Prenatal exposure to paracetamol/acetaminophen and precursor aniline impairs masculinisation of male brain and behaviour.

doi:10.1530/REP-17-0165

Paper

Prenatal exposure to paracetamol/acetaminophen and precursor aniline impairs masculinisation of male brain and behaviour.

Published Aug 1, 2017 · A. Hay-Schmidt, O. T. E. Finkielman, B. Jensen

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Abstract

Paracetamol/acetaminophen (N-Acetyl-p-Aminophenol; APAP) is the preferred analgesic for pain relief and fever during pregnancy. It has therefore caused concern that several studies have reported that prenatal exposure to APAP results in developmental alterations in both the reproductive tract and the brain. Genitals and nervous system of male mammals are actively masculinised during foetal development and early postnatal life by the combined actions of prostaglandins and androgens, resulting in the male-typical reproductive behaviour seen in adulthood. Both androgens and prostaglandins are known to be inhibited by APAP. Through intrauterine exposure experiments in C57BL/6 mice, we found that exposure to APAP decreased neuronal number in the sexually dimorphic nucleus (SDN) of the preoptic area (POA) in the anterior hypothalamus of male adult offspring. Likewise, exposure to the environmental pollutant and precursor of APAP, aniline, resulted in a similar reduction. Decrease in neuronal number in the SDN-POA is associated with reductions in male sexual behaviour. Consistent with the changes, male mice exposed in uteri to APAP exhibited changes in urinary marking behaviour as adults and had a less aggressive territorial display towards intruders of the same gender. Additionally, exposed males had reduced intromissions and ejaculations during mating with females in oestrus. Together, these data suggest that prenatal exposure to APAP may impair male sexual behaviour in adulthood by disrupting the sexual neurobehavioral programming. These findings add to the growing body of evidence suggesting the need to limit the widespread exposure and use of APAP by pregnant women.

Non-RCT

Animal Study

Study Snapshot

Prenatal exposure to paracetamol/acetaminophen and its precursor aniline impairs male brain development and sexual behavior in adulthood, highlighting the need to limit its use during pregnancy.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Prenatal exposure to paracetamol/acetaminophen and precursor aniline impairs masculinisation of male brain and behaviour.

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References

Analgesic use — prevalence, biomonitoring and endocrine and reproductive effects

High human exposure to paracetamol and salicylic acid can lead to endocrine disruption, altering reproductive function in both sexes.

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

Intrauterine exposure to paracetamol and its precursor aniline can impair female reproductive development by reducing follicle reserves and fertility in adult offspring.

Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development.

Aniline exposure, when rapidly converted into paracetamol, impairs male reproductive development by increasing 4 steroids and decreasing androgen levels.

Association Between Prenatal Acetaminophen Exposure and Future Risk of Attention Deficit/Hyperactivity Disorder in Children

Prenatal acetaminophen exposure has a mild correlation with the development of ADHD symptoms in children, but current data does not provide sufficient evidence to link it to ADHD symptoms later in life.

Ubiquitous presence of paracetamol in human urine: sources and implications.

Ubiquitous presence of paracetamol in human urine suggests exposure to aniline, nutrition, and smoking as potential sources of internal body burdens of NA4AP.

Citations

Is paracetamol a neuroendocrine disruptor of the developing sexual brain?

Paracetamol, a safe and effective pain medication, may disrupt the developing sexual brain during critical periods of development, potentially contributing to iatrogenic sexual diversity.

Plasma lipid profile and sex hormone levels in rabbits under paraceta-mol-induced oxidative stress

Chronic paracetamol injection in male rabbits leads to increased oxidative stress, decreased antioxidant defense, and changes in lipid metabolism and sex hormone levels.

Sex-specific neurobehavioral and prefrontal cortex gene expression alterations following developmental acetaminophen exposure in mice

Prenatal acetaminophen exposure in mice leads to increased pup vocalizations and decreased ambulation, with altered prefrontal cortex gene expression related to metabolism and immune systems.

Interleukin-1β-induced inflammation and acetaminophen during infancy: Distinct and interactive effects on social-emotional and repetitive behavior in C57BL/6J mice

Early-life acetaminophen exposure and interleukin-1-induced inflammation have distinct and interactive effects on social-emotional and repetitive behavior in mice, with sex-specific effects on neurodevelopmental disorders.

Maternal Paracetamol Intake During Pregnancy—Impacts on Offspring Reproductive Development

Maternal paracetamol intake during pregnancy may be associated with increased risk of cryptorchidism, shorter anogenital distance, and earlier female puberty attainment.