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

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.

Effects of progesterone and RU486 on the development and expression of adult male sexual behaviour and gene expression in the amygdala and preoptic area of the hypothalamus

The number of progesterone receptors is greater in the male than female neonatal rat hypothalamus. The aims of the present study were to determine developmental effects of progesterone on the expression of adult male sexual behaviour and whether changes in behaviour were reflected by altered gene expression within the hypothalamic preoptic area (POA) or medial amygdala. Male rats were treated with progesterone (40 µg kg–1, i.p.), the progesterone receptor antagonist RU486 (40 µg kg–1, i.p.) or an equal volume of vehicle (10% ethanol, 90% corn oil) on postnatal Days 1–5. Treatment with either progesterone or RU486 inhibited (P ≤ 0.07) the initial expression of consummatory sexual behaviour at 10.5 weeks of age without influencing growth or serum concentrations of testosterone. Sexual interest, as measured by latency to exhibiting mounting behaviour or the number of mounts achieved, was not influenced by treatment with either progesterone or RU486. The effects of treatment with progesterone or RU486 on sexual behaviour were diminished by experience. Microarray analysis of the POA indicated 61 genes that were upregulated and 49 that were downregulated (P ≤ 0.01) following RU486 treatment of male rats. However, the altered expression of selected genes was not confirmed by real-time reverse transcription–polymerase chain reaction. The expression of targeted genes within the amygdala was not influenced by treatment with either progesterone or RU486. Neonatal treatment with RU486, but not progesterone, decreased testes weight (P = 0.02) without affecting testes morphology. The results indicate that altering the progesterone environment during a critical developmental period affects the expression of behaviour, but that changes in behaviour are not mirrored by the altered expression of selected genes.