Andrusaityte, S. (Sandra)
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- Association of prenatal exposure to endocrine-disrupting chemicals with liver injury in children(2022) Papadopoulou, E. (Eleni); García, E. (Erika); Wright, J. (John); Haug, L.S. (Line Smastuen); Chatzi, L. (Lida); Vos, M.B. (Miriam B.); Roumeliotaki, T. (Theano); Conti, D.V. (David V.); Vafeiadi, M. (Marina); Maitre, L. (Léa); Heude, B. (Barbara); Gómez-Urquiza, J. (José); McEachan, R.R.C. (Rosemary R. C.); McConnell, R. (Rob); Casas, M. (Maribel); Fossati, S. (Serena); Grazuleviciene, R. (Regina); Valvi, D. (Damaskini); Basagana, X. (Xavier); Colicino, E. (Elena); Vrijheid, M. (Martine); Thomsen, C. (Cathrine); Berhane, K.T. (Kiros T.); Philippat, C. (Claire); Midya, V. (Vishal); Stratakis, N. (Nikos); Andrusaityte, S. (Sandra); Varo-Cenarruzabeitia, M.N. (Miren Nerea)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), gamma-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 (beta, 5.84 [95% CrI, 1.69-10.08] IU/L) and PBDEs (beta, 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.
- In utero exposure to mercury is associated with increased susceptibility to liver injury and inflammation in childhood(2021) Papadopoulou, E. (Eleni); García, E. (Erika); Wright, J. (John); Haug, L.S. (Line Smastuen); Chatzi, L. (Lida); Vos, M.B. (Miriam B.); Hu, H. (Howard); Robinson, O. (Oliver); Bustamante, M. (Mariona); Sabidó, E. (Eduard); Golden-Mason, L. (Lucy); Roumeliotaki, T. (Theano); Conti, D.V. (David V.); Vafeiadi, M. (Marina); Maitre, L. (Léa); Rosen, H.R. (Hugo R.); Heude, B. (Barbara); Gómez-Urquiza, J. (José); McEachan, R.R.C. (Rosemary R. C.); McConnell, R. (Rob); Casas, M. (Maribel); Meltzer, H.M. (Helle Margrete); Fossati, S. (Serena); Grazuleviciene, R. (Regina); Valvi, D. (Damaskini); Basagana, X. (Xavier); Margetaki, K. (Katerina); Vrijheid, M. (Martine); Borrás, E. (Eva); Berhane, K.T. (Kiros T.); Stratakis, N. (Nikos); Andrusaityte, S. (Sandra); Zhao, Y. (Yinqi); Varo-Cenarruzabeitia, M. N. (Miren Nerea)Background and Aims Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant-associated fatty liver disease. Approach and Results We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother-child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1 years; interquartile range [IQR], 6.5-8.7) from the European Human Early-Life Exposome cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0 mu g/L; IQR, 1.1-3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation-related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (>= 22.1 U/L for females and >= 25.8 U/L for males) and increased concentrations of circulating IL-1 beta, IL-6, IL-8, and TNF-alpha.
- Prenatal exposure to perfluoroalkyl substances associated with increased susceptibility to liver injury in children(Wiley, 2020) Papadopoulou, E. (Eleni); García, E. (Erika); Wright, J. (John); Haug, L.S. (Line Smastuen); Chatzi, L. (Lida); Vos, M.B. (Miriam B.); Robinson, O. (Oliver); Roumeliotaki, T. (Theano); Varo, N. (Nerea); Conti, D.V. (David V.); Uppal, K. (Karan); Vafeiadi, M. (Marina); Maitre, L. (Léa); Heude, B. (Barbara); Fernández-Barrés, S. (Silvia); Gómez-Urquiza, J. (José); Jin, R. (Ran); McEachan, R.R.C. (Rosemary R. C.); McConnell, R. (Rob); Casas, M. (Maribel); Fossati, S. (Serena); Grazuleviciene, R. (Regina); Valvi, D. (Damaskini); Keun, H.C. (Hector C.); Basagana, X. (Xavier); Margetaki, K. (Katerina); Vrijheid, M. (Martine); Berhane, K.T. (Kiros T.); Stratakis, N. (Nikos); Andrusaityte, S. (Sandra); Zhao, Y. (Yinqi); Siskos, A.P. (Alexandros P.)BACKGROUND AND AIMS: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children. APPROACH AND RESULTS: We used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6-9.1) from the European Human Early-Life Exposome cohort (consisting of six existing population-based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21-1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched-chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso-PC a C18:1). CONCLUSIONS: Developmental exposure to PFAS can contribute to pediatric liver injury. (Hepatology 2020;72:1758-1770).
- Prenatal and childhood exposure to air pollution and traffic and the risk of liver injury in European children(2021) Hoek, G. (Gerard); García, E. (Erika); Wright, J. (John); Chatzi, L. (Lida); Vos, M.B. (Miriam B.); Nieuwenhuijsen, M. (Mark); Slama, R. (Rémy); Roumeliotaki, T. (Theano); Aasvang, G.M. (Gunn Marit); Conti, D.V. (David V.); Vafeiadi, M. (Marina); Maitre, L. (Léa); Heude, B. (Barbara); Gómez-Urquiza, J. (José); McEachan, R.R.C. (Rosemary R. C.); McConnell, R. (Rob); Casas, M. (Maribel); Castro, M. (Montserrat) de; Fossati, S. (Serena); Grazuleviciene, R. (Regina); Valvi, D. (Damaskini); Basagana, X. (Xavier); Vrijheid, M. (Martine); Krog, N.H. (Norun Hjertager); Berhane, K.T. (Kiros T.); Stratakis, N. (Nikos); Andrusaityte, S. (Sandra); Varo-Cenarruzabeitia, M.N. (Miren Nerea)Background: Nonalcoholic fatty liver disease is the most prevalent pediatric chronic liver disease. Experimental studies suggest effects of air pollution and traffic exposure on liver injury. We present the first large-scale human study to evaluate associations of prenatal and childhood air pollution and traffic exposure with liver injury. Methods: Study population included 1,102 children from the Human Early Life Exposome project. Established liver injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and cytokeratin-18, were measured in serum between ages 6-10 years. Air pollutant exposures included nitrogen dioxide, particulate matter <10 m (PM10), and <2.5 m. Traffic measures included traffic density on nearest road, traffic load in 100-m buffer, and inverse distance to nearest road. Exposure assignments were made to residential address during pregnancy (prenatal) and residential and school addresses in year preceding follow-up (childhood). Childhood indoor air pollutant exposures were also examined. Generalized additive models were fitted adjusting for confounders. Interactions by sex and overweight/obese status were examined. Results: Prenatal and childhood exposures to air pollution and traffic were not associated with child liver injury biomarkers. There was a significant interaction between prenatal ambient PM10 and overweight/obese status for alanine aminotransferase, with stronger associations among children who were overweight/obese. There was no evidence of interaction with sex. Conclusion: This study found no evidence for associations between prenatal or childhood air pollution or traffic exposure with liver injury biomarkers in children. Findings suggest PM10 associations maybe higher in children who are overweight/obese, consistent with the multiple-hits hypothesis for nonalcoholic fatty liver disease pathogenesis.