Developmental Programming: Impact of Prenatal Testosterone Excess on Ovarian Cell Proliferation and Apoptotic Factors in Sheep

SALVETTI NR; ORTEGA HH; VEIGA-LOPEZ A; PADMANABHAN, V

BIOLOGY OF REPRODUCTION

SOC STUDY REPRODUCTION

Lugar: Madison; Año: 2012 vol. 87 p. 1 - 10

0006-3363

Prenatal testosterone (T) excess leads to reproductivedysfunctions in sheep, which include increased ovarian follicularrecruitment and persistence. To test the hypothesis thatfollicular disruptions in T sheep stem from changes in thedevelopmental ontogeny of ovarian proliferation and apoptoticfactors, pregnant Suffolk sheep were injected twice weekly withT propionate or dihydrotestosterone propionate (DHT; a nonaromatizableandrogen) from Days 30 to 90 of gestation.Changes in developmental expression of proliferating cellnuclear antigen (PCNA), BCL2, BAX, activated CASP3, andFAS/FASLG were determined at Fetal Days 90 and 140, 22 wk,10 mo, and 21 mo of age by immunocytochemisty. Prenatal Ttreatment induced changes in expression of proliferative andapoptotic markers in a follicle-, age-, and steroid-specificmanner. Changes in BAX were evident only during fetal lifeand PCNA, BCL2, and CASP3 only postnatally. Prenatal T andnot DHT increased PCNA and decreased BCL2 in granulosa/theca cells of antral follicles at 10 and 21 mo but decreasedCASP3 in granulosa/theca cells of antral follicles at 22 wk(prepubertal) and 10 and 21 mo. Both treatments decreased BAXimmunostaining in granulosa cells of Fetal Day 90 primordial/primary follicles. Neither treatment affected FAS expression atany developmental time point in any follicular compartment.Effects on BAX appear to be programmed by androgenic actionsand PCNA, BCL2, and CASP3 by estrogenic actions of T.Overall, the findings demonstrate that fetal exposure to excess Tdisrupts the ovarian proliferation/apoptosis balance, thusproviding a basis for the follicular disruptions evidenced inthese females.