Prenatal exposure to low levels of androgen accelerates female puberty onset and reproductive senescence in mice.
Sex steroid hormone production and feedback mechanisms are critical components of the hypothalamic-pituitary-gonadal (HPG) axis and regulate fetal development, puberty, fertility, and menopause. In female mammals, developmental exposure to excess androgens alters the development of the HPG axis and has pathophysiological effects on adult reproductive function. This study presents an in-depth reproductive analysis of a murine model of prenatal androgenization (PNA) in which females are exposed to a low dose of dihydrotestosterone during late prenatal development on embryonic d 16.5-18.5. We determined that PNA females had advanced pubertal onset and a delay in the time to first litter, compared with vehicle-treated controls. The PNA mice also had elevated testosterone, irregular estrous cyclicity, and advanced reproductive senescence. To assess the importance of the window of androgen exposure, dihydrotestosterone was administered to a separate cohort of female mice on postnatal d 21-23 [prepubertal androgenization (PPA)]. PPA significantly advanced the timing of pubertal onset, as observed by age of the vaginal opening, yet had no effects on testosterone or estrous cycling in adulthood. The absence of kisspeptin receptor in Kiss1r-null mice did not change the acceleration of puberty by the PNA and PPA paradigms, indicating that kisspeptin signaling is not required for androgens to advance puberty. Thus, prenatal, but not prepubertal, exposure to low levels of androgens disrupts normal reproductive function throughout life from puberty to reproductive senescence.
Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Emily A
EA
Witham
Jason D
JD
Meadows
Shadi
S
Shojaei
Alexander S
AS
Kauffman
Pamela L
PL
Mellon
D000375:Aging / Q000187:drug effects; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D013196:Dihydrotestosterone / Q000494:pharmacology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011627:Puberty / Q000187:drug effects*; D012098:Reproduction / Q000187:drug effects*
D000728:Androgens; D013196:Dihydrotestosterone