Graduation Year

2016

Document Type

Thesis

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Caralina Marín de Evsikova, Ph.D.

Committee Member

Burt Anderson, Ph.D.

Committee Member

Eric Bennett, Ph.D.

Committee Member

Robert Deschenes, Ph.D.

Keywords

obesogen, nematode, endocrine disruptor, bisphenol-A

Abstract

Obesity is a current epidemic in the United States. Greater than one third of adults and nearly one fifth of children are classified as obese (Ogden, 2014). Increased awareness of this problem has triggered interest into the potentially causal agents in our environment. These agents, termed obesogens, are a type of teratogen hypothesized to work during embryonic development by programming offspring to store excess fat. A type of teratogen, obesogens are also typically reprotoxic, affecting germline development and embryonic viability. These noxious teratogens span a variety of different chemical classes including estrogen mimics, metals and metalloids, biocides, and even voluntary exposures like cigarette smoke. The goal of this work is to use the soil nematode, Caenorhabditis elegans to model the reprotoxic and obesogenic events that take place as a result of chronic, low-dose exposure to these agents. C. elegans is especially well suited to this end. The organism has a straightforward biology, a short lifespan on the order of days, and relevant lipid metabolic gene homology to humans. We characterize here the resultant effects on egg-laying, hatching, and embryo viability after chronic parental exposure to obesogens. Through this, we are able to best recapitulate the low-dose exposure for our obesogen screen. Here, chronic, sub-lethal parental exposure to the obesogens screened yielded viable offspring that exhibited increased percentages of body area lipid stained and induced differences in stained lipid localization. Reduced pharyngeal pumping rates in two of our offspring groups highlights the potential for lasting changes on behavioral phenotype as well. Lastly, we employed phylogenetic guided analysis to functionally assess putative C. elegans nuclear hormone receptors (NHRs) to human Peroxisome Proliferator Activated Receptors (PPARs). These human PPARs have implications in lipid metabolism and obesity. We report here novel findings that NHR-85 and SEX-1 may act to repress lipid storage in the nematode, thereby serving as potential homologs of human PPARα. The results presented in this study highlight the lasting effects of chronic parental exposure to noxious environmental teratogens on the function of the reproductive system. Furthermore, the nematode can be used as an in vivo model to screen sublethal doses of these teratogens for their potential to act as obesogens. Bioinformatics guided analysis of C. elegans NHR homologs to human NHRs can continue to yield novel insight on this fat storage and its regulation in the nematode.

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