Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility

Abstract

Studies report that fetal exposure to paracetamol/acetaminophen by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (nonpharmaceutical) sources, such as metabolic conversion from the ubiquitous industrial compound aniline. In this study, we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that fetal hormone signaling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Fetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum fetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life.

Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen

“…9). Similar effects on gonad development and reproductive health of F0 adult female rodents have been described after exposure to high doses of APAP or indomethacin (26,27). However, fertility of adult male rats (26) and sperm parameters in mice (25) were not altered by exposure in utero to these drugs.…”

“…Similarly, in vivo administration of APAP or indomethacin to pregnant rats during embryogenesis decreases the number of fetal germ cells and accelerates their embryonic differentiation but does not affect the fertility of adult male rats (26). In females, the number of primordial germ cells is reduced (27) and meiotic entry delayed (26) in fetal mouse and rat ovaries, respectively, leading to a decreased number of follicles in adult mouse ovaries (27) and reduced fertility in F1 and F2 rat females (26). In addition, exposure of ex vivo cultures of human embryonic ovaries to IBU induces a decrease in the germ-cell pool due to a decrease in their proliferation and an increase in their apoptosis (28).…”

Hypothalamus – Response to early paracetamol exposure in male rats offspring

“…This effect is a result of inhibition of prostaglandin biosynthesis playing role in the testosterone synthesis in fetal testes (Gupta and Goldaman, 1986; Gupta, 1989). Nevertheless it seems, that paracetamol and other mild analgesics, regardless of gender, causes a decline in reproductive health (Dean et al, 2016; Holm et al, 2016). Recent data reported that in rodents the exposure to paracetamol or its precursor – aniline during pregnancy impairs also female reproductive development and fertility.…”

“…Recent data reported that in rodents the exposure to paracetamol or its precursor – aniline during pregnancy impairs also female reproductive development and fertility. These chemicals can decrease female anogenital development, reducing the reserve of primordial and growing follicles and the number of gonocytes (Holm et al, 2016).…”

Prenatal Exposure to Acetaminophen and Overweight in Childhood

“…Recent experimental studies have suggested that acetaminophen exhibits endocrine disruptive effects and in utero exposure could affect fetal development . Intrauterine exposure to acetaminophen inhibited fetal testosterone production in ex vivo fetal rat testes , while female mouse fetuses exposed to acetaminophen showed perturbed proliferation of the primordial germ cells, resulting in a reduction of ovarian follicle reserves . Epidemiological studies have also found that prenatal acetaminophen exposure was associated with increased occurrence of cryptorchidism and shorter anogenital distance in male infants as well as earlier pubertal development in female offspring .…”