Endocrine Abstracts

Reproductive disorders in males that manifest at birth (cryptorchidism, hypospadias), or young adulthood (low sperm count, lower testosterone levels, testicular cancer) may share a common origin and constitute a ‘testicular dysgenesis syndrome’ (TDS). Normal reproductive tract development is programmed by androgens within the ‘masculinisation programming window’ (MPW, e15.5–e18.5-rats; ~8–14 weeks’ gestation-humans). In rats, TDS disorders can arise because of deficiencies in this programming. Epidemiological studies have shown that acetaminophen (paracetamol) use by women during pregnancy during the presumptive MPW is associated with increased risk of cryptorchidism in boys at birth. Furthermore, exposure of rats to acetaminophen has been shown to reduce testosterone production by the fetal testis and to cause a small significant reduction in anogenital distance (AGD, which provides a read-out of testosterone production/action during the MPW). We investigated the effects of acetaminophen exposure (350 mg/kg per day) on fetal rat masculinisation and on human fetal testis testosterone production using an ex-vivo xenograft system. In utero exposure of pregnant rats to acetaminophen increased bodyweight postnatally, but not in fetal life. Intratesticular testosterone was significantly reduced at embryonic day (e)17.5 after acetaminophen exposure, which accounted for a small but significant reduction in AGD at e21.5; AGD was unaffected in pubertal and adult rats. No effects on postnatal testis weight, penis length, and occurrence of hypospadias or cryptorchidism were observed in rats exposed in utero to acetaminophen (although offspring number studied was low). Similar acetaminophen exposure (1 week) of castrate nude mice bearing human fetal testis xenografts non-significantly lowered blood testosterone levels, but significantly reduced host seminal vesicle weight. In conclusion, gestational exposure to acetaminophen causes a mild reduction in fetal testosterone production in the rat and human fetal testis, which may explain the increased risk of cryptorchidism reported after maternal use of acetaminophen in late 1st/early 2nd trimester of pregnancy.

Declaration of funding

This work was supported by the UK Medical Research Council (grant number G33253).