Date of Award

August 2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Environmental & Occupational Health

First Advisor

Michael J. Carvan III

Committee Members

Niladri Basu, Michael Laiosa, Kurt Svoboda, Peter Tonellato

Abstract

Methylmercury (MeHg) is an environmental neurotoxicant of global concern. It is considered one of the top ten chemicals of public health concern by the World Health Organization. Prenatal exposure to MeHg has been associated with altered neurodevelopment, neurobehavioral and neurocognitive functions. The effects of low dose MeHg exposure are more subtle and can range from impaired motor function to sensory defects. Using quantitative neurobehavioral assays and zebrafish as a model organism, our laboratory has demonstrated that developmental MeHg exposure causes neurological dysfunction in adult zebrafish. Recently, a wide range of environmental insults (e.g., pesticides, fungicides, plasticizers and endocrine disruptors) has been shown to induce disease phenotypes in individuals whose great grandparents were exposed to the toxicant. This phenomenon is known as transgenerational inheritance. To date, studies have shown that in transgenerational inheritance of diseases due to developmental exposure, heritable changes occurred in the epigenome not the genome and were transmitted to subsequent generations without further exposure. Based on this evidence, we hypothesized that ancestral developmental exposure to MeHg induces transgenerational neurobehavioral deficits in F3 generation zebrafish. The F1-generation zebrafish embryos (less than 4 hour post fertilization) were exposed to either 0, 0.001, 0.003, 0.01, 0.03 or 0.1 µM MeHg for 24 hrs. These concentrations of MeHg are sublethal and environmentally relevant. Quantitative neurobehavioral assays for visual startle response and locomotor activity were used to assess MeHg-induced neurotoxicity in F3 generation. Our study demonstrated that developmental exposure to MeHg induces transgenerational visual deficits and locomotor dysfunctions in zebrafish. Altered retinal electrophysiology was also observed in the transgenerational population with visual deficits. To identify the genes and pathways involved with the phenotypes observed in the transgenerational population, we analyzed the whole transcriptome of the brain and retina of the transgenerational lineage animals, using RNAseq. Tissue specific altered gene expression was observed in both brain and retina. This is the first evidence of a transgenerational transcriptome induced by ancestral developmental exposure to MeHg. Gene set enrichment analysis revealed the correlation between dysregulated functional pathways and the observed phenotypic variation, including vision, phototransduction, motor activity, and retinal electrophysiology. Our studies also identify that the mode of germline transmission varies between the transgenerational phenotypes. This research has identified new mechanisms associated with MeHg-induced phenotypes which may have significant impacts on public health, in terms of developing biomarkers to identify susceptible populations and developing preventative measures. The long term effects of MeHg observed in this study could be used to improve the awareness of reproductive age group women to monitor the type of fish that they consume. Since we observed the neurobehavioral deficits in a fish species, our findings have ecological impacts including the feeding behavior of fish, survival and reproduction. The findings made in this thesis also set the stage for future research into the identification of new transgenerational phenotypes associated with ancestral developmental exposure to MeHg.

Available for download on Saturday, October 14, 2017

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