GSE122547
Transcriptomic analysis of 13.5dpc embryonic ovaries exposed to the acetaminophen (APAP) and ibuprofen (IBU) combination in mice
Nonsteroidal anti-inflammatory drugs such as ibuprofen (IBU) and analgesic drugs, such as acetaminophen (APAP), are the most frequently medications taken by pregnant women, even in combination. They were shown to target fetal gonadal development acting as endocrine disruptors, that might favour genital malformations in new-born boys and reproductive disorders in adults, in an intergenerational manner. However, the consequences on postnatal ovarian development and female reproductive health after in utero exposure are still unknown. Here, we show that in utero exposure to therapeutic doses of the widely used APAP-IBU combination during the sensitive window of sex determination leads to an increased proliferation of female embryonic germ cells and a delayed entry into meiosis in 13.5dpc exposed ovaries. Consequently, the primordial follicle formation is enhanced in postnatal ovaries and is followed by a reduced follicular activation through the Akt/FoxO3 pathway and an increased follicular apoptosis. Subsequently, a reduced ovarian reserve in adult ovaries of exposed animals and in their offspring (F1) is observed. This leads to the subfertility of 6-month-old F1 animals that show an accelerated ovarian aging, a Premature Ovarian Insufficiency-like phenotype, with an abnormal persistence of corpora lutea due to the decreased apoptosis and an increased luteal Akt-mediated cell survival. Our data suggest that the use of APAP+IBU during this critical period of development that occurs during the first trimester of gestation (6 to 10 weeks), could lead in humans to adverse effects that could be passed to the offspring. Overall design: mRNA profiles of 13.5 days post coitum wild type and APAP+IBU exposed ovaries were generated by deep sequencing, in triplicate