The effects of prenatal PCBs on adult social behavior in rats

“1) was used as the testing arena (Crews et al., 2012; Moy et al., 2004).”

“conspecific compared to the familiar, in accordance with the literature (Cox and Rissman, 2011; Nadler et al., 2004; Wolstenholme et al., 2011).”

“It is known that the female rat is most sensitive to stress during proestrus (Viau and Meaney, 1991); thus, the increase observed only in the A1221 (0.”

“Because it is known that male and female rats differ in their basal concentrations of corticosterone (Kitay, 1961; Gillette et al., 2014) and, further, that circulating levels of corticosterone influence social behaviors in rats (Veenit et al.”

“Developmental EDC exposure can also lead to sex-specific changes in behavior (Jacobsen et al., 2012; Kundakovic et al., 2013; Sobolewski et al., 2014; Williams et al., 2013).”

“Pregnant rats were exposed to one of four treatments, administered via intraperitoneal injections, on E16 and E18, the beginning of the period of brain sexual differentiation (Davis et al., 1996; Jacobson et al., 1980).”

“1) was used as the testing arena (Crews et al., 2012; Moy et al., 2004).”

“Consistentwith the literature on social behavior in this particular paradigm (Choleris et al., 2006; Engelmann et al., 1995), there was a strong social preference, with the experimental animals spending more time in the chamber containing the stimulus animal than the chamber containing an empty stimulus cage.”

“Consistentwith the literature on social behavior in this particular paradigm (Choleris et al., 2006; Engelmann et al., 1995), there was a strong social preference, with the experimental animals spending more time in the chamber containing the stimulus animal than the chamber containing an empty stimulus cage.”

“conspecific compared to the familiar, in accordance with the literature (Cox and Rissman, 2011; Nadler et al., 2004; Wolstenholme et al., 2011).”

“BPA also perturbs social recognition in mice (Wolstenholme et al., 2013).”

“Pregnant rats were exposed to one of four treatments, administered via intraperitoneal injections, on E16 and E18, the beginning of the period of brain sexual differentiation (Davis et al., 1996; Jacobson et al., 1980).”

“Research has shown sex differences in these behaviors, as male rats tend to spend more time interacting with an unfamiliar, same-sex conspecific than do females (Carrier and Kabbaj, 2012; Slamberová et al., 2011; Stack et al., 2010).”

“Developmental EDC exposure can also lead to sex-specific changes in behavior (Jacobsen et al., 2012; Kundakovic et al., 2013; Sobolewski et al., 2014; Williams et al., 2013).”

“The dosages used were based on prior work conducted in the Gore lab that showed physiological, behavioral, and neuroendocrine effects (Steinberg et al., 2007, 2008; Dickerson et al., 2011a; Walker et al., 2013a, 2013b): (1) Vehicle (3% DMSO/sesame oil mix), (2) Estradiol benzoate (EB; 50 μg/kg),…”

“conspecific compared to the familiar, in accordance with the literature (Cox and Rissman, 2011; Nadler et al., 2004; Wolstenholme et al., 2011).”

“…were based on prior work conducted in the Gore lab that showed physiological, behavioral, and neuroendocrine effects (Steinberg et al., 2007, 2008; Dickerson et al., 2011a; Walker et al., 2013a, 2013b): (1) Vehicle (3% DMSO/sesame oil mix), (2) Estradiol benzoate (EB; 50 μg/kg), (3) Aroclor 1221…”

“Developmental EDC exposure can also lead to sex-specific changes in behavior (Jacobsen et al., 2012; Kundakovic et al., 2013; Sobolewski et al., 2014; Williams et al., 2013).”

“current study – also disrupt sexual behavior in female rats (Chung and Clemens, 1999; Steinberg et al., 2007).”

“Most research has been conducted for bisphenol A (BPA), exposure to which causes a decrease in the territorial marking of male mice (Williams et al., 2013), as well as female-specific alteration of one-on-one social interactions in juvenile mice (Wolstenholme et al., 2011) and prairie voles…”

“While the increased interactions in male rats have been previously observed (Meaney and Stewart, 1979), to our knowledge the reported differences in latency-toinvestigation are novel.”

“…been conducted for bisphenol A (BPA), exposure to which causes a decrease in the territorial marking of male mice (Williams et al., 2013), as well as female-specific alteration of one-on-one social interactions in juvenile mice (Wolstenholme et al., 2011) and prairie voles (Sullivan et al., 2014).”

“…Sciences, The University of Texas at Austin, Austin, TX 78712, USA c Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA d Section of Integrative Biology, The University of Texas at Austin, Austin, TX 78712, USA a b s t r a c ta r t i c l e i n f o”

“Exposure to other EDCs such as atrazine (mice: Belloni et al., 2011), PCBs (rats: Jolous-Jamshidi et al., 2010), and chlorpyrifos (mice: Venerosi et al., 2012) are associated with perturbations of normal social interactions.”

“The pups were weaned at P21 and rehoused in same-sex groups where they were monitored daily for signs of pubertal development: vaginal opening in females and preputial separation in males (Steinberg et al., 2007;Walker et al., 2012).”

“, 2014) and, further, that circulating levels of corticosterone influence social behaviors in rats (Veenit et al., 2013), we also measured concentrations of this hormone in our experimental rats.”

“Exposure to other EDCs such as atrazine (mice: Belloni et al., 2011), PCBs (rats: Jolous-Jamshidi et al., 2010), and chlorpyrifos (mice: Venerosi et al., 2012) are associated with perturbations of normal social interactions.”

“Adrenal weights were heavier in females than in males, consistent with observations of Richter (1956) and our previous work using a transgenerational EDC (vinclozolin) exposure and evaluation of F3 descendants (Gillette et al., 2014).”

“…conducted in the Gore lab that showed physiological, behavioral, and neuroendocrine effects (Steinberg et al., 2007, 2008; Dickerson et al., 2011a; Walker et al., 2013a, 2013b): (1) Vehicle (3% DMSO/sesame oil mix), (2) Estradiol benzoate (EB; 50 μg/kg), (3) Aroclor 1221 (A1221, 0.5 mg/kg), or…”

“Although we did not measure body burden or tissue content in the exposed offspring, the literature suggests that maternal–fetal transfer results in an exposure to approximately 1–2 μg/kg A1221, and 100 ng/kg EB, in the fetuses (Takagi et al., 1986).”

“…Sciences, The University of Texas at Austin, Austin, TX 78712, USA c Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA d Section of Integrative Biology, The University of Texas at Austin, Austin, TX 78712, USA a b s t r a c ta r t i c l e i n f o”

“Research has shown sex differences in these behaviors, as male rats tend to spend more time interacting with an unfamiliar, same-sex conspecific than do females (Carrier and Kabbaj, 2012; Slamberová et al., 2011; Stack et al., 2010).”

“Research has shown sex differences in these behaviors, as male rats tend to spend more time interacting with an unfamiliar, same-sex conspecific than do females (Carrier and Kabbaj, 2012; Slamberová et al., 2011; Stack et al., 2010).”

“) on GD 16 and 18 reduced social interaction with a novel conspecific in male adult offspring [91].”

“As E2 most likely affects the expression of several genes with identified EREs, what are the evidences that E2-mediated upregulation of PV is a most likely cause for the attenuation of the ASD-like phenotype in E2-treated PV mice? Moreover, one has to take into account that E2 modulates social behavior in rats (Reilly…”

“…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…”

“costerone levels after PCBs exposition [49], chiefly in female rats [50], or indirectly through reduction of hypothalamic corticosterone-releasing-factor mRNA [51].”

“In contrast, the four rats studies (three of which were performed in the same laboratory), demonstrated that perinatal exposures to either a mixture of PCBs 47 and 77 [84] or Aroclor 1221 [83,85,86] generally decreased sociability metrics in males and had mixed effects in females depending on the dose and timing of ad…”

“Experimental studies in rodents showed that prenatal exposure to PCBs resulted in elevated cortisol levels in female animals [49].”

“Results on tests of sociability and social novelty have been published (Reilly et al., 2015).”

“It is notable that we did not find any body weight effect in the F1 generation, which is inconsistent with our previous studies showing increased body weight in F1-A1221 rats [12, 13].”

“Fourth, our lab has previously utilized a very short exposure window for A1221 (E16 and E18 only) to determine its effects during the beginning of the critical window of sexual differentiation [37,38].”

“These females were tested for sexual behaviors using a paced mating paradigm (Coopersmith and Erskine 1994; Erskine 1985; Martínez and Paredes 2001; Paredes and Vazquez 1999; Steinberg et al. 2007).”

“MP Biomedicals' corticosterone (125)I RIA #07120103) radioimmunoassay was used following manufacturer's protocols and as published (Reilly et al., 2015).”

“In addition, rodent studies demonstrate that PCBs exert subtle but chronic effects on a range of social and anxiety related behaviors (Elnar et al., 2012; Jolous-Jamshidi et al., 2010; Reilly et al., 2015; Tian et al., 2011).”

“For nose touching, which we consider to be the most sensitive and nuanced index of interest and investigation between rats [5,6], the preference of females for a hormone over a no-hormone male was decreased by NeuroMix and stress independently.”

“Once cleaned of fat and weighed, paired adrenals and gonads were normalized to the individual's body weight and multiplied by 1000 and 100 respectively, to obtain the adrenosomatic (ASI) and gonadosomatic (GSI) indices (Crews et al., 2012; Reilly et al., 2015).”

“Nevertheless, E2 might have effects per se, previously evidenced by its role in modulation of social behavior [48] and modulation of neural circuits via direct or indirect activation of multiple downstream signaling pathways [49].”

“5 and 1 mg/kg) on sociability and preference for social novelty of male and female adult offspring rats, revealing a limited impact of prenatal PCB exposure on later adult social behavior in rats (Reilly et al., 2015).”

“We first conducted the social preference test, using apparatus designed to assess priority for processing of social versus non-social stimuli [19, 20, 21].”

“55 Rats tend to spend more time interacting with a novel rat versus one they have encountered previously.”

“…have also been investigated for effects of developmental EDC exposures, this research has exclusively relied upon two-choice systems (Belloni et al., 2011; Crews et al., 2012; Gillette et al., 2014; Reilly et al., 2015; Venerosi, Ricceri, Tait, & Calamandrei, 2012; Wolstenholme et al., 2011).”

“This is a particularly important but untested concept considering the real-world scenario that humans and animals today were likely exposed to high levels of PCBs 50 years ago, leading to a potentially heritable “imprint,” and now their descendants are subjected to exposures to modern classes of EDCs such as VIN.”

“This observation is consistent with a previous study of Sprague Dawley rats that reported exposure to Aroclor 1221 in the maternal diet during gestation and lactation did not alter social approach in adult animals (Reilly et al., 2015).”

“The exquisite sensitivity of the developing brain to hormones means that exogenous EDC exposures may perturb these processes, and increase the predisposition for disease and dysfunction later in life [16], including sexually dimorphic behaviors: juvenile play, adult learning, anxiety, and social and sexual behavior [1…”

“ANY-Maze (Stoelting, Wood Dale, IL, USA) was used to track the position, speed, and distance traveled of the experimental rat in each compartment of the chamber [16, 44, 46].”

“…1) have broader behavioral effects in female rats compared to males (Gillette et al., 2022; Gore et al., 2022); 2) cause hormonally mediated behavioral disruptions in females (Reilly et al., 2015); and 3) involve neuromolecular-mediated disruptions, more so in male rats (Gore et al., 2022, 2021).”

“oestradiol benzoate (eB) has been widely used to investigate the oestrogen-like effects of various eds, which can eliminate the interference of other types of ed toxicity (9,10).”

“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, Sou…”

“Importantly, A1221 has been associated with a number of behavioral changes observed in adulthood (Bell et al., 2016; Gillette et al., 2017; Hernandez Scudder et al., 2021; Reilly et al., 2015; Steinberg et al., 2007), which may be influenced by this neuromolecular reorganization.”

“In short, five studies, including one conducted in mice [258], and four in rats [182,183,259,260], have been published examining how PCBs affect different measures of social behavior.”

“…Hiemke, 1998; Shah and Treit, 2003), dyadic sociability (Crawley, 2004; Kaidanovich-Beilin et al., 2011; Loureiro et al., 2015; Moy et al., 2004; Reilly et al., 2015), Porsolt forced swim test (Porsolt et al., 1977), wire hang (Bie-siadecki et al., 1998; Nagakannan et al., 2012; Saccone et al.,…”

“…and PFAAs, and HPA axis alterations are unknown; however, previous research has reported direct and indirect associations between other EDCs (e.g. BPA, PFOS, phthalates and polychlorinated biphenyls) and HPA axis activity (Egalini et al., 2022; Reilly et al., 2015; Salgado-Freiria et al., 2018).”

“Importantly, several behavioral neuroscience studies using female rats without estrous cycle monitoring have produced valid and reproducible results [67,68].”

“31 Chemical mixtures with other contaminants including PCBs were associated with transcriptional changes in female offspring aged to postnatal day 350 (though no measures in this study were influenced by perinatal Aroclor 1254 exposure alone).”

“According to previous literature reports (Bell et al. 2016; Reilly et al. 2015; Steinberg et al. 2007; Steinberg et al. 2008; Walker et al. 2013), the dose of 1 mg/kg intraperitoneal injection of Aroclor1221 at E16 and E18 is close to the observed exposure of humans and wild animals in PCBs contaminated areas.”