Date of Award

2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

John R. Kicklick

Second Advisor

John W. Brock

Third Advisor

Lori Cruze

Fourth Advisor

Roger B. Newman

Fifth Advisor

Bethany J. Wolf

Abstract

Phthalates are plasticizers commonly detected in humans due to widespread exposure from PVC plastics, food packaging, and personal care products. Several phthalates are known antiandrogens, raising concern for prenatal exposures during critical windows of fetal development. The goal of the research presented here is to 1) Determine if certain demographics have greater or lesser phthalate concentrations, 2) Evaluate associations between prenatal phthalate exposure and AGD, a marker of in utero androgen exposure, in newborns, and 3) Investigate the prevalence and bioactivity of a novel phthalate replacement, DINCH. We sampled urine from 378 pregnant women during the second trimester of pregnancy living in Charleston, SC and measured the following eight phthalate metabolites and three DINCH metabolites by LC-MS/MS: monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5- oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), monomethyl phthalate (MMP), cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester (OH- MINCH), cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester (oxo-MINCH), and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (cx-MINCH). We prospectively measured anopenile (APD) and anoscrotal (ASD) distances from 171 boys and anoclitoral (ACD) and anofourchette (AFD) distances from 128 girls at delivery. Sociodemographic factors and clinical data were collected from questionnaires and delivery records. DINCH estrogenic and progestogenic activity was measured using in vitro transactivation assays. Phthalate metabolites were detected in 100% and OH-MINCH was detected in 98% of urine samples. Sociodemographic characteristics associated with elevated phthalate concentrations included being unmarried, less educated, having a low income, higher BMI, and/or being African American. We identified inverse associations between phthalates and APD among boys and a longer ASD with higher concentrations of four phthalates, without evidence for racial interaction. Among girls, we found no association for AFD, but detected racial interactions, in which ACD was longer for Caucasians and shorter for African Americans, following exposure to four phthalate metabolites. DINCH metabolites did not exhibit estrogenic or progestogenic activity. Results from this study provide evidence for significant racial and demographic variations in phthalate exposure. Our findings also suggest race and sex play important roles in phthalate-associated reproductive developmental toxicity. Finally, phthalates are being replaced by alternatives whose safety has not been thoroughly investigated.

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