Two-hit exposure to polychlorinated biphenyls at gestational and juvenile life stages: 1. Sexually dimorphic effects on social and anxiety-like behaviors

Abstract

Endocrine disrupting chemicals (EDCs) are widespread environmental contaminants that affect many neuroendocrine functions. The brain is particularly vulnerable to EDCs during critical periods of gestational development when gonadal hormones exert organizational effects on sexually dimorphic behaviors later in life. Peripubertal development is also a time of continued neural sensitivity to organizing effects of hormones, yet little is known about EDC actions at these times. We sought to determine effects of prenatal or juvenile exposures to a class of EDCs, polychlorinated biphenyls (PCBs) at human-relevant dosages on development, physiology, and social and anxiety-related behaviors later in life, and the consequences of a second juvenile “hit” following prenatal treatment. We exposed male and female Sprague-Dawley rats to PCBs (Aroclor 1221, 1mg/kg/day, ip injection) and/or vehicle during prenatal development (embryonic days 16, 18, 20), juvenile development (postnatal days 24, 26, 28), or both. These exposures had differential effects on behaviors in sex and age-dependent ways; while prenatal exposure had more effects than juvenile, juvenile exposure often modified or unmasked the effects of the first hit. Additionally, females exhibited altered social and anxiety behavior in adolescence, while males displayed small but significant changes in sociosexual preferences in adulthood. Thus, the brain continues to be sensitive to organizing effects of EDCs through juvenile development. As humans are exposed to EDCs throughout multiple periods in their life, these findings have implications for our understanding of EDC effects on physiology and behavior.

Two-hit exposure to polychlorinated biphenyls at gestational and juvenile life stages: 2. Sex-specific neuromolecular effects in the brain

“…Weaned pups were housed with same sex littermates (2–3 per cage), and were weighed and handled for at least 5 minutes weekly. Animals were tested for social and anxiety behaviors in adolescence and adulthood, with results published in a sister paper (Bell et al, 2015). Because of the large number of animals necessary for both studies, the animals were raised in 3 cohorts over 1.5 years, with treatments equally distributed across each cohort.…”

“…Rats were euthanized in adulthood (between P93-P108) by rapid decapitation 1–3 hours before lights out, on proestrus in females and 3–9 days after the last behavioral test (reported in the companion study; Bell et al, 2015) in both sexes. Brains were immediately removed and placed in ice for 5 minutes prior to placing in an ice-cold stainless steel brain matrix.…”

“…In this case, an interaction was identified by testing for effects of one treatment while holding the other constant and vice versa. Prior to tissue collection, the sociosexual behavior of these same animals was assessed (Bell et al 2015). PCB exposure affected the production of ultrasonic vocalizations after being placed in a novel testing apparatus prior to the introduction of a stimulus animal and the time spent with a hormone- or a no-hormone-treated opposite sex stimulus animal in a three chamber test of sociosexual partner preference in adult male animals.…”

“…We recently demonstrated that exposing rats to PCBs during juvenile development, with or without prior prenatal exposure, affected several types of behavior in a sex- and age-specific manner (Bell et al, 2015). Two hits of PCBs, the first in late gestation and the second in juvenile development, resulted in abnormal levels of play and anxiety-like behavior in adolescent females, and caused disruptions of opposite-sex partner preference in adult males.…”

Epigenetic impacts of endocrine disruptors in the brain

“…In the rat brain, PCBs alter sexual differentiation of the AVPV and mPOA (Dickerson et al, 2011a; Dickerson et al, 2011b), reproductive senescence [aging; (Walker et al, 2013)], behavior [(Steinberg et al, 2007; Reilly et al, 2015; Bell et al, 2016b); reviewed in (Walker and Gore, 2007)] and cognition [(Widholm et al, 2001); Reviewed in (Schantz and Widholm, 2001; Boucher et al, 2009; Dzwilewski and Schantz, 2015)], outcomes that are influenced by changes in DNA methylation. Additionally, there is some evidence that perinatal exposure to PCBs altered expression of the methylation enzymes, DNMT1 and DNMT3a.…”