Metabolomic Markers of Phthalate Exposure in Plasma and Urine of Pregnant Women

Abstract

Phthalates are known endocrine disruptors and found in almost all people with several associated adverse health outcomes reported in humans and animal models. Limited data are available on the relationship between exposure to endocrine disrupting chemicals and the human metabolome. We examined the relationship of metabolomic profiles in plasma and urine of 115 pregnant women with eleven urine phthalate metabolites measured at 26 weeks of gestation to identify potential biomarkers and relevant pathways. Targeted metabolomics was performed by selected reaction monitoring liquid chromatography and triple quadrupole mass spectrometry to measure 415 metabolites in plasma and 151 metabolites in urine samples. We have chosen metabolites with the best defined peaks for more detailed analysis (138 in plasma and 40 in urine). Relationship between urine phthalate metabolites and concurrent metabolomic markers in plasma and urine suggested potential involvement of diverse pathways including lipid, steroid, and nucleic acid metabolism and enhanced inflammatory response. Most of the correlations were positive for both urine and plasma, and further confirmed by regression and PCA analysis. However, after the FDR adjustment for multiple comparisons, only 9 urine associations remained statistically significant (q-values 0.0001–0.0451), including Nicotinamide mononucleotide, Cysteine T2, Cystine, and L-Aspartic acid. Additionally, we found negative associations of maternal pre-pregnancy body mass index (BMI) with more than 20 metabolomic markers related to lipid and amino-acid metabolism and inflammation pathways in plasma (p = 0.01–0.0004), while Mevalonic acid was positively associated (p = 0.009). Nicotinic acid, the only significant metabolite in urine, had a positive association with maternal BMI (p = 0.002). In summary, when evaluated in the context of metabolic pathways, the findings suggest enhanced lipid biogenesis, inflammation and altered nucleic acid metabolism in association with higher phthalate levels. These results provide new insights into the relationship between phthalates, common in most human populations, and metabolomics, a novel approach to exposure and health biomonitoring.

Pregnancy lipidomic profiles and DNA methylation in newborns from the CHAMACOS cohort

“…We observed numerous associations of metabolomic markers involved in lipid and nucleic acid metabolism and the inflammatory response with both urinary phthalate metabolites and maternal BMI. This study aims to determine the association between maternal metabolomic profiles in pregnancy and child DNA methylation at birth, emphasizing metabolites enriched for lipid pathways that were confirmed as relevant in previous work in CHAMACOS [18]. This study will contribute to the growing body of evidence of the influence of the early life environment on epigenetic mechanisms.…”

“…In this study, we focused on maternal metabolites previously identified to be relevant to lipid biosynthesis, arachidonate enrichment and release, and inflammatory signaling [18]. The 92 plasma metabolites in the study included fatty acids, lysolipids, phospholipids, sphingolipids, monoacylglycerols, diacylglycerols, and triacylglycerols (Table 2, Figs 1 and 2).…”

“…In this study, we characterized the lipidomic profiles of pregnant women from the CHAMACOS cohort, building upon previous research that identified associations of metabolomic data with phthalates, endocrine disrupting chemicals, and maternal pre-pregnancy BMI [18]. We focused on maternal metabolite levels assessed around 26 weeks gestation, rather than at child delivery, due to the availability of existing metabolomic data and more importantly, to better capture exposures relevant during fetal development that could relate to newborn epigenetic profiles.…”

“…Biological samples collected from 115 CHAMACOS women around 26 weeks gestation (mean = 26.4, SD = 3.2) were analysed to characterize maternal metabolomics profiles during pregnancy. Detailed descriptions of the metabolomics analyses in the CHAMACOS cohort have been previously described in Zhou et al [18]. Briefly, blood from the women was analysed in duplicates by selected reaction monitoring (SRM) liquid chromatography and triple quadrupole mass spectrometry, a method previously validated by the Nomura research group [31].…”

“…Previous research in the CHAMACOS cohort examined the association between maternal prenatal phthalate urine metabolite levels and targeted metabolomic compounds present in plasma and urine, collected at 26 weeks gestation [18]. In addition, we assessed the relationship between pre-pregnancy body mass index (BMI) and maternal metabolomics profiles.…”