When exposure to phthalates disturbs mouse sexual communication

Sakina Mhaouty-Kodja’s team1, at the Institute of Biology Paris-Seine (IBPS) published in Environmental Health Perspectives2 results showing that male adult mice chronically exposed to low doses of di(2-ethylhexyle) phthalate (DEHP) emit less ultrasonic vocalisations in the presence of sexually receptive females. DEHP-exposed males are less attractive since females spent more time close to control males. This alteration of the precopulatory phase of sexual behavior delays the initiation of mating.

DEHP is an environmental pollutant listed in the Priority Substances under the water framework directive in EU due to its large use as a plasticizer in many day life products. Experimental studies have described the effects of prenatal and postnatal exposure to this molecule on the development and functioning of the male reproductive tract in rodents. Epidemiological studies have also suggested an association between levels of DEHP’s metabolites and reduction of the anogenital distance in boys. So far, potential effects of the adult exposure to DEHP on the central control of reproductive behaviors at doses close to the environmental exposure have not yet been addressed.

In order to identify the molecular targets to DEHP exposure, researchers compared the proteome of the hypothalamic preoptic nucleus, a key region in the motivation to vocalize and mate, between control and exposed subjects. Results showed that the majority of proteins differentially expressed between the groups was connected to the androgen receptor. In collaboration with a CNRS / INRA research team3, it has been shown that the expression of this receptor was reduced in DEHP-exposed mice, while the gonadotropic axisand circulating levels of testosterone were unaffected. Authors then concluded that exposure to DEHP induces an anti-androgenic effect in the cerebral circuit underlying sexual behavior. This leads to cellular and molecular modifications likely responsible for the observed behavioral alterations. Interestingly, genetic invalidation of the androgen receptor in the nervous system alters in a similar way that exposure to DEHP ultrasonic vocalisations and mating.

This work reveals for the first time the critical role of the neural androgen receptor in the emission of courtship vocalisations and underlines the possibility that the vulnerability of this signalling pathway to exposure to endocrine disruptors such as DEHP might be harmful for sexual communication and mating in several species. Several avenues are yet to be explored for future research, in particular the molecular mechanisms underlying down regulation of the neural androgen receptor by DEHP. This study is part of a research field, which represents environmental and health issues. Several challenges still need to be met regarding the understanding of the effects and mechanisms of endocrine disruptor compounds, particularly in neuroendocrine systems.

This study has been featured as a press alert by the CNRS and has been published on the INSB website.

1. Team Neuroplasticity of reproductive behaviors (Neurosciences Paris-Seine, UMR 8246 / INSERM U 1130)

2. Neural mechanisms underlying disruption of courtship behavior by adult exposure to DEHP in male miceEnvironmental Health Perspectives, 1er septembre 2017. Dombret C*, Capela D*, Poissenot K, Parmentier C, Bergsten E, Pionneau C, Chardonnet S, Grange-Messent V, Keller K, Franceschini I, Mhaouty-Kodja S. *Equal contribution.

3. Laboratoire Physiologie de la Reproduction et des Comportements (INRA / CNRS / Université François Rabelais de Tours / Institut français du cheval et de l'équitation).