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-hydroxyhexyl) phthalate (5OH-MEHP), 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. The metabolites 2cx-MMHP and 5oxo-MEHP were synthesized. To synthesize 5oxo-MEHP, an enolate alkylation was performed with methyl 5-hexenoate to form methyl 2-ethylhept-6-enoate. A reduction with LAH was then performed to produce 2-ethylhept-6-en-1-ol. This was then esterified with phthalic anhydride and subsequently oxidized to produce 5oxo-MEHP. This procedure was then repeated with methyl hexanoate and ethyl butyrate to synthesize 2cx-MMHP and 5cx-MEPP, respectively. Secondary-oxidized metabolite binding to PPARs will be measured using a thermal shift assay (TSA) to determine the metabolite with the greatest binding affinity to the nuclear receptors. The information gained surrounding the toxicity of DEHP and its metabolites may be extended to other phthalates and explain the endocrine-disrupting effects seen from exposure to phthalate plasticizers by addressing the fundamental question of their cellular targets.

Synthesis of the oxidative metabolites of di(2-ethylhexyl) phthalate and analysis of metabolite binding with peroxisome proliferator-activated receptors

ACS Fall 2020 Virtual Meeting

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