Sexually dimorphic effects of endocrine disruptors on brain and behavior

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ABSTRACT Every human has a body burden of endocrine-disrupting chemicals (EDCs), and levels of EDCs correlate with reproductive, endocrine, and neurobehavioral deficiencies. As environmental stressors, EDCs interact with other types of stressors to increase chronic disease and impair the quality of life. This proposal seeks to understand how the developmental trajectory of an individual is shaped by the interaction of behavioral stress during two life stages in the context of contamination. We focus on the social behavioral phenotype, as shifts in the reaction norms of social behavior can profoundly change an individual’s relationship to its community, his/her reproductive success, and mental health. We postulate that neurodevelopment in a contaminated world changes an individual’s baseline social phenotype, and that further life stressors overlaid upon the EDC phenotype create greater deflections from the behavioral norm. We will approach this question in several novel ways. First, we will model constant low-level exposure to a mixture of common-use EDCs throughout life, and assess emotional reactivity and sociality. Second, we will examine the effects of a typical life challenge (mild stress) during two critical life periods: to the mother (during pregnancy), to the individual during adolescence, or both. Third, we will compare males and females; this enables us to identify susceptibilities that may relate to well-established gender differences in disease and neurobehavioral dysfunction. Finally, by measuring changes in neuromolecular activity and neuroanatomical organization in a defined network of interconnected limbic and forebrain nuclei regulating the social phenotype, we can gain mechanistic insights into these processes. Thus, our overarching hypothesis is that each life stressor (lifelong EDC exposures, mild prenatal stress, and mild stress during adolescence) concatenates to shift the reaction norms for neurodevelopment and social behavior, and that the combination of stressors exacerbates adverse outcomes for neurobiological health. Mechanistically, we further propose that EDCs and stressors modulate this phenotype through perturbing the normal complementarity of estrogen and androgen signaling in the social decision-making network of the brain. There are 3 Specific Aims. Aim I will establish the sexually dimorphic behavioral phenotype of a lifetime of exposure to low levels of a mixture of common-use EDCs, upon which is superimposed mild stress during critical life stages (gestational, adolescent, or both). Aim II will determine underlying neuromolecular mechanisms for the changes caused by lifelong EDC exposures and gestational/adolescent stressors, focusing on estrogen/androgen-sensitive circuits. Aim III will identify neuroanatomical and cytoarchitectural substrates for the changes caused by EDCs and stressors, prioritizing estrogen-androgen signaling pathways. Proposed work has the potential to have a broad impact, ranging from societal and government policies, the health crisis caused by increasing chronic disease, and understanding fundamental biological principles at the molecular, cellular and organismal levels.