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Activin A and Equine Chorionic Gonadotropin Recover Reproductive Dysfunction Induced by Neonatal Exposure to an Estrogenic Endocrine Disruptor in Adult Male Mice¹

Department of Bioresource and Agrobiosciences,³ Graduate School of Science and Technology, Kobe University, Kobe 657-8501, Japan Department of Anatomy and Neurobiology,⁵ Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan Departments of Veterinary Anatomy⁶ and Experimental Animal Science,⁷ School of Veterinary Medicine and Animal Sciences, Kitasato University, Aomori 034-8628, Japan Department of Histology and Embryology,⁸ Veterinary College, Jilin University, Jilin 130062, China Department of Animal Science,⁴ Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan Department of Molecular Biochemistry,⁹ Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan

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 µg 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.

activin, activin A, androgen receptor, diethylstilbestrol, endocrine disruptor, equine chorionic gonadotropin, Leydig cells, luteinizing hormone, male sexual function, steroidogenic acute regulatory protein

¹Supported in part by Grants-in-Aid for Scientific Research (C) (12836014) and (B) (15390510) and for Scientific Research on Priority Areas (1) (14042260) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan to N.H.

Correspondence: ²FAX: 81 78 803 5811; e-mail: nobhoshi{at}kobe-u.ac.jp