Prenatal androgen excess affects ovarian function, PPARG and chemerin systems

MARIA JOSÉ FERRER; MARIA FLORENCIA HEBER; ALICIA BEATRIZ MOTTA; GISELLE ADRIANA ABRUZZESE; SILVANA ROCIO FERREIRA

Melbourne

Congreso; XIth World DOHaD Congress 2019; 2019

DOHaD Society

Background/Aims: Reproductive functions are tightly relatedto metabolic ones. The peroxisome proliferator-activatedreceptors gamma (PPARG) and the adipokine chemerin aremolecules that act as links between metabolic status and ovarianfunctions. We aimed to evaluate the effect of prenatal hyperandrogenismon these energy sensors signaling and its impact onovarian function at adult age.Method: Pregnant rats were hyperandrogenized with testosteroneand a Control group was obtained by vehicle injection.Prenatally hyperandrogenized (PH) female offspring andControls were characterized according to the estrous cycle byvaginal smears. We have previously reported several derangementsat early ages. Here, we evaluated at adult age body weight,basal glucose and insulin levels, and HOMA-IR. We assessedhormonal profile, ovarian morphology and quantified byqPCR and western blot the levels of PPARG, its co-activatorPGC1a, chemerin and its receptor, Cmklr1. We evaluatedthe interaction between PPARG and PGC1a by co-immunoprecipitation,and measured the mRNA levels of steroidogenicmediators (Star, 3bhsd, Cyp17a1, 17bhsd, Cyp19a1).Results: At adult life Control rats showed 100% regular estrouscycles, 51% of the PH group showed irregular cycles (PHirr),whereas 49% were acyclic and remained in diestrus or metaestrus(PHac). Both PHphenotypes displayed ovarian cysts, high glucoseand insulin levels and an increased HOMA-IR index, withoutoverweight. PPARG mRNA and protein levels were decreasedin the PH group. PGC1a levels were decreased in the PHirr animals.PPARG and PGC1a interaction was decreased in both PHphenotypes. Chemerin and Cmklr1 mRNA levels were decreasedin the PH group, while chemerin protein levels remainedunaltered. Both PH phenotypes showed altered hormonal profile(with low estradiol and high testosterone in the PHac phenotype)and impaired steroidogenesis, in a phenotype specific pattern.Conclusions: Prenatal androgen excess exposure leads to fetalprogramming and exerts long-term effects on metabolic andovarian functions, affecting, at adult life, ovarian metabolicsensors (PPARG and chemerin) and inducing alterations onovarian morphology and steroidogenesis.