Endocrine Disruption of the Developing Dopamine System

点击翻译按钮获取中文摘要

PROJECT SUMMARY Endocrine-disrupting chemicals (EDCs) affect a wide range of endocrine and neurobiological functions. Animal models show causal relationships between exposure and adverse outcomes, and epidemiological data in humans support correlations between EDC exposure and neurobehavioral deficits. My proposal seeks to investigate the effects of perinatal EDC exposure on the development of estrogen-sensitive neural midbrain dopamine (DA) circuits involved in attentional and affective reward-processing behaviors. Here, I will test the hypothesis that perinatal EDC exposure will lead to deficits in DAergic behaviors via disruption of estrogenic signaling mechanisms that regulate cellular, molecular and epigenetic processes in the developing brain DA system. Furthermore, gestational exposure affects both the fetus and developing germ cells within the fetal gonad that become the sperm/ova leading to the F2 generation. Therefore, my work will focus on rats of both sexes in the F1 and F2 generations. To do this, I will utilize a well-established EDC model of polychlorinated biphenyls using Aroclor 1221 (A1221), a weakly estrogenic mixture. Gestational exposure to A1221 perturbs neurobiological development, and has latent effects on neuroendocrine functions, gene expression in the brain, and behavior, in a sex-specific manner. However, its influence on attentional and affective reward- processing behaviors is unknown; this is an important gap in knowledge. Effects of exposures will be observed across two generations: F1 (exposed during gestation) and F2 (exposed as developing germ cells). A primary outcome will be the display of attentional and affective reward- processing behavioral outcomes during adulthood, as these behaviors are estrogen-sensitive and associated with sex-biased mental health disorders in humans. Additionally, I will quantify corresponding changes in the neuroanatomical organization of the brain’s dopamine system, and expression of genes involved in estrogen and dopamine signaling. Because at least part of the mechanism for brain organization is through actions of hormones on DNA methylation to “program” how these genes function later in life, the research will also determine if epigenetic changes (DNA methylation) are a mechanism for long-term changes in gene expression in response to EDC exposure during critical developmental periods. These goals meet the NIEHS’ strategic goal to “investigate the effects of the environment on genome structure and function”, including epigenetic regulation of biological processes, while including sex as a biological variable. Moreover, the proposal extends our understanding of environmental influences on behavioral and molecular endpoints relevant to cognitive and behavioral disorders in humans.