137 巻 11 号 p. 1373-1379

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 Dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are responsible for producing serious toxic effects in the next generation, such as sexual immaturity. Our laboratory found that treating pregnant rats on gestational day 15 with TCDD (1 μg/kg orally) targets pituitary luteinizing hormone (LH) to attenuate testicular steroidogenesis in fetuses. Because sex steroids during a short window (“the critical period”) in the perinatal stage stimulate brain differentiation closely linked to sexual maturation, it is likely that TCDD imprints sexual immaturity on the offspring due to the lowered expression of LH during the fetal period. To address this hypothesis, we first investigated the effect of supplementation of equine chorionic gonadotropin (eCG), an LH-mimicking hormone, in fetuses exposed to TCDD. The result showed that eCG ameliorated defects in sexual behavior in adulthood as well as in steroidogenesis during the fetal stage. We also found that maternal exposure to TCDD induced the pituitary expression of histone deacetylases (HDACs) in fetuses. In agreement with this, TCDD deacetylated the histones wrapped around the LHβ gene, and valproic acid, an HDAC inhibitor, blocked the reduced level of LHβ caused by TCDD. These observations strongly suggest that TCDD induces the expression of HDACs to attenuate fetal LH production. Finally, such a transient reduction in steroidogenesis of the pituitary-gonadal axis causes a decrease in the expression of hypothalamic gonadotropin-releasing hormone, resulting in defects in sexual behavior in adulthood. This review increases our understanding of the developmental toxicities caused by endocrine disruptors including dioxins.

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© 2017 The Pharmaceutical Society of Japan
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