title: Maternal exposure to dioxin imprints sexual immaturity of the pups through fixing the status of the reduced expression of hypothalamic gonadotropin-releasing hormone.
abstract: Our previous studies have shown that treatment of pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 1 μg/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 LH-mimicking 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (T.T., M.F., Y.H., T.S., Y.I., H.Y.); and Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Japan (M.Y., M.H.).
authors.forename: Tomoki
authors.initials: T
authors.lastname: Takeda
authors.forename: Misaki
authors.initials: M
authors.lastname: Fujii
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hattori
authors.forename: Midori
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Takao
authors.initials: T
authors.lastname: Shimazoe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Masaru
authors.initials: M
authors.lastname: Himeno
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006063:Chorionic Gonadotropin / Q000627:therapeutic use; D019175:DNA Methylation; D004622:Embryo, Mammalian; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D018392:Genomic Imprinting; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D006736:Horses; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D008431:Maternal-Fetal Exchange; D010902:Pituitary Gland / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000188:drug therapy / Q000209:etiology / Q000523:psychology*; D051381:Rats; D017208:Rats, Wistar; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013737:Testis / Q000378:metabolism; D013997:Time Factors
chemical_list: D006063:Chorionic Gonadotropin; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D007987:Gonadotropin-Releasing Hormone