Access Type

Open Access Dissertation

Date of Award

January 2021

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmacology

First Advisor

Tracie Baker

Abstract

The environmental presence of toxicants such as persistent organic pollutants, heavy metals, and contaminants of emerging concern is estimated to contribute to over 2 million deaths worldwide and health care costs ranging from ~3-9% of total global expenditures yearly. Many of the above toxicants are classified as endocrine-disrupting chemicals capable of interfering with endogenous hormonal function at environmentally relevant levels. Exposures during sensitive developmental windows can lead to reproductive, neurodevelopmental, and metabolic dysfunction that can last across the lifespan and/or be passed down to future generations. Such long-term effects remain to be well-understood; therefore, we modeled the effects of various developmental toxicant exposures in zebrafish (Danio rerio), a vertebrate fish with fully-sequenced genome, rapid development, and short generation time. Previous work found that sublethal juvenile TCDD exposure resulted in transgenerational male-mediated infertility (F0-F2 generations); subsequent analysis of testicular histology revealed a shift in the proportion of germ cells towards immature spermatogonia in F0 and F1 males, as well as altered transcriptomic pathways related to infertility in the testes of F0-F2 fish. Exploring the underlying epigenetic factors driving this inheritance revealed site-specific alterations in F0 DNA methylation, with many linked to reproductive and epigenetic genes; however, there was no change in global methylation and minimal overlap between differentially expressed and differentially methylated genes. We also reported transgenerational outcomes of developmental exposure to a different toxic and persistent pollutant; lead exposure from 2-24 hours post fertilization resulted in previously characterized avoidance learning deficits in F0 and F2 adults. Examining the transcriptomic profile of F2 adult brains revealed both sex-specific and overall dysregulation in ancestrally lead-exposed fish. Multiple targeted pathways were involved in neurogenesis, learning, memory, and synaptic function in addition to endocrine function and epigenetic modification. The third contaminant is one of recent concern: as the presence of plastic waste and personal care products containing microplastics increases environmentally, the potential health effects on ubiquitously exposed wildlife and humans deserve investigation. We exposed larval zebrafish to a range of concentrations (1-10,000 parts per billion) of 50 or 200 nm fluorescent polystyrene nanoplastics, assessing a variety of developmental endpoints. Accumulation of nanoplastics was visible in the liver, gastrointestinal tract, and cranial region at 5 dpf for both 50 and 200 nm nanoplastics, while only the 200 nm plastics induced larval hyperactivity or altered the larval transcriptome. Affected pathways involved neuromuscular activity, neuronal development, metabolic, cardiac, and hepatic function, gastrointestinal homeostasis, and epigenetic regulation; all of which make excellent goals for further later-life and multigenerational studies. In conclusion, these novel data on the generational and developmental effects of both persistent and emerging contaminants will be a useful foundation supporting future mechanistic and intervention-based investigations into environmentally induced disease.

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