Long-Term Neonatal Exposure to Estrogen Inhibits LH Pulses By Suppressing Arcuate Kiss1 Expression Via Estrogen Receptor α in Female Rodents

Presentation Number: SUN 477
Date of Presentation: April 2nd, 2017

Shiori Minabe*1, Nahoko Ieda1, Naoko Inoue1, Yoshihisa Uenoyama1, Kei-ichiro Maeda2 and Hiroko Tsukamura1
1Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan, 2Department of Veterinary Medical Sciences, The University of Tokyo, Tokyo, Japan


Exposure to estrogen during the developmental period causes reproductive dysfunction in mammals, as the developing brain is highly sensitive to estrogens. Kisspeptin neurons in the arcuate nucleus (ARC) co-express neurokinin B (NKB) and dynorphin A (Dyn), and are therefore referred to as KNDy neurons. The KNDy neurons are considered to be involved in gonadotropin-releasing hormone (GnRH) pulse generation. The present study aims to examine if a long-term exposure to estrogen during the neonatal critical period causes an irreversible suppression of Kiss1 (kisspeptin gene) Tac2 (NKB gene) and Pdyn (Dyn gene) expressions in the ARC, resulting in reproductive dysfunction in female rodents. 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 luteinizing hormone (LH) pulses and ARC Kiss1/kisspeptin expression even after ovariectomy at adulthood. Furthermore, the current neonatal EB treatment also suppressed Tac2 and Pdyn expressions in ARC. LH secretory response to exogenous kisspeptin was spared in female rats with neonatal long-term estrogen, suggesting that the LH pulse suppression may be due to the cell death of KNDy neurons and/or persistent silencing of these genes in the neurons. It is likely that neonatal estrogen acts through estrogen receptor α (ERα) but not ERβ, because EB exposure significantly reduced the number of ARC Kiss1-expressing cells in wild-type and ERβ knockout (KO) mice but not in ERα KO mice. Taken together, long-term exposure to estrogen in the developing brain might cause defects in ARC KNDy neurons via ERα, resulting in inhibition of pulsatile LH release and consequently lack of estrous cyclicity. This work was supported in part by Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research 26252046 (to H.T.).


Nothing to Disclose: SM, NI, NI, YU, KIM, HT