Phthalates, a class of synthetic chemicals with a wide spectrum of commercial uses, are ubiquitous endocrine disruptors, with demonstrated anti-androgenic properties. Past studies have shown an association between higher preconception exposure to phthalates and lower fertility in women; however, the biological mechanisms remain unclear. Our study aimed to utilize untargeted high-resolution metabolomics to identify serum metabolites and pathways associated with maternal preconception phthalate exposure. Our analysis included 184 women in the Environment and Reproductive Health (EARTH) study that underwent in vitro fertilization (IVF) at the Massachusetts General Hospital Fertility Center (2005-2016). On the same day during controlled ovarian stimulation, women provided a serum sample, which was analyzed for metabolomics using liquid chromatography coupled with high-resolution mass spectrometry and two chromatography columns, and a urine sample, which was analyzed for 11 phthalate metabolites. We used multivariable generalized linear models to identified metabolic features associated with urinary phthalate metabolite concentrations, followed by enriched pathway analysis. A total of 10,803 and 12,968 metabolic features were detected in the serum in the C18 negative and HILIC positive columns, respectively. Metabolic pathway enrichment analysis revealed 50 pathways in the C18 negative column and 50 pathways in the HILIC positive column that were significantly associated with at least one of the 11 urinary phthalate metabolites or molar sum of di-2-ethylhexyl phthalate metabolites (∑DEHP). The classes of pathways that were most often associated with phthalate exposure were lipid metabolism, amino acid metabolism, and oxidative stress. Our study provides further insight into the biological pathways, including lipid and amino acid metabolism and oxidative stress, that may be mediating the observed associations between phthalate exposures and lower fertility in women.
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