Maternal exposure to dioxin imprints sexual immaturity of the pups through fixing the status of the reduced expression of hypothalamic gonadotropin- releasing hormone

Tomoki Takeda, Misaki Fujii, Yukiko Hattori, Midori Yamamoto, Takao Shimazoe, Yuji Ishii, Masaru Himeno, Hideyuki Yamada

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Our previous studies have shown that treatment of pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 1 mg/kg) at gestational day (GD) 15 reduces the pituitary synthesis of luteinizing hormone (LH) during the late fetal and early postnatal period, leading to the imprinting of defects in sexual behaviors at adulthood. However, it remains unclear how the attenuation of pituitary LH is linked to sexual immaturity. To address this issue, we performed a DNA microarray analysis to identify the gene(s) responsible for dioxin-induced sexual immaturity on the pituitary and hypothalamus of male pups, born of TCDD-treated dams, at the age of postnatal day (PND) 70. Among the reduced genes, we focused on gonadotropin-releasing hormone (GnRH) in the hypothalamus because of published evidence that it has a role in sexual behaviors. An attenuation by TCDD of GnRH expression emerged at PND4, and no subsequent return to the control level was seen. A change in neither DNA methylation nor histone acetylation accounted for the reduced expression of GnRH. Intracerebroventricular infusion of GnRH to the TCDD-exposed pups after reaching maturity restored the impairment of sexual behaviors. Supplying equine chorionic gonadotropin, an LHmimicking hormone, to the TCDD-exposed fetuses at GD15 resulted in a recovery from the reduced expression of GnRH, as well as from the defects in sexual behavior. These results strongly suggest that maternal exposure to TCDD fixes the status of the lowered expression of GnRH in the offspring by reducing the LH-assisted steroidogenesis at the perinatal stage, and this mechanism imprints defects in sexual behaviors at adulthood.

Original languageEnglish
Pages (from-to)74-82
Number of pages9
JournalMolecular Pharmacology
Volume85
Issue number1
DOIs
Publication statusPublished - Jan 2014

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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