Phenotypes and mechanisms of epigenetic transgenerational inheritance due to prenatal exposure of endocrine disrupting chemicals




Gillette, Ross

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Nearly 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.


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