Environmental Pollution and the Developmental Origins of Childhood Liver Disease
Authors: Matthew C. Cave
Journal: Hepatology (2020)

Supported, in part, by the National Institute of Environmental Health Sciences (R35ES028373, P42ES023716, P30ES030283, and R21ES031510), the National Institute on Alcohol Abuse and Alcoholism (5P50AA024337), and the National Institute of General Medical Sciences (P20GM113226). Potential conflict of interest: Nothing to report. See Article on Page 1758 Environmental hepatology is an emerging field focused on the environmental contribution to liver health and disease. Although lifestyle choices such as drugs, alcohol, diet, and exercise are major environmental influences, the potential contribution of chemical pollutants is less clear. Nonetheless, accumulating evidence suggests that these exposures may increase liver disease risk, with the greatest evidence occurring for nonalcoholic fatty liver disease (NAFLD).(1,2) In this issue of hepatology, Stratakis et al present rigorous environmental epidemiology research, "Prenatal Exposures to Perfluoroalkyl Substances Associated With Increased Susceptibility to Liver Injury in Children."(3) Gestational exposures to a mixture of perfluoroalkyl substances (PFAS) were positively associated with higher liver enzymes and increased liver injury risk during childhood (median age 8.2 years). Moreover, these developmental exposures were associated with an altered serum metabolome. Latent variable analysis identified a profile for at‐risk children characterized by high prenatal PFAS exposures and disrupted amino acid and glycerophospholipid metabolism. The study's major results are illustrated in Fig. 1. The most likely explanation for the observed liver injury is NAFLD, based on the results of previously published pediatric and adult PFAS exposure cohort studies(4,5) and rodent models of gestational and adult PFAS exposures.(1,2,5‐7) Several novel concepts believed to be important for hepatologists and liver investigators are raised by Stratakis et al First, the underappreciated but potentially significant environmental contribution to chronic liver disease is highlighted. Even more concerning is the possibility that in utero exposures to environmental pollutants could increase liver disease risk by altering postnatal metabolism. Should the identified associations subsequently be confirmed as causal, this knowledge has the potential to profoundly impact the understanding of liver disease pathogenesis and potentially patient care and policy.FIG. 1: Prenatal exposures to the environmental pollutants PFAS were associated with metabolic disruption and increased risk for childhood liver disease.In order to better contextualize these data, overviews of environmental liver disease and PFAS are required. In an article published in hepatology in 2010, our group coined the term "toxicant‐associated steatohepatitis" (TASH) to describe the fatty liver disease occurring in vinyl chloride workers in the absence of other risk factors.(8) This report provided proof‐of‐concept that high‐level occupational chemical exposures could cause steatohepatitis. Cross‐sectional cohort studies were then conducted which identified specific low‐level environmental contaminants (including PFAS) which were associated with liver injury and suspected fatty liver disease.(1,2) Model systems elucidated mechanisms by which specific pollutants either caused hepatic steatosis or interacted with lifestyle factors to increase the severity of diet‐induced nonalcoholic steatohepatitis (NASH).(1,2) Thus, the lines between NASH and TASH were blurred. Chemical pollutants have been associated with other related metabolic diseases, including type 2 diabetes (T2D), obesity, hypercholesterolemia, and metabolic syndrome (MetS). In 2017, the metabolism‐disrupting chemical (MDC) hypothesis(2) postulated that "environmental chemicals have the ability to promote metabolic changes that can result in obesity, T2D or fatty liver in animals including humans; these metabolic alterations may play an important role in the global epidemics of obesity, T2D and MetS." MDCs exert their effects at low doses, may have nonmonotonic dose responses, and may exhibit sexually dimorphic effects.(2) Like maternal nutritional status (Barker's hypothesis) and other endocrine‐disrupting chemicals, such as diethylstilbestrol, MDCs may act at prenatal windows of susceptibility to promote disease onset later in life. This concept is now called the "developmental origins of health and disease" (DOHaD) hypothesis. The developmental origins of several metabolic diseases, including NAFLD, have been demonstrated for several pollutants including PFAS, at least in model systems.(2,6) Proposed mechanisms include hepatic exposure–induced epigenetic changes and transcriptional reprogramming. In this issue of hepatology, Stratakis et al present the first evidence implicating PFAS in the developmental origins of human liver disease. PFAS are emerging chemicals of concern. Widespread use began in the 1970s for myriad industrial and household consumer applications including nonstick cookware (e.g., Teflon); products that confer resistance to grease, stains (e.g., ScotchGuard), or water; and firefighting foams. Some PFAS have been released into the environment, where they persist due to their high thermodynamic stability and resistance to degradation. PFAS have been called "forever chemicals" due to their decades‐long half‐lives. Human exposures typically occur through ingestion of contaminated water or food, although transplacental exposures occur.(9) Most people from industrialized countries have detectable PFAS in blood.(9) While the human health effects of PFAS require further investigation, several PFAS are MDCs associated with hypercholesterolemia, obesity, diabetes, and liver disease in animal models and/or human studies.(1,2,4‐6) More recently, PFAS pollution has garnered considerable attention from community residents, scientists, government agencies, and media outlets. This is related, in part, to the 2019 Hollywood feature film Dark Waters and the detection of higher‐level PFAS contamination in drinking water near some US military installations and surrounding communities. The 2018 the National Defense Authorization Act authorized the Centers for Disease Control and Prevention's Agency for Toxic Substances and Disease Registry (CDC/ATSDR) to investigate PFAS exposures and health effects (including liver injury) in communities near military bases or industrial facilities affected by contaminated drinking water. While these studies are ongoing, the ATSDR has recently released scientific and clinical guidance on PFAS based on currently available information.(9) The US Environmental Protection Agency (EPA) has recently published research on PFAS and fatty liver disease,(7) and federal maximum contaminant level standards are under development for some of these substances. Thus, Stratakis et al present timely and relevant environmental health data. Their article is the first linking prenatal PFAS exposures to subsequently increased liver disease risk (DOHaD) and possible NAFLD in a human cohort. Other results were consistent with the MDC hypothesis, suggesting possible mechanisms. These include (1) an altered serum metabolome consistent with metabolic disruption, (2) observable effects with low‐level exposures, (3) some nonmonotonic dose responses, and (4) sexually dimorphic effects. The increased liver disease risk was independent of obesity, suggesting that the hepatic effects of prenatal PFAS exposures were independent of any potential obesogenic effects of these substances. The observed alterations in amino acid and glycerophospholipid metabolism were similar to the group's recent publication linking childhood PFAS exposures to pediatric NAFLD histologic severity.(4) While "Prenatal Exposures to Perfluoroalkyl Substances Associated With Increased Susceptibility to Liver Injury in Children" could have a transformative impact in the field, it may point only to the tip of the iceberg. The developmental origins of liver disease, as well as the broader field of environmental hepatology, warrant broader recognition and further investigation. While considerable resources are justifiably being diverted to address the ongoing coronavirus global pandemic, the timing may soon be right for the American Association for the Study of Liver Diseases and its members to become increasingly involved with environmental health science research. Collaborative opportunities may exist with government organizations (e.g., the National Institute of Environmental Health Sciences, EPA, CDC/ATSDR, etc.) already working in this area. Perhaps the National Institute of Environmental Health Sciences Translational Research Framework(10) could be applied to achieve environmental impact while promoting liver health. Interactions between environmental contaminants and traditional liver disease risk factors (e.g., diet, ethanol, viral hepatitis) require further investigation, and stronger disease biomarkers (e.g., histology or imaging) should be used when possible. Likewise, interventions to mitigate the adverse health effects of MDCs have recently been proposed,(11) but the efficacy of these strategies specifically for the treatment of liver diseases warrants investigation.