title: Activin A and equine chorionic gonadotropin recover reproductive dysfunction induced by neonatal exposure to an estrogenic endocrine disruptor in adult male mice.
abstract: We aimed to elucidate the mechanism of action of estrogenic endocrine disruptors and the rescue of reproductive function, particularly the responsiveness of testes to eCG and/or activin A (ACT) after establishing reproductive disorders. Newborn male mice (n = 29) were randomly divided into an untreated group and three treatment groups that received diethylstilbestrol (DES; 100 mug per animal) subcutaneously on Postnatal Day 3 to establish reproductive disorders and daily treatment with PBS (controls: DES + PBS), eCG (eCG group: DES + eCG), or eCG + ACT (eCG + ACT group: DES + eCG + ACT) at 6-8 wk of age prior to mating. After treatment, the controls showed diminished Leydig cells in the testes and thin germ cell layers containing pyknotic germ cells and multinucleated cells. In the eCG and eCG + ACT groups, spermatids and Leydig cells increased markedly. The immunoexpression of androgen receptors in the eCG group and steroidogenic acute regulatory (STAR) protein in the eCG and eCG + ACT groups recovered to approximately the levels in the untreated group; plasma LH and testosterone levels also increased relative to those in the controls. In addition, the cell proliferation index, which is estimated from 5-bromo-2'-deoxyuridine immunoexpression in spermatogonia, increased significantly under eCG treatment, and even more with eCG + ACT. However, the numbers of germ and Leydig cells decreased at 12 wk of age. Thus, ACT and eCG help the testes to recover from the dysfunction induced by neonatal DES administration. Furthermore, the permanent male reproductive disorder induced by neonatal exposure to estrogenic agents may be more likely to result from dysfunction of the hypothalamic-pituitary axis than from dysfunction of the lower reproductive organs.
authors.affiliation: Department of Bioresource and Agrobiosciences, Graduate School of Science and Technology, Kobe University, Kobe, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Warita
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Okamoto
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Mutoh
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Zhan-Peng
authors.initials: ZP
authors.lastname: Yue
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Miki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Teruo
authors.initials: T
authors.lastname: Sugawara
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hoshi
mesh_terms: D028341:Activins / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000627:therapeutic use*; D004054:Diethylstilbestrol / Q000633:toxicity*; D004822:Epididymis / Q000187:drug effects; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D007150:Immunohistochemistry; D007248:Infertility, Male / Q000139:chemically induced / Q000188:drug therapy*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D012669:Seminal Vesicles / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D006063:Chorionic Gonadotropin; D004968:Estrogens, Non-Steroidal; C422405:activin A; D028341:Activins; D004054:Diethylstilbestrol; D007986:Luteinizing Hormone