Access Type

Open Access Dissertation

Date of Award

January 2025

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

Marianna Sadagurski

Abstract

Substantial evidence demonstrates that parental pollutant exposures can induce harmful health effects in the offspring, including the predisposition to Type II Diabetes. As rates of Type II Diabetes continue to rise in younger populations, a crucial gap lies in understanding the role of parental influence in the etiology of later-life metabolic disease. Therefore, the central goal of this work was to determine how early life exposure to smoking level benzene, an endocrine-disrupting air pollutant, affects the metabolic health of offspring, and to identify potential developmental mechanisms involved in disease susceptibility. This goal was achieved using two models of early life air pollution exposure in mice, the first during pregnancy to represent maternal in utero pollutant exposure, the second in adult male mice representing pre-conceptional pollutant exposure. First, we assessed the effects of gestational benzene exposure on offspring in early postnatal life and adulthood. In offspring of benzene-exposed dams, we identified sex-specific developmental impairments in the neural circuitry central to metabolic control, associated with a neuroinflammatory response. In adulthood, offspring exhibited whole-body metabolic dysfunction, further apparent at the transcriptional level. To gain a deeper understanding of the effects of gestational benzene on microglial developmental programming, we then examined the transcriptional profiles of microglia from postnatal-aged offspring. Transcriptomic analyses revealed that gestational benzene exposure modulated IGF-1-related inflammatory, myelination, and glucose homeostatic processes in both sexes, with further sex-specific developmental effects. Finally, we sought to determine the contribution of the father to pollutant-induced metabolic dysfunction in offspring. We found that male offspring of benzene-exposed fathers showed a predisposition to metabolic imbalance when challenged with poor diet in adulthood, through the inheritance of pollutant-altered transcriptional signatures passed through the germline. In summary, our findings reveal that parental exposure to the pollutant benzene predisposes offspring to the development of Type II Diabetes through early-life metabolic reprogramming. This work calls for efforts to reduce environmental pollution levels and prevent the negative impact of pollution on the health of future generations.

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