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Neural Mechanisms Underlying the Disruption of Male Courtship Behavior by Adult Exposure to Di(2-ethylhexyl) Phthalate in Mice.

ABSTRACT: Courtship behavior plays a critical role in attracting females and reproduction success. However, the effects of exposure to a ubiquitous contaminant di(2-ethylhexyl) phthalate (DEHP) on these behaviors and, in particular, on courtship vocalizations have not been examined.The effects of adult exposure to DEHP on courtship and mating behaviors and gonadotropic axis and neural mechanisms involved in DEHP-induced effects were analyzed in male mice.Adult C57BL/6J males were orally exposed to DEHP (0, 0.5, 5, and 50?g/kg/d) for 4 wk. Olfactory preference, ultrasonic vocalizations (USVs), partner preference and mating, as well as locomotor activity and motor coordination, were measured. The kisspeptin system and testosterone levels were analyzed. Proteomic and molecular studies were conducted on the hypothalamic preoptic nucleus, the key region involved in sexual motivation to vocalize and mate.DEHP at 50?g/kg/d reduced the emission of USVs, whereas lower doses changed the ratio of syllable categories. This was associated with diminished sexual interest of female partners toward males exposed to 5 or 50?g/kg/d and increased latency to mate, despite normal olfactory preference. The kisspeptin system and circulating testosterone levels were unaffected. In DEHP-exposed males, proteomic analysis of the preoptic nucleus identified differentially expressed proteins connected to the androgen receptor (AR). Indeed, exposure to 5 or 50?g/kg/d of DEHP induced selective AR downregulation in this nucleus and upstream chemosensory regions. The involvement of AR changes in the observed alterations was further supported by the reduced emission of courtship vocalizations in males with disrupted neural AR expression.These data demonstrate the critical role of neural AR in courtship vocalizations and raises the possibility that the vulnerability of this signaling pathway to exposure to endocrine disrupters may be detrimental for courtship communication and mating in several species. https://doi.org/10.1289/EHP1443.

SUBMITTER: Dombret C

PROVIDER: S-EPMC5915199 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Neural Mechanisms Underlying the Disruption of Male Courtship Behavior by Adult Exposure to Di(2-ethylhexyl) Phthalate in Mice.

Dombret Carlos C Capela Daphné D Poissenot Kevin K Parmentier Caroline C Bergsten Emma E Pionneau Cédric C Chardonnet Solenne S Hardin-Pouzet Hélène H Grange-Messent Valérie V Keller Matthieu M Franceschini Isabelle I Mhaouty-Kodja Sakina S

Environmental health perspectives 20170901 9

<h4>Background</h4>Courtship behavior plays a critical role in attracting females and reproduction success. However, the effects of exposure to a ubiquitous contaminant di(2-ethylhexyl) phthalate (DEHP) on these behaviors and, in particular, on courtship vocalizations have not been examined.<h4>Objective</h4>The effects of adult exposure to DEHP on courtship and mating behaviors and gonadotropic axis and neural mechanisms involved in DEHP-induced effects were analyzed in male mice.<h4>Methods</h ...[more]

PMID: 28934723

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Project description:BackgroundWe have previously shown that chronic exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate (DEHP) altered male sexual behavior and induced down-regulation of the androgen receptor (AR) in the neural circuitry controlling this behavior.ObjectivesThe cellular mechanisms induced by chronic exposure of adult male mice to low doses of DEHP alone or in an environmental phthalate mixture were studied.MethodsTwo-month-old C57BL/6J males were exposed orally for 8 wk to DEHP alone (0, 5, or 50μg/kg/d) or to DEHP (50μg/kg/d) in a phthalate mixture. Behavior, dendritic density per 50-μm length, pre-/postsynaptic markers, synapse ultrastructure, and bioenergetic activity were analyzed.ResultsMice exposed to DEHP either alone or in a phthalate mixture differed in mating, emission of ultrasonic vocalizations, and the ability to attract receptive females in urinary preference tests from control mice. Analyses in the medial preoptic area, the key hypothalamic region involved in male sexual behavior, showed lower dendritic spine density and protein levels of glutamate receptors and differences in other postsynaptic components and presynaptic markers between the treated groups. Ultrastructural observation of dendritic synapses by electron microscopy showed comparable morphology between the treated groups. Metabolic analyses highlighted differences in hypothalamic metabolites of males exposed to DEHP alone or in a phthalate mixture compared to control mice. These differences included lower tryptophan and higher NAD+ levels, respectively, a precursor and end product of the kynurenine pathway of tryptophan metabolism. The protein amounts of the xenobiotic aryl hydrocarbon receptor, one of the targets of this metabolic pathway and known negative regulator of the AR, were higher in the medial preoptic area of exposed male mice.DiscussionDifferences in behavior of male mice exposed to environmental doses of phthalates were associated with differences in neural structure and metabolism, with possibly a key role of the kynurenine pathway of tryptophan metabolism in the effects mediated by these substances. https://doi.org/10.1289/EHP11514.

Project description:BackgroundWe have previously shown that adult male mice exposure to low doses of an ubiquitous endocrine disruptor, di(2-ethylhexyl) phthalate (DEHP), alters courtship behavior.ObjectiveThe effects of adult exposure to low doses of DEHP alone or in an environmental phthalate mixture on estrous cyclicity, reproductive behavior, and underlying neural structures were analyzed in female mice.MethodsTwo-month-old C57BL/6J females were exposed orally for 6 wk to DEHP alone (0, 5 or 50μg/kg/d) or to DEHP (5μg/kg/d) in a phthalate mixture. Estrous cyclicity was analyzed in intact mice, and behavior [lordosis, olfactory preference, partner preference, ability to stimulate male ultrasonic vocalizations (USVs)] was measured in ovariectomized mice primed with estradiol and progesterone. Immunohistochemical studies were conducted in the neural structures involved in behavior for estrogen receptor (ER) α and progesterone receptor (PR).ResultsExposure to DEHP alone or in mixture lengthened the estrous cycle duration, with a shorter proestrus and longer estrus and metestrus stages. Under normalized hormonal levels, females exposed to DEHP alone or in mixture exhibited altered olfactory preference. A lower lordosis behavior and ability to attract and stimulate male emission of courtship USVs was observed, probably due to modifications of pheromonal emission in exposed females. The behavioral alterations were associated with a lower number of PR-expressing neurons, without changes in ERα, in the neural circuitry underlying sexual behavior. The majority of effects observed was comparable between the two DEHP doses and were driven by DEHP in the mixture.ConclusionsExposure to environmental doses of DEHP alone or in mixture altered several components of female sexual behavior in mice, probably through selective disruption of neural PR signaling. Together with the previously reported vulnerability of male mice, this finding suggests a major impact of exposure to phthalates on sexual reproduction, including in other species with similar neural regulatory processes. https://doi.org/10.1289/EHP7662.

Project description:We previously demonstrated that the androgenic and anti-androgenic effects of endocrine disruptors (EDs) alter reproductive function and exert distinct effects on developing male reproductive organs. To further investigate these effects, we used an immature rat model to examine the effects of di-(2 ethylhexyl) phthalate (DEHP) and flutamide (Flu) on the male reproductive system. Immature male SD rats were treated daily with DEHP and Flu on postnatal days (PNDs) 21 to 35, in a dose-dependent manner. As results, the weights of the testes, prostate, and seminal vesicle and anogenital distances (AGD) decreased significantly in response to high doses of DEHP or Flu. Testosterone (T) levels significantly decreased in all DEHP- treated groups, whereas luteinizing hormone (LH) plasma levels were not altered by any of the two treatments at PND 36. However, treatment with DEHP or Flu induced histopathological changes in the testes, wherein degeneration and disorders of Leydig cells, germ cells and dilatation of tubular lumen were observed in a dose-dependent manner. Conversely, hyperplasia and denseness of Leydig, Sertoli and germ cells were observed in rats given with high doses of Flu. The results by cDNA microarray analysis indicated that 1,272 genes were up-regulated by more than two-fold, and 1,969 genes were down-regulated in response to DEHP, Flu or both EDs. These genes were selected based on their markedly increased or decreased expression levels. These genes have been also classified on the basis of gene ontology (e.g., steroid hormone biosynthetic process, regulation of transcription, signal transduction, metabolic process, biosynthetic process...). Significant decreases in gene expression were observed in steroidogenic genes (i.e., Star, Cyp11a1 and Hsd3b). In addition, the expression of a common set of target genes, including CaBP1, Vav2, Plcd1, Lhx1 and Isoc1, was altered following exposure to EDs, suggesting that they may be marker genes to screen for the anti-androgenic or androgenic effects of EDs. Overall, our results demonstrated that exposure to DEHP, Flu or both EDs resulted in a alteration of gene expression in the testes of immature male rats. Furthermore, the toxicological effects of these EDs on the male reproductive system resulted from their anti-androgenic effects. Taken together, these results provide a new insight into the molecular mechanisms underlying the detrimental impacts of EDs, in regards to anti-androgenic effects in humans and wildlife.

Dataset Information

Neural Mechanisms Underlying the Disruption of Male Courtship Behavior by Adult Exposure to Di(2-ethylhexyl) Phthalate in Mice.

Publications

Neural Mechanisms Underlying the Disruption of Male Courtship Behavior by Adult Exposure to Di(2-ethylhexyl) Phthalate in Mice.

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