title: Long-Term Neonatal Estrogen Exposure Causes Irreversible Inhibition of LH Pulses by Suppressing Arcuate Kisspeptin Expression via Estrogen Receptors α and β in Female Rodents.
abstract: Exposure to estrogen during the developmental period causes reproductive dysfunction in mammals, because the developing brain is highly sensitive to estrogens. In the present study, we report that long-term exposure to supraphysiological doses of estrogen during the neonatal critical period causes irreversible suppression of Kiss1/kisspeptin expression in the arcuate nucleus (ARC) via estrogen receptor-alpha (ERα) and ERβ, resulting in reproductive dysfunction in female rats. Daily estradiol-benzoate (EB) administration from days 0 to 10 postpartum caused persistent vaginal diestrus in female rats. The female rats showed profound suppression of pulsatile luteinizing hormone (LH) release and ARC Kiss1/kisspeptin expression even after ovariectomy at adulthood. In contrast, female rats treated with a single EB injection at day 5 postpartum exhibited persistent vaginal estrus and showed comparable LH pulses and numbers of ARC Kiss1-expressing cells to vehicle-treated controls after ovariectomy at adulthood. Because the LH secretory response to exogenous kisspeptin was spared in female rats with neonatal long-term estrogen exposure, the LH pulse suppression was most probably due to ARC kisspeptin deficiency. Furthermore, neonatal estrogen might act through both ERα and ERβ, because EB exposure significantly reduced the number of ARC Kiss1-expressing cells in wild-type mice but not in ERα or ERβ knockout mice. Taken together, long-term exposure to supraphysiological doses of estrogen in the developing brain might cause defects in ARC kisspeptin neurons via ERα and ERβ, resulting in inhibition of pulsatile LH release and lack of estrous cyclicity.
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Minabe
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Ieda
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan.
authors.forename: Youki
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoue
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Uenoyama
authors.affiliation: Department of Veterinary Medical Sciences, University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Kei-Ichiro
authors.initials: KI
authors.lastname: Maeda
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsukamura
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D059648:Kisspeptins / Q000235:genetics* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D059648:Kisspeptins; D007986:Luteinizing Hormone