Male urinary phthalate metabolite concentrations and serum metabolic signatures in relation to live birth among couples undergoing in vitro fertilization.

Phthalate exposure has been linked to reduced fertility in men and poorer reproductive outcomes among couples attending a fertility center. However, the potential biological mechanisms explaining these associations remain unclear. We examined the associations between urinary phthalates and serum metabolic perturbations and whether these metabolomic pathways were related to live birth. We hypothesized that some urinary phthalates will be associated with serum metabolites and live birth. In this observational study, we prospectively evaluated 115 couples undergoing in vitro fertilization (2004-2017). Men provided a serum and urine sample on the same day. The serum was analyzed for metabolomics using liquid chromatography coupled with high-resolution mass spectrometry and two chromatography columns. The urine sample was analyzed for 11 phthalate metabolites using targeted approaches. We used multivariable generalized linear models to identified serum metabolic features associated with urinary phthalate metabolites and, in separate models, also associated with live birth, followed by enriched pathway analysis. We then used a meet-in-the-middle approach to identify overlapping pathways and features. Pathway enrichment analysis revealed 41 pathways in the C18 column and 30 pathways in the HILIC column that were associated with at least one of the 11 urinary phthalates or molar sum of di-2-ethylhexyl phthalate metabolites. Overall, we observed that some phthalates were mostly associated with pathways involved in lipid, amino acid, DNA, carbohydrate and vitamin metabolisms among these men. Furthermore, several amino acid metabolism pathways (arginine and proline, lysine and urea cycle/amino group metabolisms) were associated with both live birth and at least one phthalate metabolite. We also observed that male serum sucrose was higher among men with higher urinary MEP concentrations and higher among men whose IVF cycles ended in live birth. Our study provides further insight into the serum metabolites and metabolomics pathways that may underlie the observed negative associations between male phthalate exposures and clinical fertility endpoints such as IVF success rates.