Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Marisa S. Bartolomei

Abstract

Early life environment can impact disease risk later in life, a concept known as the developmental origins of health and disease (DOHaD). Furthermore, the effects may persist across several generations of offspring. The underlying molecular dysregulation driving these phenotypes, however, remain unknown. Using the ubiquitous endocrine disrupting chemical (EDC) bisphenol A (BPA) as a model estrogen, we investigated the physiological and molecular consequences of chronic, low-dose developmental BPA exposure across the lifespan, using a mouse model system. To assess the transmission of phenotypes across generations, we examined physiological endpoints across two generations of offspring in each study. In Chapter 2, we report a depressive-like behavioral phenotype in BPA-exposed offspring that is exclusive to males in the first filial (F1) generation. Molecular assessments in the adult hippocampus using RNA-sequencing and HPLC revealed sex-specific reductions in the neurotransmitter serotonin, a critical regulator of mood. Additionally, levels of dehydroepiandrosterone, a sex steroid intermediate, were reduced in serum and hippocampal tissue, which could also explain the observed behavioral changes. In Chapter 3, we report impaired metabolic health in F1 and F2 generation adult male offspring that may be partially due to increased expression of the imprinted insulin-like growth factor 2 (Igf2) gene. Gestational glucose intolerance could also be contributing to the phenotype in F1, but not F2, generation offspring. Finally, in Chapter 4, we describe our early findings on BPA exposure-associated skeletal changes. Developmental BPA exposure is associated with thinner and weaker bones in F1 male mice, while F2 males exhibit an adaptive response. Whether the sex-specific phenotypes reported in these studies manifest at a younger age, prior to puberty, remains an ongoing area of study. Taken together, work in this dissertation demonstrates sex-, dose- and generation-specific effects associated with early life BPA exposure. Understanding the exposure-associated effects and mechanism(s) of BPA and other EDC actions is critical for assessing chemical safety. Identifying dysregulated pathways may also allow for targeted intervention strategies to reduce or prevent EDC exposure-associated effects. Ultimately, findings from these studies and others utilizing models representative of human exposure may aid in future regulatory decision-making.

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Supplemental Dataset 1.xls (5822 kB)

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