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. 2022 Jul 1;5(7):e2220176.
doi: 10.1001/jamanetworkopen.2022.20176.

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

Vishal Midya  1 , Elena Colicino  1 , David V Conti  2 , Kiros Berhane  3 , Erika Garcia  2 , Nikos Stratakis  2 , Sandra Andrusaityte  4 , Xavier Basagaña  5   6   7 , Maribel Casas  5   6   7 , Serena Fossati  5   6   7 , Regina Gražuleviciene  4 , Line Småstuen Haug  8 , Barbara Heude  9 , Léa Maitre  5   6   7 , Rosemary McEachan  10 , Eleni Papadopoulou  8 , Theano Roumeliotaki  11 , Claire Philippat  12 , Cathrine Thomsen  8 , Jose Urquiza  5   6   7 , Marina Vafeiadi  11 , Nerea Varo  13 , Miriam B Vos  14 , John Wright  10 , Rob McConnell  2 , Martine Vrijheid  5   6   7 , Lida Chatzi  2 , Damaskini Valvi  1
Affiliations

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

Vishal Midya et al. JAMA Netw Open. .

Abstract

Importance: 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.

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

Design, setting, and participants: 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.

Exposures: 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.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Colicino reported receiving grants from the National Institute of Environmental Health Sciences (NIEHS) during the conduct of the study. Dr Conti reported receiving grants from the NIEHS during the conduct of the study. Dr Berhane reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Stratakis reported receiving grants from the Ministry of Science and Innovation and State Research Agency through the Centro de Excelencia Severo Ochoa 2019-2023 Program and the European Union NextGeneration European Pollutant Release and Transfer Register during the conduct of the study. Dr McEachan reported receiving grants from the Horizon 2020: Human Early-Life Exposome (HELIX) project. Dr Vos reported receiving grants from Target Real World Solutions and personal fees from ProSciento, Takeda Pharmaceutical Company Limited, Boehringer Ingelheim, and Eli Lilly and Company outside the submitted work. Dr McConnell reported receiving grants from the NIH during the conduct of the study. Dr Vrijheid reported receiving grants from the European Commission during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Prenatal Endocrine-Disrupting Chemical (EDC) Concentrations and Correlation Plot
Error bars indicate 2*SE log (base = 2) concentration. As indicates inorganic arsenic; BPA, bisphenol A; BUPA, N-butyl paraben; Cd, cadmium; Co, cobalt; Cs, caesium; Cu, copper; DDE, dichlorodiphenyldichloroethylene; DDT, dichlorodiphenyltrichloroethane; DEP, diethyl phthalate; DETP, diethyl thiophosphate; DMP, dimethyl phthalate; DMTP, dimethylthiophosphate; ETPA, ethyl paraben; HCB, hexachlorobenzene; Hg, mercury; HMWPs, high-molecular-weight phthalates; LMWPs, low-molecular-weight phthalates; MBzP, monobenzylphthalate; MECPP, methylerythritol cyclodiphosphate; MEHHP, mono(2-ethyl-5-hydroxyhexyl) phthalate; MEHP, mono-2-ethylhexyl phthalate; MEOHP, mono(2-ethyl-5-oxohexyl) phthalate; MEP, monoethyl phthalate; MEPA, methyl paraben; MiBP, mono-iso-butyl phthalate; Mn, manganese; MnBP, mono-n-butyl phthalate; Mo, molybdenum; OC, organochlorine; OHMiNP, mono-hydroxy-isononyl phthalate; OP, organophosphate; OXBE, oxybenzone; OXOMiNP, mono-oxo-isononyl phthalate; Pb, lead; PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; PFASs, perfluoroalkyl substances; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoic acid; PFOA, perfluoro-octanoic acid; PFOS, perfluoro-octane sulfonate; PFUnDA, perfluoroundecanoic acid; PRPA, propyl paraben; and TCS, triclosan.
Figure 2.
Figure 2.. Forest Plots and Estimated Posterior Weights of Exposure-Mixture Groups on Liver Injury and Cytokeratin 18 (CK-18) Levels Using the Bayesian Weighted Quantile Sum Method
Within an exposure-mixture group, the estimated weights total 1, implying relative contribution of each exposure to the overall group association. Blue horizontal lines for the estimated weights denote expected weights if all chemicals within a group contributed equally to the exposure mixture. All models were adjusted for subcohort, maternal age, maternal prepregnancy body mass index, maternal educational level, parity, child sex, and child age. As indicates inorganic arsenic; BPA, bisphenol A; BUPA, N-butyl paraben; Cd, cadmium; Co, cobalt; Cs, caesium; Cu, copper; DDE, dichlorodiphenyldichloroethylene; DDT, dichlorodiphenyltrichloroethane; DEP, diethyl phthalate; DETP, diethyl thiophosphate; DMP, dimethyl phthalate; DMTP, dimethylthiophosphate; ETPA, ethyl paraben; HCB, hexachlorobenzene; Hg, mercury; HMWPs, high-molecular-weight phthalates; LMWPs, low-molecular-weight phthalates; MBzP, monobenzylphthalate; MECPP, methylerythritol cyclodiphosphate; MEHHP, mono(2-ethyl-5-hydroxyhexyl) phthalate; MEHP, mono-2-ethylhexyl phthalate; MEOHP, mono(2-ethyl-5-oxohexyl) phthalate; MEP, monoethyl phthalate; MEPA, methyl paraben; MiBP, mono-iso-butyl phthalate; Mn, manganese; MnBP, mono-n-butyl phthalate; Mo, molybdenum; OC, organochlorine; OHMiNP, mono-hydroxy-isononyl phthalate; OP, organophosphate; OXBE, oxybenzone; OXOMiNP, mono-oxo-isononyl phthalate; Pb, lead; PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; PFASs, perfluoroalkyl substances; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoic acid; PFOA, perfluoro-octanoic acid; PFOS, perfluoro-octane sulfonate; PFUnDA, perfluoroundecanoic acid; PRPA, propyl paraben; and TCS, triclosan.
Figure 3.
Figure 3.. Forest Plots and Scaled Posterior Inclusion Probabilities (PIPs) of Exposure-Mixture Groups for Liver Injury and Cytokeratin 18 (CK-18) Levels Using the Bayesian Kernel Machine Regression (BKMR) Method
Blue horizontal lines in the BKMR models denote expected scaled PIPs if all chemicals within a group were included equally while estimating mixture associations. As indicates inorganic arsenic; BPA, bisphenol A; BUPA, N-butyl paraben; Cd, cadmium; Co, cobalt; Cs, caesium; Cu, copper; DDE, dichlorodiphenyldichloroethylene; DDT, dichlorodiphenyltrichloroethane; DEP, diethyl phthalate; DETP, diethyl thiophosphate; DMP, dimethyl phthalate; DMTP, dimethylthiophosphate; ETPA, ethyl paraben; HCB, hexachlorobenzene; Hg, mercury; HMWPs, high-molecular-weight phthalates; LMWPs, low-molecular-weight phthalates; MBzP, monobenzylphthalate; MECPP, methylerythritol cyclodiphosphate; MEHHP, mono(2-ethyl-5-hydroxyhexyl) phthalate; MEHP, mono-2-ethylhexyl phthalate; MEOHP, mono(2-ethyl-5-oxohexyl) phthalate; MEP, monoethyl phthalate; MEPA, methyl paraben; MiBP, mono-iso-butyl phthalate; Mn, manganese; MnBP, mono-n-butyl phthalate; Mo, molybdenum; OC, organochlorine; OHMiNP, mono-hydroxy-isononyl phthalate; OP, organophosphate; OXBE, oxybenzone; OXOMiNP, mono-oxo-isononyl phthalate; Pb, lead; PBDEs, polybrominated diphenyl ethers; PCBs, polychlorinated biphenyls; PFASs, perfluoroalkyl substances; PFHxS, perfluorohexane sulfonate; PFNA, perfluorononanoic acid; PFOA, perfluoro-octanoic acid; PFOS, perfluoro-octane sulfonate; PFUnDA, perfluoroundecanoic acid; PRPA, propyl paraben; and TCS, triclosan.
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