UC Irvine

ABSTRACT OF THESIS

Is there a Relationship Between Polycyclic Aromatic Hydrocarbon Exposure and Ovarian Reserve Markers in Humans?

by

Gillian Nelson, MD

Master of Science in Environmental Health Sciences

University of California, Irvine, 2016

Ulrike Luderer, MD, PhD, MPH, Chair

About 12% of American women suffer from infertility, and premature ovarian failure (POF) is a major cause of infertility. Most cases of POF are of unknown etiology. Environmental toxicants such as polycyclic aromatic hydrocarbons (PAHs) have been shown in animal models and human tissue cultures to destroy ovarian primordial follicles. The aim of this study is to assess whether PAH exposure is associated with diminished ovarian reserve in humans.

Hypotheses: Women with higher levels of PAH exposure will have decreased ovarian reserve compared to women with lower levels of PAH exposure. Women who have enzyme polymorphisms that alter Phase II metabolism of PAHs will have increased susceptibility to the ovarian toxicity of PAHs compared to women who do not have these polymorphisms.

Methods: This cross-sectional data analysis of a longitudinal study involved 51 women of reproductive age who resided in Orange County, California. Urinary monohydroxylated PAH metabolites (OH-PAHs) were used as biomarkers for exposure to PAHs. Anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH) and inhibin B served as markers of ovarian reserve. Null polymorphisms in the Phase II enzymes GSTT1 and GSTM1 were determined. Multiple linear regression models were generated and Principal Component Factor analysis with varimax rotation was used to assess co-linearity of the OH-PAHs. The OH-PAHs with the strongest associations with each of the ovarian reserve markers were forced into the regression models. Potential confounders identified in bivariate analyses were entered into the models and retained if they changed the beta coefficients for the OH-PAHs by 10% or more.

Results: Concentrations of urinary OH-PAHs in the study population were similar to those reported for women in the National Health and Nutrition Examination Survey (NHANES'). The OH-PAHs with the strongest associations with the ovarian reserve markers were 2-hydroxy naphthalene (NAP2) and 9-hydroxy fluorene (FLUO9) for the AMH model, 3- hydroxy fluorene (FLUO3) for the inhibin B model, and 3-hydroxy phenanthrene (PHEN3) for the FSH model. Factor analysis identified two factors that explained 37% and 63 % of the variation in the OH-PAHs, respectively. Factor 1 primarily loaded on 1-hydroxy phenanthrene (PHEN1), 2-hydroxy phenanthrene (PHEN2), PHEN3, and FLUO9. Factor 2 primarily loaded on 2-hydroxy fluorene (FLUO2), FLUO3, 1-hydroxy naphthalene (NAP1), and NAP2. In the final models, the beta coefficients for the OH-PAHs were in the expected direction (negative for AMH and inhibin B models and positive for the FSH model), but none of them was statistically significant at the P=0.05 level.

We examined effect modification by GSTM1 and GSTT1 null polymorphisms in stratified analyses. Our models revealed non-significant associations between OH-PAHs and ovarian reserve markers in the expected directions for the strata with ≥ 1 allele and no or opposite than expected associations for the strata with null alleles. However, the numbers in each stratum were very small.

Conclusions: Our findings are suggestive that environmental exposure to PAHs may be associated with decreased ovarian reserve. Larger studies are needed and could be conducted with techniques used in this pilot study.