title: Maternal exposure to dioxin disrupts gonadotropin production in fetal rats and imprints defects in sexual behavior.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related substances are a class of environmental pollutants with suspected toxic effects on reproductive and developmental processes. This study investigated a hypothesis that maternal exposure to TCDD damages gonadotropin-regulated steroidogenesis in fetal gonads to imprint defects in sexual behavior as well as the maturation of gonadal tissues. Oral administration of 1 microg/kg TCDD to pregnant Wistar rats at gestational day (GD) 15 attenuated the expression of luteinizing hormone (LH), a regulator of gonadal steroidogenesis, in the pituitaries of male and female fetuses at GD20. TCDD treatment also reduced the fetal expression of testicular and ovarian steroidogenic proteins, including steroidogenic acute-regulatory protein. These changes in pituitary and gonadal proteins were fetus-specific, and this seems not to be because of the greater delivery of TCDD to the brain of fetuses than adults. This is because a reduction in LH production was not reproduced even although TCDD was administered intraventricularly to adult rats. Direct supplementation of equine chorionic gonadotropin (eCG), an LH-mimicking hormone, to TCDD-exposed fetuses at GD17 restored the reduced expression of gonadal steroidogenic proteins. Maternal exposure to TCDD delayed the development of gonadal tissues in male and female pups and impaired their sexual behavior. However, eCG treatment at the fetal stage again restored not only tissue maturation but also many of the behavioral defects that occurred at adulthood. These results demonstrate that TCDD disrupts steroidogenesis in fetuses by targeting pituitary gonadotropin production and imprints demasculinization in males and defeminization in females in terms of their copulatory behavior.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Takeda
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Koga
authors.forename: Junpei
authors.initials: J
authors.lastname: Mutoh
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Takao
authors.initials: T
authors.lastname: Shimazoe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Takumi
authors.initials: T
authors.lastname: Ishida
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000494:pharmacology / Q000627:therapeutic use; D012734:Disorders of Sex Development / Q000209:etiology / Q000517:prevention & control; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006065:Gonadotropins, Pituitary / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood / Q000235:genetics; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D010053:Ovary / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology* / Q000517:prevention & control; D011467:Prostate / Q000187:drug effects / Q000254:growth & development; D051381:Rats; D017208:Rats, Wistar; D012726:Sexual Behavior, Animal / Q000187:drug effects*; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D006063:Chorionic Gonadotropin; D006065:Gonadotropins, Pituitary; D010750:Phosphoproteins; D000072317:Polychlorinated Dibenzodioxins; D000098682:Steroidogenic Acute Regulatory Protein; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013254:Steroid 17-alpha-Hydroxylase