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

Commun Biol. 2019 Aug 13;2:310. doi: 10.1038/s42003-019-0552-x. eCollection 2019.

Abstract

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.

Keywords: Infertility; Oogenesis; Risk factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / adverse effects*
  • Aging / physiology*
  • Animals
  • Animals, Newborn
  • Cell Proliferation / drug effects
  • Female
  • Fertility
  • Forkhead Box Protein O3 / metabolism
  • Germ Cells / drug effects
  • Germ Cells / pathology
  • Ibuprofen / adverse effects*
  • Luteolysis
  • Mice
  • Ovary / embryology
  • Ovary / pathology
  • Pregnancy
  • Prenatal Exposure Delayed Effects / pathology*
  • Prenatal Exposure Delayed Effects / physiopathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reproduction / physiology*
  • Signal Transduction

Substances

  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • Acetaminophen
  • Proto-Oncogene Proteins c-akt
  • Ibuprofen