title: Excess androgens in utero alters fetal testis development.
abstract: Prenatal androgenization induces a polycystic ovary syndrome-like phenotype in adult female offspring, which is associated with alterations that can be detected in the fetal ovary, suggesting gestational origins of this condition. We therefore investigated whether increased prenatal androgen exposure also altered testicular development using ovine animal models. Biweekly maternal testosterone propionate (TP; 100 mg) from day 62 to day 70/day 90 of gestation altered male developmental trajectory. In male fetuses serum LH was decreased (P < .01), and testicular STAR, CYP11, and CYP17 abundance were reduced. Coincident with this, basal testicular T synthesis was decreased in vitro (P < .001). Leydig cell distribution was severely perturbed in all testes prenatally exposed to TP (P < .001). To examine the contribution of estrogens, fetuses were injected with TP (20 mg), the potent estrogen agonist, diethylstilbestrol (DES; 20 mg), or vehicle control at day 62 and day 82 and assessed at day 90. The effects of fetal (direct) TP treatment, but not DES, paralleled maternal (indirect) TP exposure, supporting a direct androgen effect. Cessation of maternal androgenization at day 102 returned Leydig cell distribution to normal but increased basal T output, at day 112, demonstrating Leydig cell developmental plasticity. Earlier maternal androgen exposure from day 30 similarly influenced Leydig cell development at day 90 but additionally affected the expression of Sertoli and germ cell markers. We show in this study that increased prenatal androgen exposure alters development and function of Leydig cells at a time when androgen production is paramount for male development. This supports the concept that gestational antecedents associated with polycystic ovary syndrome may have effects on the male fetus.
authors.affiliation: Medical Research Council Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom. f.connolly@sms.ed.ac.uk
authors.forename: Fiona
authors.initials: F
authors.lastname: Connolly
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rae
authors.forename: Lilli
authors.initials: L
authors.lastname: Bittner
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hogg
authors.forename: Alan S
authors.initials: AS
authors.lastname: McNeilly
authors.forename: W Colin
authors.initials: WC
authors.lastname: Duncan
mesh_terms: D000728:Androgens / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D000818:Animals; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005333:Fetus / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D009994:Osmolar Concentration; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000503:physiopathology; D012733:Sex Differentiation / Q000187:drug effects; D012756:Sheep; D013737:Testis / Q000187:drug effects* / Q000196:embryology*; D014770:Virilism / Q000097:blood / Q000196:embryology
chemical_list: D000728:Androgens