Phthalate Exposures and Hormonal Disruption in Relation to Birth Outcomes

Abstract

Preterm birth affects 1 out of every 10 pregnancies in the United States and is one of the leading causes of infant death. Other negative birth outcomes, including preeclampsia and gestational diabetes, are associated with comorbidities for the mother and fetus later in life. Widespread exposures to environmental contaminants, such as phthalates, have been hypothesized as playing a casual role in the risk for adverse birth outcomes. Phthalates are endocrine disrupting chemicals, which interfere with hormone levels and regulation inside the body. Regulation of numerous endocrine pathways is essential for maintaining a healthy pregnancy. Exposures to phthalate chemicals may elicit an endocrine response deleterious to the pregnancy, resulting in elevated risk for adverse birth outcomes. This dissertation sought to investigate whether phthalate exposures were associated with disruption of various classes of hormone concentrations including thyroid and reproductive hormones, and whether hormone disruption mediated the association between exposure to mixtures of phthalate metabolites and adverse birth outcomes.

Aim 1 of this dissertation assessed associations between repeated measures of urinary phthalate metabolites and serum hormones in the PROTECT pregnancy cohort. In aim 1, we observed numerous significant associations between phthalate metabolites and hormones that were consistent based on molecular weight of the phthalate. Of note, low molecular weight metabolites were positively associated with testosterone while high molecular weight metabolites were inversely associated with testosterone, pointing to possible mechanistic differences. Aim 1 also revealed effect modification by timing of study visit and fetal sex across many observed associations, which showed phthalate exposure resulting in decreased hormone concentrations among pregnancies with a female fetus and increased hormone concentrations among pregnancies with a male fetus. Aim 2 investigated associations between repeated measures of hormone concentrations and adverse birth outcomes. Various associations were observed which highlighted the importance of progesterone, estriol, and thyroxine (T4). Progesterone was inversely associated with gestational age at birth, and thyroid hormones were positively associated with risk of spontaneous preterm birth. Few differences were observed by timing of study visit, but many differences were present between fetal sexes which suggested elevated risk of birth outcomes among male pregnancies with increases in most hormone concentrations. Finally, aim 3 explored the mediating effects of hormone concentrations on the associations between mixtures of phthalate metabolites and adverse birth outcomes. Among pregnancies with a male fetus, an interquartile range increase in the mixture of low molecular weight (LMW) metabolites was associated with increased odds of preterm birth at visit 2 (OR: 1.82, 95% CI: 1.01, 3.31) and with spontaneous preterm birth at visit 3 (OR: 2.74, 95% CI: 1.23, 6.13). We observed 17.3% of the association between LMW phthalate exposure at visit 3 and preterm birth was mediated by TSH. CRH, progesterone, and testosterone also mediated 28%, 18%, and 29% of the association between LMW phthalate exposure at visit 1 and spontaneous preterm birth.

Overall, this dissertation advances our understanding of the relationship between environmental phthalate exposure and risk of adverse birth outcomes. We have explored the possible mechanisms by which phthalates may elicit deleterious effects on pregnancy in an endocrine framework. Our findings may be useful in early detection of pregnancies at elevated risk for delivering preterm. Future work should seek to utilize higher case numbers of adverse pregnancy outcomes to substantiate these findings and to broaden our understanding of environmental endocrine disruption during pregnancy.