Social and neuromolecular phenotypes are programmed by prenatal exposures to endocrine-disrupting chemicals

Abstract

Exposures to endocrine-disrupting chemicals (EDCs) affect the development of hormone-sensitive neural circuits, the proper organization of which are necessary for the manifestation of appropriate adult social and sexual behaviors. We examined whether prenatal exposure to polychlorinated biphenyls (PCBs), a family of ubiquitous industrial contaminants detectable in virtually all humans and wildlife, caused changes in sexually-dimorphic social interactions and communications, and profiled the underlying neuromolecular phenotype. Rats were treated with a PCB commercial mixture, Aroclor 1221 (A1221), estradiol benzoate (EB) as a positive control for estrogenic effects of A1221, or the vehicle (4% DMSO), on embryonic day (E) 16 and 18. In adult F1 offspring, we first conducted tests of ultrasonic vocalization (USV) calls in a sociosexual context as a measure of motivated communications. Numbers of certain USV call types were significantly increased by prenatal treatment with A1221 in males, and decreased by EB in females. In a test of sociosexual preference for a hormone- vs. a non-hormone-primed opposite sex conspecific, male (but not female) nose-touching with opposite-sex rats was significantly diminished by EDCs. Gene expression profiling was conducted in two brain regions that are part of the social decision-making network in the brain: the medial preoptic nucleus (MPN) and the ventromedial nucleus (VMN). In both regions, many more genes were affected by A1221 or EB in females than males. In female MPN, A1221 changed expression of steroid hormone receptor and neuropeptides (e.g., Ar, Esr1, Esr2, and Kiss1). In male MPN, only Per2 was affected by A1221. The VMN had a number of genes affected by EB (females: Kiss1, Kiss1r, Pgr; males: Crh) but not A1221. These differences between EB and A1221 indicate that the mechanism of action of A1221 goes beyond estrogenic pathways. These data show sex-specific effects of prenatal PCBs on adult behaviors and the neuromolecular phenotype.

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

“…The animal literature describing the effects of developmental PCB exposure on social behavior was recently reviewed [69,73]. Briefly, five studies, one in mice [82] and four in rats [83][84][85][86], have been published that describe PCB effects on various metrics of sociability. In the mouse study, animals were exposed via the maternal diet to a mixture of six NDL PCB congeners found in human blood at levels approximating those in the human diet (10 or 1000 ng/kg/d).…”

Exposure to prenatal PCBs shifts the timing of neurogenesis in the hypothalamus of developing rats

“…While PCBs are known to interact with ERα at low doses, we cannot assert that the effects observed in this study were due changes in transcription induced by ERα without directly measuring downstream targets (Bonefeld-Jorgensen, Andersen, Rasmussen, & Vinggaard, 2001). It is likely that multiple developmental processes are interrupted by PCB exposure and are associated with disruptions of behaviors including those regulated by VMN (Topper et al, 2019). As a whole, this study provides a potential mechanism by which environmental EDCs may impair processes involved in reproductive behaviors, the normal expression of which is necessary for reproductive success.…”

“…Exposures to PCBs during developmental periods of life when hormonally sensitive neural circuits are becoming organized are particularly important in determining neuroendocrine outcomes later in life. Indeed, early life exposures of rats or mice to PCBs led to increased anxiety-like behaviors and reduced or altered social and sociosexual interactions in adolescents and adults (Bell, Thompson, Rodriguez, & Gore, 2016;Gillette et al, 2017;Jolous-Jamshidi, Cromwell, McFarland, & Meserve, 2010;Karkaba, Soualeh, Soulimani, & Bouayed, 2017;Reilly et al, 2015;Steinberg, Juenger, & Gore, 2007;Topper et al, 2019;Wang, Fang, Nunez, & Clemens, 2002). In a few studies, these behavioral outcomes were associated with changes to gene and/or protein expression measured in the same adolescent or adult animals (Bell et al, 2016;Topper et al, 2019), but the mechanism for how the PCBs might cause these changes is unknown.…”

“…Previously, we showed that prenatal exposure to the PCB mixture Aroclor 1221 (A1221) led to sex-specific alterations in hypothalamic gene and protein expression, and adult behavior in rats (Gillette et al, 2017;Reilly et al, 2015;Topper et al, 2019). In the present study, we tested whether exposure to A1221 would affect the timing of neurogenesis in two hypothalamic brain regions, the ventromedial nucleus (VMN) and the preoptic area (POA), involved in the control of sociosexual behavior (Kuroda & Numan, 2014;Oomura, Aou, Koyama, Fujita, & Yoshimatsu, 1988;Robarts & Baum, 2006;Spiteri et al, 2010;Will, Hull, & Dominguez, 2014;Williamson, Romeo, & Curley, 2017;Yang et al, 2013) and regions in which A1221 changes profiles of gene expression (Topper et al, 2019). The laboratory rat is an excellent model for bidirectional translation to humans and wildlife species because of the high conservation of the hypothalamus in all vertebrate species.…”

Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity

“…Interestingly, this effect was seen at the lower dose (0.5 mg/kg/d) and not the higher dose (1.0 mg/kg/d) of Aroclor 1221. In a second study from this group using the same exposure paradigm, USV calls in a sociosexual context (i.e., in the presence of a conspecific of the opposite sex) increased but nose-nose sniff interactions decreased in adult offspring [92]. A separate rat study that also evaluated Aroclor 1221, but used a different exposure paradigm (1 mg/kg i.p.…”