An integrative analysis of the multi- and transgenerational effects of endocrine-disrupting chemicals on behavior and neurobiology




Krishnan, Krittika

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Endocrine-disrupting chemicals (EDCs) are ubiquitous environmental pollutants that are known to interfere with hormone action. Exposure to EDCs during hormone-sensitive periods of prenatal development can result in disease and dysfunction later in life. Furthermore, EDC effects have been reported in individuals several generations removed from the initial exposure. In this dissertation, I investigated the effects of preconceptional (F2 germ cell) exposure to EDCs, and the potential mechanisms by which these effects are transmitted transgenerationally (F3 generation). Two EDCs, a weakly estrogenic polychlorinated biphenyl (PCB) mixture and an anti-androgenic fungicide vinclozolin (VIN), were used in this dissertation to understand the impact of chemicals with differential mechnisms of action. We hypothesized that these EDCs would alter the behavioral, physiological and neuromolecular phenotype of adult F2 and F3 individuals in a sex and lineage specific manner. The results from the first study in this dissertation indicates that F2 males descended from the paternal lineage were most vulnerable to PCB exposure, as evidenced by altered serum hormone levels, number and acoustic properties of ultrasonic vocalizations (USVs) and male sexual behavior. To determine if EDCs affected the underlying neuromolecular phenotype of these F2 males, we assessed the expression of candidate genes in the medial preoptic area (POA) and ventromedial nucleus (VMN) of the hypothalamus. These regions are both hormone-sensitive and involved in the regulation of reproductive behaviors. These results did not parallel our behavioral findings from the previous chapter, since F2 males descended from the paternal lineage were most vulnerable to VIN exposure. Finally, we investigated whether ancestral EDC exposure, in combination with EDC-altered F2 maternal care, altered the anxiety phenotype of the F3 offspring. F2 individuals’ maternal care toward their F3 offspring, and the F3 neonatal USVs were altered depending on the EDC and the lineage of descended. Adult anxiety behaviors were mostly unaltered. Taken together, the findings from these studies suggest that exposure to EDCs during critical periods of development can result in multi- and transgenerational effects on behavior, physiology and neurobiology in a lineage and sex dependent manner. These results have implications for human and wildlife reproductive health, and could inform interventions for EDC exposures in the near future



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