# Association of Prenatal Exposure to Endocrine-Disrupting Chemicals With Liver Injury in Children

## TL;DR

Exposure to endocrine-disrupting chemicals during pregnancy is linked to increased risk of liver injury and cell damage in children.

## Contribution

This study is the first to investigate the association between prenatal EDC exposure and hepatocellular apoptosis in children.

## Key findings

- Prenatal exposure to EDC mixtures increases the risk of liver injury in children.
- Higher CK-18 levels were associated with prenatal exposure to polychlorinated biphenyls and PBDEs.
- Phenols and high-molecular-weight phthalates were linked to decreased odds of liver injury.

## Abstract

Is prenatal exposure to endocrine-disrupting chemicals (EDCs) associated with liver injury and hepatocellular apoptosis in school-aged children?

In the Human Early-Life Exposome population-based cohort study of 1108 mother-child pairs from 6 European countries, prenatal exposures to EDC mixtures, including organochlorine pesticides, polybrominated diphenyl ethers, perfluoroalkyl substances, and metals, significantly increased the risk for liver injury and/or hepatocellular apoptosis in school-aged children.

These findings suggest that exposure to mixtures of EDCs during the sensitive pregnancy period may increase the risk for liver injury and hepatocellular apoptosis in childhood, potentially contributing to the current epidemic of pediatric nonalcoholic fatty liver disease.

Prenatal exposures to endocrine-disrupting chemicals (EDCs) may increase the risk for liver injury in children; however, human evidence is scarce, and previous studies have not considered potential EDC-mixture effects. Furthermore, the association between prenatal EDC exposure and hepatocellular apoptosis in children has not been studied previously.

To investigate associations of prenatal exposure to EDC mixtures with liver injury risk and hepatocellular apoptosis in childhood.

This prospective cohort study used data collected from April 1, 2003, to February 26, 2016, from mother-child pairs from the Human Early-Life Exposome project, a collaborative network of 6 ongoing, population-based prospective birth cohort studies from 6 European countries (France, Greece, Lithuania, Norway, Spain, and the UK). Data were analyzed from April 1, 2021, to January 31, 2022.

Three organochlorine pesticides, 5 polychlorinated biphenyls, 2 polybrominated diphenyl ethers (PBDEs), 3 phenols, 4 parabens, 10 phthalates, 4 organophosphate pesticides, 5 perfluoroalkyl substances, and 9 metals.

Child serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and CK-18 were measured at 6 to 11 years of age. Risk for liver injury was defined as having ALT, AST, and/or GGT levels above the 90th percentile. Associations of liver injury or cytokeratin 18 (CK-18) levels with each chemical group among the 45 EDCs measured in maternal blood or urine samples collected in pregnancy were estimated using 2 complimentary exposure-mixture methods: bayesian weighted quantile sum (BWQS) and bayesian kernel machine regression.

The study included 1108 mothers (mean [SD] age at birth, 31.0 [4.7] years) and their singleton children (mean [SD] age at liver assessment, 8.2 [1.6] years; 598 [54.0%] boys). Results of the BWQS method indicated increased odds of liver injury per exposure-mixture quartile increase for organochlorine pesticides (odds ratio [OR], 1.44 [95% credible interval (CrI), 1.21-1.71]), PBDEs (OR, 1.57 [95% CrI, 1.34-1.84]), perfluoroalkyl substances (OR, 1.73 [95% CrI, 1.45-2.09]), and metals (OR, 2.21 [95% CrI, 1.65-3.02]). Decreased odds of liver injury were associated with high-molecular-weight phthalates (OR, 0.74 [95% CrI, 0.60-0.91]) and phenols (OR, 0.66 [95% CrI, 0.54-0.78]). Higher CK-18 levels were associated with a 1-quartile increase in polychlorinated biphenyls (β, 5.84 [95% CrI, 1.69-10.08] IU/L) and PBDEs (β, 6.46 [95% CrI, 3.09-9.92] IU/L). Bayesian kernel machine regression showed associations in a similar direction as BWQS for all EDCs and a nonlinear association between phenols and CK-18 levels.

With a combination of 2 state-of-the-art exposure-mixture approaches, consistent evidence suggests that prenatal exposures to EDCs are associated with higher risk for liver injury and CK-18 levels and constitute a potential risk factor for pediatric nonalcoholic fatty liver disease.

This population-based multinational cohort study investigates the association of the prenatal exposure to endocrine-disrupting chemicals with pediatric liver injury and hepatocellular apoptosis among mother-child pairs.