Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model

Abstract

Context: Acetaminophen (APAP, paracetamol) is widely used by pregnant women. Although long considered safe, growing evidence indicates that APAP is an endocrine disruptor since in utero exposure may be associated with a higher risk of male genital tract abnormalities. In rodents, fetal exposure has long-term effects on the reproductive function of female offspring. Human studies have also suggested harmful APAP exposure effects. Objective: Given that disruption of fetal ovarian development may impact women's reproductive health, we investigated the effects of APAP on fetal human ovaries in culture. Design and Setting: Human ovarian fragments from 284 fetuses aged 7 to 12 developmental weeks (DW) were cultivated ex vivo for 7 days in the presence of human-relevant concentrations of APAP (10-8 to 10-3 M) or vehicle control. Main Outcome Measures: Outcomes included examination of postculture tissue morphology, cell viability, apoptosis, and quantification of hormones, APAP, and APAP metabolites in conditioned culture media. Results: APAP reduced the total cell number specifically in 10- to 12-DW ovaries, induced cell death, and decreased KI67-positive cell density independently of fetal age. APAP targeted subpopulations of germ cells and disrupted human fetal ovarian steroidogenesis, without affecting prostaglandin or inhibin B production. Human fetal ovaries were able to metabolize APAP. Conclusions: Our data indicate that APAP can impact first trimester human fetal ovarian development, especially during a 10- to 12-DW window of heightened sensitivity. Overall, APAP behaves as an endocrine disruptor in the fetal human ovary.