Browsing by Subject "Vinclozolin"
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Item An integrative analysis of the multi- and transgenerational effects of endocrine-disrupting chemicals on behavior and neurobiology(2018-05) Krishnan, Krittika; Gore, Andrea C., 1964-; Crews, David P; Hofmann, Hans A; Champagne, Frances AEndocrine-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 futureItem Endocrine-disrupting chemicals alter embryonic brain development and adult neurobehavioral phenotypes(2020-04-28) Hernandez, Morgan Elizabeth; Gore, Andrea C., 1964-; Crews, David; Dominguez, Juan; Champagne, Frances; Melamed, EstherEndocrine-disrupting chemicals are detectable in nearly every environment on the planet. Humans and wildlife are exposed to myriad of these pollutants throughout their life. Because these chemicals interfere with hormone systems in the body, exposure to them during early life development can have a severe impact on later neurobiological and reproductive health. In this dissertation, I investigated how prenatal exposure to two specific EDCs affected the organization of the embryonic brain and changed neuromolecular and behavioral phenotypes in adulthood. The weakly estrogenic mixture of polychlorinated biphenyls (PCBs), Aroclor 1221 (A1221), and the antiandrogenic fungicide vinclozolin (VIN) offer insight through their different mechanisms of interrupting normal endocrine function. I hypothesized that these chemicals would affect the brain and behavior of adult rats in a sex- and compound-specific manner. The first study in this dissertation demonstrates that prenatal exposure to these EDCs can disrupt an important sociosexual behavior in adult rats together with changes in the patterns of expression of associated genes. More specifically, in a test of sociosexual preference, adult rats failed to demonstrate the sex-typical preference for a mate after prenatal exposure to PCBs or VIN in males, and PCBs in females. The second study extends the previous findings by probing for deficits in the ability to distinguish between and/or prefer odorants that convey information about a mate’s fitness, i.e., hormonal status. I deduced that while changes to odor preference strongly resemble the mate preference phenotype, odor discrimination ability is not impaired. However, the activation of the ventrolateral portion of the ventromedial nucleus, a brain region known to regulate mate preference behavior, was altered by PCB exposure in females, suggesting that improper central processing of odor signals may explain some of the results. In the third study, I found that PCB exposure shifted the timing of the hormone-sensitive process of embryonic neurogenesis in the ventromedial nucleus but not the preoptic area. Taken together, these studies demonstrate a possible mechanism by which an EDC can change brain organization and functionally transfer the effects of a prenatal exposure into adulthood.Item Phenotypes and mechanisms of epigenetic transgenerational inheritance due to prenatal exposure of endocrine disrupting chemicals(2018-05) Gillette, Ross; Crews, David; Gore, Andrea C; Atkinson, Nigel S; McCarrey, John RNearly all humans and animals carry a measurable body burden of endocrine disrupting chemicals (EDCs), which interfere with or alter endogenous hormone signaling and cause various disease phenotypes depending on their composition, dose, and period of exposure. Furthermore, EDCs impart deleterious phenotypes on multiple generations without subsequent exposure. The inheritance of diseased phenotypes is believed to be the result of heritable mutations to the epigenome (epimutations) within the germline. It is essential that we understand how EDC exposure affects mammals and that we identify the mechanisms responsible for inheritance. It is the goal of this dissertation to describe and test the phenotypes associated with the transgenerational inheritance of epimutations due to two representative but common categories of EDCs; estrogenic – polychlorinated biphenyls (PCBs) and anti-androgenic – vinclozolin. To achieve this, I used a multidisciplinary and systems biology approach across animal behavior, physiology, brain metabolism, neural gene expression, and genetic sequencing. Pregnant dams were injected with vinclozolin, PCBs, or a vehicle control during mid to late gestation. The resulting generation was bred to obtain the F2 and F3 generation without further exposure. To understand how a diseased past might interact with a troubled present, ancestral EDC exposure was challenged with chronic restrain stress (CRS) during puberty. Last, both male and female animals were subjected to treatment to determine how development and different hormonal milieus altered the outcome. I found that ancestral exposure to vinclozolin decreased anxiety behavior, increased body weight, and altered the metabolic capacity of brain nuclei involved in anxiety behaviors. Exposure to CRS often exacerbated these effects. Gene expression analysis within discrete nuclei of the brain identified neural proliferation factors, thermoregulatory genes, and epigenetic machinery was altered by ancestral vinclozolin exposure. Males and females differed in their response to ancestral vinclozolin exposure and CRS; the hippocampus is more vulnerable in females and the amygdala is more vulnerable in males. Prenatal PCB exposure increased body weight in males and females but only affected anxiety behavior in males. Last, direct and ancestral exposure to vinclozolin and PCBs caused epimutations in the germline and brain of males. Substantial over lap in the affected sites suggest a common mechanism of interaction between EDCs and the epigenome.Item The effects of gestational exposure to endocrine-disrupting chemicals on the adult social behavior in male and female rats(2018-06-13) Reilly, Michael Patrick; Gore, Andrea C., 1964-; Crews, David; Vasquez, Karen; Dominguez, Juan; Richburg, JohnEndocrine disrupting chemicals (EDC) exposures during critical periods of development influence neuronal development and the manifestation of sexually dimorphic behaviors that emerge in adulthood. Among these behaviors, social information processing is sexually dimorphic and regulated by sex steroids. Oxytocin and vasopressin serve as primary neurotransmitters mediating these behaviors; these neuroendocrine circuits are hormone sensitive and potential targets of prenatal EDC exposures. In dissertation, I assess the effects of gestational exposure to EDCs on the social behavior of male and females later in adulthood. A weakly estrogenic PCB mixture, Aroclor 1221, was administered to pregnant Sprague-Dawley rat dams during the time when the hypothalamus undergoes sexual differentiation. The brains of these animals were also used to quantify the presence of oxytocin or vasopressin in the two main regions of production: the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). Another experiment extended this treatment paradigm to encompass a longer period of gestational development, added another EDC treatment group (Vinclozolin), and looked at similar behavioral outcomes. Lastly, I provide a novel way of modeling complex social behaviors in a laboratory setting. Through all of this work, we show that the sexes are differentially susceptible to endocrine disruption by PCBs or vinclozolin. Additionally, we provide evidence that the traditional choice models of social behavior in the rodent may not be reflective of how an animal behaves in a more complex, naturalistic, environment.