RESUMEN
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 neuropeptide genes (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 compared to vehicle (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.
Asunto(s)
Disruptores Endocrinos/toxicidad , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/patología , Conducta Social , Animales , Corticosterona/sangre , Femenino , Regulación de la Expresión Génica , Masculino , Preferencia en el Apareamiento Animal , Fenotipo , Embarazo , Área Preóptica/metabolismo , Ratas Sprague-Dawley , Caracteres Sexuales , Espectrografía del Sonido , Testosterona/sangre , Núcleo Hipotalámico Ventromedial/metabolismo , Vocalización AnimalRESUMEN
Exposure to polychlorinated biphenyls (PCBs), a class of endocrine-disrupting chemicals, can result in altered reproductive behavior in adulthood, especially when exposure occurs during critical periods of brain sexual differentiation in the fetus. Whether PCBs alter other sexually dimorphic behaviors such as those involved in anxiety is poorly understood. To address this, pregnant rat dams were injected twice, on gestational days 16 and 18, with the weakly estrogenic PCB mixture Aroclor 1221 (A1221) at one of two low dosages (0.5mg/kg or 1.0mg/kg, hereafter 1.0 and 0.5), estradiol benzoate (EB; 50µg/kg) as a positive estrogenic control, or the vehicle (3% DMSO in sesame oil). We also conducted a comprehensive assessment of developmental milestones of the F1 male and female offspring. There were no effects of treatment on sex ratio at birth and age at eye opening. Puberty, assessed by vaginal opening in females and preputial separation in males, was not affected in females but was advanced in males treated with A1221 (1.0). Males and females treated with A1221 (both dosages) were heavier in early adulthood relative to controls. The earliest manifestation of this effect developed in males prior to puberty and in females slightly later, during puberty. Anxiety-like behaviors were tested using the light:dark box and elevated plus maze tests in adulthood. In females, anxiety behaviors were unaffected by treatment. Males treated with A1221 (1.0) showed reduced indices of anxiety and increased activity in the light:dark box but not the elevated plus maze. EB failed to replicate the phenotype produced by A1221 for any of the developmental and behavioral endpoints. Collectively, these results indicate that PCBs increase body weight in both sexes, but their effects on anxiety-like behaviors are specific to males. Furthermore, differences between the results of A1221 and EB suggest that the PCBs are likely acting through mechanisms distinct from their estrogenic activity.
Asunto(s)
Ansiedad/inducido químicamente , Disruptores Endocrinos/toxicidad , Bifenilos Policlorados/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/psicología , Animales , Arocloros/administración & dosificación , Arocloros/toxicidad , Relación Dosis-Respuesta a Droga , Disruptores Endocrinos/administración & dosificación , Estradiol/análogos & derivados , Estradiol/farmacología , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Bifenilos Policlorados/administración & dosificación , Embarazo , Ratas , Ratas Sprague-Dawley , Reproducción/efectos de los fármacos , Caracteres Sexuales , Diferenciación Sexual/efectos de los fármacos , Maduración Sexual/efectos de los fármacosRESUMEN
This study examined developmental changes and sexual dimorphisms in hypothalamic microRNAs, and whether gestational exposures to environmental endocrine-disrupting chemicals (EDCs) altered their expression patterns. Pregnant rat dams were treated on gestational days 16 and 18 with vehicle, estradiol benzoate, or a mixture of polychlorinated biphenyls. Male and female offspring were euthanized on postnatal days (P) 15, 30, 45, or 90, and microRNA and mRNA targets were quantified in the medial preoptic nucleus (MPN) and ventromedial nucleus (VMN) of the hypothalamus. MicroRNAs showed robust developmental changes in both regions, and were sexually dimorphic in the MPN, but not VMN. Importantly, microRNAs in females were up-regulated by EDCs at P30, and down-regulated in males at P90. Few changes in mRNAs were found. Thus, hypothalamic microRNAs are sensitive to prenatal EDC treatment in a sex-, developmental age-, and brain region-specific manner.
Asunto(s)
Contaminantes Ambientales/administración & dosificación , Estradiol/análogos & derivados , MicroARNs/genética , Bifenilos Policlorados/administración & dosificación , Núcleo Hipotalámico Ventromedial/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Contaminantes Ambientales/farmacología , Estradiol/administración & dosificación , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Masculino , MicroARNs/efectos de los fármacos , Bifenilos Policlorados/farmacología , Embarazo , Área Preóptica/crecimiento & desarrollo , Área Preóptica/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , Ratas , Caracteres Sexuales , Núcleo Hipotalámico Ventromedial/metabolismoRESUMEN
Endocrine disrupting chemical (EDC) exposures during critical periods of development may influence neuronal development and the manifestation of sexually dimorphic sociability and social novelty behaviors in adulthood. In this study, we assessed the effects of gestational exposure to PCBs on the social behavior of males and females later in adulthood. A weakly estrogenic PCB mixture, Aroclor 1221 (A1221, 0.5 or 1mg/kg) was administered to pregnant Sprague-Dawley rat dams. Both a positive control (estradiol benzoate; EB, 50µg/kg) and negative control (dimethylsulfoxide; DMSO in sesame oil vehicle) were similarly administered to separate sets of dams. The sexes responded differently in two tasks essential to sociality. Using a three-chamber apparatus that contained a caged, same-sex, gonadectomized stimulus animal and an empty stimulus cage, we found that both sexes showed a strong preference for affiliating with a stimulus animal (vs. an empty cage), an effect that was much more pronounced in the males. In the second task, a novel and a familiar stimulus animal were caged at opposite ends of the same apparatus. Females displayed a higher degree of novelty preference than the males. During both tests, females had significantly higher social approach behaviors while male engaged in significantly more interactive behaviors with the conspecific. Of particular interest, males born of dams that received prenatal A1221 (0.5mg/kg) exhibited an overall decrease in nose-to-nose investigations. These behavioral data suggest that the males are more sensitive to A1221 treatment than are females. In addition to behavioral analysis, serum corticosterone was measured. Females born of dams treated with A1221 (0.5mg/kg) had significantly higher concentrations of corticosterone than the DMSO female group; males were unaffected. Females also had significantly higher corticosterone concentrations than did males. Overall, our results suggest that the effects of gestational exposure to PCBs on adult social behavior are relatively limited within this particular paradigm.
Asunto(s)
Conducta Animal/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Bifenilos Policlorados/toxicidad , Efectos Tardíos de la Exposición Prenatal/psicología , Conducta Social , Animales , Arocloros/toxicidad , Corticosterona/sangre , Estradiol/análogos & derivados , Estradiol/toxicidad , Conducta Exploratoria/efectos de los fármacos , Femenino , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
Alcohol has a wide variety of effects on physiology and behavior. One of the most well-recognized behavioral effects is disinhibition, where behaviors that are normally suppressed are displayed following intoxication. A large body of evidence has shown that alcohol-induced disinhibition in humans affects attention, verbal, sexual, and locomotor behaviors. Similar behavioral disinhibition is also seen in many animal models of ethanol response, from invertebrates to mammals and primates. Here we describe several examples of disinhibition in the nematode C. elegans. The nematode displays distinct behavioral states associated with locomotion (crawling on land and swimming in water) that are mediated by dopamine. On land, animals crawl and feed freely, but these behaviors are inhibited in water. We found that additional behaviors, including a variety of escape responses are also inhibited in water. Whereas alcohol non-specifically impaired locomotion, feeding, and escape responses in worms on land, alcohol specifically disinhibited these behaviors in worms immersed in water. Loss of dopamine signaling relieved disinhibition of feeding behavior, while loss of the D1-like dopamine receptor DOP-4 impaired the ethanol-induced disinhibition of crawling. The powerful genetics and simple nervous system of C. elegans may help uncover conserved molecular mechanisms that underlie alcohol-induced disinhibition of behaviors in higher animals.