SAT-140 - Evaluating the Roles of Elevated Cholesterol in the Associations of per- and Polyfluoroalkyl Substances with Sex-Steroid Hormones in Pregnancy

Background: We and others have previously reported that per- and poly-fluoroalkyl substances (PFAS) are associated with elevated cholesterol and sex-steroid hormones in pregnancy. To understand how these disruptions are related, we applied a causal mediation framework to evaluate whether associations of PFAS with elevated sex-steroid hormones in pregnancy can be partly explained by elevated cholesterol in response to PFAS exposure.

Methods: Pregnant women (n=488) from Illinois provided fasted blood samples at median 17 weeks gestation, in which we quantified seven serum PFAS and measured plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, estradiol, progesterone, and testosterone. We calculated low-density lipoprotein (LDL) cholesterol from total cholesterol, HDL cholesterol, and triglycerides using established methods. To further support the basis of mediation analyses, covariate-adjusted multivariable linear regression models accounting for sociodemographic, lifestyle, and health factors first evaluated associations of maternal cholesterol with sex-steroid hormones. Using a formal mediation framework, we assessed whether associations of PFAS with elevated cholesterol partially explained associations of PFAS with elevated sex-steroid hormones.

Results: In this sample of primarily non-Hispanic White women with relatively high socioeconomic status, each doubling of total cholesterol was associated with 0.2% (95% confidence interval (CI): 0.1, 0.3) and 0.3% (95%CI: 0.2, 0.5) higher progesterone and estradiol, respectively. Similarly, each doubling of HDL cholesterol was associated with 0.2% (95%CI: 0.1, 0.3) and 0.3% (95%CI: 0.1, 0.4) higher progesterone and estradiol, respectively. In line with our prior findings that PFOS was associated with higher total cholesterol, HDL, progesterone, and estradiol, in formal causal mediation analyses, we observed that 21.9% of the positive association of PFOS with estradiol was explained by the association of PFOS with higher total cholesterol (total effect, %: 0.09, 95%CI: 0.03, 0.15; indirect effect, %: 0.02, 95%CI: 0.00, 0.04), but not HDL cholesterol. The association of PFOS with progesterone was not explained by total cholesterol or HDL cholesterol.

Conclusions: Our findings suggest associations of PFOS with elevated estradiol concentrations in pregnancy could be partially explained via elevated availability of cholesterol as a substrate for sex-steroid synthesis. Further studies are needed to understand the consequences of these disruptions for maternal and child health.

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