Prenatal paracetamol modulates sexually dimorphic behaviour and steroidogenesis in adult male and female mice

Prenatal exposure to paracetamol (also known as acetaminophen; N-acetyl-para-aminophenol; APAP) has been implicated in the disruption of sexual differentiation of the brain during neurodevelopment, potentially leading to altered sexual behaviour. This study aimed to evaluate the long-term effects of prenatal APAP exposure on sexually dimorphic behaviour in adult mice. Pregnant C57BL/6 dams were administered 150 mg/kg/day of APAP or tap water from 7 days post-coitum until birth. Behavioural assays, anogenital distance measurements, and steroidal and morphological analyses of gonads were performed on adult offspring at 16-17 weeks postnatally. Prenatal APAP exposure resulted in reduced anogenital distance and alterations in sexually dimorphic behaviour in adult mice, indicating that APAP disrupted both urogenital and brain sexual development. As expected, significant sex differences in spontaneous behaviour were observed in vehicle-treated mice. These differences were absent in APAP-exposed mice, suggesting that the sexes had become more similar in their behavioural patterns. Furthermore, APAP exposure influenced gonadal steroidogenesis, as evidenced by decreased testicular corticosteroid 11-deoxycortisol in males and decreased ovarian 17OH-progesterone and androstenedione levels in females. These findings demonstrate that prenatal APAP exposure disrupts sexually dimorphic neurodevelopment with persistent effects in adults, underscoring the necessity for further research on the implications of APAP use during pregnancy.