Exposure to environmental pollutants, particularly during pregnancy, can have adverse consequences on child development but little is known about the effects of pollutant mixtures on endogenous metabolism in pregnant women. We aimed to identify urinary metabolic signatures associated with low level exposure to multiple environmental pollutants in pregnant women from the INMA (INfancia y Medio Ambiente) birth cohort (Spain, N = 750). 35 chemical exposures were quantified in first trimester blood samples (organochlorine pesticides, PCBs, PFAS), in cord blood (mercury), and twice in urine at 12 and 32 weeks of pregnancy (metals, phthalates, bisphenol A). 1H nuclear magnetic resonance (NMR) metabolic profiles of urine were acquired in the same samples as pollutants. We explored associations between exposures and metabolism through an exposome-metabolome wide association scan and multivariate O2PLS modeling. Novel and reproducible associations were found across two periods of pregnancy for three nonpersistent pollutants and across two subcohorts for four of the persistent pollutants. We found novel metabolic signatures associated with arsenic exposure: TMAO and dimethylamine possibly related to gut microbial methylamine metabolism and homarine related to fish intake. Tobacco smoke exposure was related to coffee metabolism and PCBs with 3-hydroxyvaleric acid, usually released under ketoacidosis. These findings will have implications for further understanding of maternal-fetal health, and health across the life-course.

This work was supported by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 308333–the HELIX project, the Medical Research Council Integrative Toxicology Training Partnership (ITTP) through a PhD studentship (recipient LM), an MRC-ITTP career development fellowship (recipient MC), an MRC early career fellowship (recipient OR), and the Medical Research Council–Public Health England (MRC-PHE) Centre for Environment and Health (MR/L01341X/1). The subcohort studies were funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, FIS-PI06/0867, FIS-PS09/00090 and FIS-PI13/02187), Generalitat de Catalunya-CIRIT 1999SGR 00241, Department of Health of the Basque Government (2005111093, 2009111069, and 2013111089), and the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001). Convenios anuales con los ayuntamientos de la zona del estudio (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). We thank Olivier Cloarec and Ekaterina (Katya) Nevedomskaya for developing the in-house script to perform O2PLS models.