Assessing metabolic and reproductive consequences of prenatal paracetamol exposure in female CD1 mice

Abstract

Paracetamol is a widely used analgesic during pregnancy; however, emerging evidence suggests it may act as an endocrine/ metabolism disrupting compound. Using an F1 female CD1 mouse model, this study scrutinized the long- term metabolic and reproductive consequences linked to intrauterine paracetamol exposure. Pregnant dams were administered paracetamol at three dose levels (Cmax/10, Cmax, and Cmax × 10) during a critical window of organogenesis (gestational days 7.5–16.5). Offspring were monitored until 17 weeks of age to assess growth, glucose homeostasis, lipidomic profiles, and ovarian his tology. Prenatal exposure did not significantly affect total body weight but induced a dose- dependent increase in peritoneal adipose tissue mass, particularly in the Cmax × 10 group. Metabolic assessments revealed impaired glucose tolerance in the Cmax/10 group and increased insulin sensitivity across all dose groups. Adipose tissue gene expression analysis demonstrated upregulation of adipogenic markers (Pparγ, Lpl, Fasn), while untargeted lipidomics revealed consistent dysregulation of lipid species, including lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), sphingomyelins (SMs), and triacylglycerols (TGs), indicating altered lipid storage and inflammatory signaling. Histological evaluation showed a marked reduction in total follicle number and increased follicular atresia following paracetamol exposure. Degenerative changes in oocytes and granulosa cells were observed, and multi- oocyte follicles (MOFs) were detected exclusively in the Cmax/10. Collectively, these findings demonstrate that intrauterine paracetamol exposure induces persistent developmental reprogramming in female off spring, characterized by visceral adiposity, disrupted lipid homeostasis, and depletion of the ovarian reserve. Notably, several endpoints exhibited non- monotonic dose–response relationships, underscoring the sensitivity of developing systems to even subtherapeutic paracetamol exposure.