In utero exposure to acetaminophen and ibuprofen leads to intergenerational accelerated reproductive aging in female mice

Moïra Rossitto (1) , Margot Ollivier (2, 1) , Stéphanie Déjardin (1) , Alain Pruvost (3) , Christine Brun (1) , Candice Marchive (1) , Anvi Laetitia Nguyen (3) , Aurelie Ghettas (3) , Celine Keime (4) , Bernard de Massy (1) , Francis Poulat (1) , Pascal Philibert (1, 5) , Brigitte Boizet-Bonhoure (1)

1 IGH - Institut de génétique humaine
2 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
3 SPI - Service de Pharmacologie et Immunoanalyse
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 CHU - Hôpital Lapeyronie [Montpellier]

Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesic drugs, such as acetaminophen (APAP), are frequently taken during pregnancy, even in combination. However, they can favour genital malformations in newborn boys and reproductive disorders in adults. Conversely, the consequences on postnatal ovarian development and female reproductive health after in utero exposure are unknown. Here, we found that in mice, in utero exposure to therapeutic doses of the APAP-ibuprofen combination during sex determination led to delayed meiosis entry and progression in female F1 embryonic germ cells. Consequently, follicular activation was reduced in postnatal ovaries through the AKT/FOXO3 pathway, leading in F2 animals to subfertility, accelerated ovarian aging with abnormal corpus luteum persistence, due to decreased apoptosis and increased AKT-mediated luteal cell survival. Our study suggests that administration of these drugs during the critical period of sex determination could lead in humans to adverse effects that might be passed to the offspring.

Domaines: Sciences du Vivant [q-bio]; Biologie du développement

Moïra Rossitto, Margot Ollivier, Stéphanie Déjardin, Alain Pruvost, Christine Brun, et al.. In utero exposure to acetaminophen and ibuprofen leads to intergenerational accelerated reproductive aging in female mice. Communications Biology, 2019, 2 (1), ⟨10.1038/s42003-019-0552-x⟩. ⟨hal-02402594⟩