Date of Award

Fall 12-11-2020

Document Type

Honors Project

Degree Name

Bachelor of Science

Department

Chemistry and Physics

Department Chair or Program Director

Asper, Janet

First Advisor

Oldham, Davis E.

Major or Concentration

Biochemistry

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a persistent organic pollutant that is added to increase the flexibility of soft plastics, such as polyvinyl chloride (PVC). Since DEHP is not bound to the polymer, it leaches into the environment, leading to human exposure. When DEHP is metabolized by the body, it is cleaved into mono-(2-ethylhexyl) phthalate (MEHP). MEHP is then oxidized to produce the secondary-oxidized metabolites mono-(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP), mono-(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP), and mono-[2-(carboxymethyl)hexyl]phthalate (2cx-MMHP). DEHP and its metabolites interact with peroxisome proliferator-activated receptors (PPARs), which can alter lipid metabolism. To synthesize 5cx-MEHP, an enolate alkylation was performed with ethyl butyrate to form ethyl 2-ethyl-6-heptenoate. A reduction with LiAlH4 was performed to produce 2-ethyl-6-hepten-1-ol. The alcohol was esterified with phthalic anhydride and subsequently oxidized to produce 5cx-MEHP. This procedure was then repeated to synthesize 2cx-MMHP and 5oxo-MEPP, replacing the enolate alkylation with a malonic ester alkylation and modifying the final oxidation. Binding of the metabolites of DEHP to PPARγ can be assessed using a thermal shift assay. A protocol for the thermal shift assay was developed using the binding of PPARγ and rosiglitazone, a known PPARγ ligand. The information gained surrounding the binding of DEHP and its metabolites to PPARγ may explain the endocrine-disrupting effects seen from exposure to phthalate plasticizers by addressing the fundamental question of their cellular targets.

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