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Access Type
WSU Access
Date of Award
January 2022
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Pharmacology
First Advisor
Tracie R. Baker
Second Advisor
Sokol Todi
Abstract
The developmental origins of health and disease (DOHaD) hypothesis provides a framework for understanding how exposure during critical windows of development differentially affects organisms based on timing of exposure.. Contaminants in the environment have long been known to harm developing organisms, including permanent damage to the reproductive system. Infertility is a global issue, affecting both those seeking to conceive and their societies at large. About half of infertility is male-driven, and is often idiopathic. One likely cause of idiopathic infertility is exposure to the many contaminants in the environment during early and juvenile development. Previous work in the field connected juvenile 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure to damaged semen quality in adult humans; this was repeated in the model organism the zebrafish (Danio rerio). It is largely unknown how contaminants affect future generations in humans, however, heritable effects of exposure have been recorded in the subsequent two unexposed generations of TCDD-exposed zebrafish, showcasing zebrafish as an excellent model for multi- and transgenerational research. In recent years, the zebrafish has also been employed to study the widespread, persistant per- and polyfluoroalyl substances (PFAS). PFAS readily cross the placental barrier, and pose a risk to developing fetuses. In this work, we used the zebrafish model to assess the reproductive health effects of early-life contaminant exposure at environmentally-relevant concentrations of TCDD and PFAS. We found that brief TCDD exposure is associated with increased testicular apoptosis years after exposure cessation, which may be caused by meiotic arrest; this may mechanistically explain the infertility phenotype observed in previous studies. PFAS exposure was not found to affect most reproductive outcomes. The main outcomes of PFAS exposure were gene expression dysregulation increasing in each future (unexposed) generation, including epigenomic-related genes and encompassing pathways relevant to reproduction; and behavioral changes in response to light and dark stimuli in every generation. Overall, the results suggest that some effects of early exposure to TCDD and PFAS are enduring and heritable across multiple generations. This work supports the belief that environmental contaminants can help explain idiopathic infertility, and supports remediation and investment in removing PFAS from the environment, and particularly from drinking water.
Recommended Citation
Haimbaugh, Alex, "Persistent Transcriptomic Effects Of Brief Developmental Exposure To Environmental Contaminants" (2022). Wayne State University Dissertations. 3671.
https://digitalcommons.wayne.edu/oa_dissertations/3671