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Reproduction. 2017 Aug;154(2):145-152. doi: 10.1530/REP-17-0165. Epub 2017 May 30.

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

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Department of Neuroscience and PharmacologyFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of BiologyFaculty of Science, University of Copenhagen, Copenhagen, Denmark.
Department of Growth and ReproductionRigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Department of PhysiologyUniversidade Federal do Paraná, Curitiba, Brazil.
Department of Environmental Medicine and Public HealthIcahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Health SciencesKarlstad University, Karlstad, Sweden.
Novo Nordisk Foundation Center for Protein ResearchUniversity of Copenhagen, Copenhagen, Denmark.
Inserm (Institut national de la santé et de la recherche médicale)IRSET, U1085, Rennes, France.
EHESP-School of Public HealthRennes, France.
Inserm (Institut national de la santé et de la recherche médicale)IRSET, U1085, Rennes, France


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.

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