title: Endocrine disruption of brain sexual differentiation by developmental PCB exposure.
abstract: In mammals, sexual differentiation of the hypothalamus occurs during prenatal and early postnatal development due in large part to sex differences in hormones. These early organizational processes are critically important for the attainment and maintenance of adult reproductive functions. We tested the hypothesis that perinatal exposure to polychlorinated biphenyls (PCBs) that disrupt hormonal pathways would perturb reproductive maturation and the sexually dimorphic development of neuroendocrine systems in the preoptic area (POA). Pregnant Sprague-Dawley rats were injected on gestational d 16 and 18 with vehicle (dimethylsulfoxide), Aroclor 1221 (A1221, an estrogenic PCB mix), a reconstituted PCB mixture representing those highest in human body burden (PCBs 138, 153, 180), or estradiol benzoate, an estrogenic control. Male and female pups were monitored for somatic and reproductive development. In adulthood, some rats were perfused and used for immunohistochemistry of estrogen receptor α, kisspeptin, and coexpression of Fos in GnRH neurons. Other rats were used to obtain fresh-frozen POA dissections for use in a PCR-based 48-gene expression array. Pubertal onset was advanced and estrous cyclicity irregular in endocrine-disrupted females. Furthermore, sexual differentiation of female neuroendocrine systems was masculinized/defeminized. Specifically, in the adult female anteroventral periventricular nucleus, estrogen receptor α-cell numbers and kisspeptin fiber density were significantly decreased, as was GnRH-Fos coexpression. PCR analysis identified androgen receptor, IGF-I, N-methyl-d-aspartate receptor subunit NR2b, and TGFβ1 mRNAs as significantly down-regulated in endocrine-disrupted female POAs. These data suggest that developmental PCBs profoundly impair the sexual differentiation of the female hypothalamus.
authors.affiliation: Division of Pharmacology and Toxicology and Center for Molecular and Cellular Toxicology, The University of Texas at Austin, Texas 78712-0125, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dickerson
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Cunningham
authors.forename: Heather B
authors.initials: HB
authors.lastname: Patisaul
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Woller
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Gore
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D059648:Kisspeptins; D008297:Male; D009490:Neurosecretory Systems / Q000187:drug effects*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011301:Preoptic Area; D011506:Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D012733:Sex Differentiation / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; C491406:Kiss1 protein, rat; D059648:Kisspeptins; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D011944:Receptors, Androgen; D016194:Receptors, N-Methyl-D-Aspartate; D016212:Transforming Growth Factor beta; D007987:Gonadotropin-Releasing Hormone; D007334:Insulin-Like Growth Factor I; D011078:Polychlorinated Biphenyls