Background and Aims Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on liver injury limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver injury and effect modification by folic acid (FA) supplementation in mother-child pairs. Methods We studied ~200 mother-child pairs from the Mexican PROGRESS cohort, with measured 43 MDCs during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide [OP] metabolites), and serum liver enzymes (ALT, AST) at ~9 years post-parturition. We defined liver injury as elevated liver enzymes in children, and using established clinical scores for steatosis and fibrosis in mothers (i.e., AST:ALT, FLI, HSI, FIB-4). Bayesian Weighted Quantile Sum regression assessed MDC-mixture associations with liver injury outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. Results In children, many MDC-mixtures were associated with liver injury outcomes. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95%CI: 1.67%, 19.4%) and AST by 5.27% (95% CI: 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations (p-interactions<0.05). In mothers, only the LMWP-mixture was associated with liver injury [OR=1.53 (95%CI: 1.01, 2.28) for HSI>36, and OR=1.62 (95%CI: 1.05, 2.49) for AST:ALT<1]. In mothers and children, most associations were attenuated (null) at FA supplementation≥600mcg/day (p-interactions<0.05). Conclusions Pregnancy MDC exposures may increase liver injury risk, particularly in children. These associations may be attenuated by higher FA supplementation and maternal cobalt levels.

The authors have declared no competing interest.

This study was supported by grants from the National Institute of Environmental Health Sciences: R01ES033688, R21ES035148 and P30ES023515. Additional funding from NIEHS included R01ES035773 (PI: Valvi); R01ES032242, R01ES034521 (PI: Colicino); R01ES013744, R24ES028522, R01ES014930, U2CES026561, R01ES026033 (PI: Wright); R35ES030435, U2CES030859, R01ES026033 (PI: Arora); R01ES032552 (PI: Oulhote).

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This study was approved by the Institutional Review Boards of Icahn School of Medicine at Mount Sinai (US) and the National Institute of Public Health (Mexico).

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