Scientists at UofL, along with colleagues from Boston University and the University of Massachusetts Lowell, have identified perfluorooctane sulfonate (PFOS) as a potential environmental factor that worsens alcohol-associated liver disease.

PFOS is a man-made chemical belonging to the group known as per- and polyfluoroalkyl substances (PFAS), often referred to as “forever chemicals” because they do not readily break down in the environment or the human body. These substances have been used for decades in products such as non-stick cookware, water-resistant clothing, fast-food packaging, stain-resistant carpets and upholstery, and firefighting foams. Their extensive use has led to widespread contamination in the environment. show that PFAS can be detected in approximately 95% of Americans, sparking increasing concern about their long-term health effects.

At the same time, alcohol consumption remains a significant global health issue. , and its consumption continues to rise globally. In the U.S. alone, excessive alcohol use is responsible for approximately 95,000 deaths annually, making it one of the leading causes of preventable death and a major contributor to liver disease.

“Given the increasing prevalence of alcohol consumption and the widespread presence of PFAS in the environment, many individuals who drink alcohol may be inevitably exposed to these persistent pollutants. This makes it critically important to study how combined exposures to alcohol and environmental chemicals like PFOS might influence liver health,” said Matthew Cave, UofL professor of medicine and publication co-author.

Although it is well known that both alcohol and PFOS cause liver damage individually, little has been understood about their combined effects until now. , indicating that additional factors such as genetics, sex, microbiome and environmental exposures may contribute to individual susceptibility.

“This work helps explain why two people with similar alcohol consumption may experience very different liver outcomes,” said Frederick Ekuban, assistant professor of medicine at UofL and first author of the study. “Environmental exposures like PFOS may be the missing link.”

Using animal models, the researchers simulated real-world exposures to both alcohol and PFOS. The study showed that co-exposure to alcohol and PFOS significantly increased fat accumulation and markers of liver damage, as well as clear signs of disrupted metabolism and activation of genes and pathways predicted to be associated with oxidative stress and cancer development.

In short, the study demonstrates that PFOS exposure can significantly worsen liver damage when combined with alcohol consumption. While this research used high levels of alcohol to understand the underlying mechanisms, the findings reveal important biological pathways that warrant further investigation across different drinking patterns.

The research team also found that PFOS interferes with the liver’s ability to manage fats, disrupts its natural protective and repair systems and activates pathways that promote liver injury.

“While the liver typically has a remarkable capacity to recover from alcohol-induced stress, PFOS appears to push that resilience beyond its limits, resulting in compounded and more severe damage,” said Jennifer Schlezinger professor of environmental health at Boston University and co-author of the publication.

Perhaps most concerning, the team discovered that 60% of all PFOS exposure ended up concentrated in the liver, exactly where alcohol damage occurs.

Ongoing research at UofL is examining how other PFAS compounds may interact with alcohol, whether males and females respond differently to these exposures and what the long-term consequences of combined exposures might be. The team is also exploring whether targeted therapies can be developed to prevent or mitigate this type of liver damage.

Although more studies are needed, people can take practical steps now to limit their exposure to PFAS. These include:

• Choose stainless steel or cast-iron cookware instead of non-stick pans
• Use water filters, especially in areas near industrial zones
• Avoid stain-resistant treatments on furniture and carpets
• Reduce consumption of packaged fast foods and microwave popcorn.
• Select household products with PFAS-free labels

Given that liver disease affects millions of Americans and is becoming more prevalent worldwide, the findings of this research support growing calls for stronger regulation and oversight of persistent chemical contaminants. By better understanding the hidden interactions between environmental toxicants and lifestyle behaviors, scientists and policymakers may be better equipped to prevent and treat liver disease.

��Article by Sarah Jump

“Essentially, the idea is if you are exposed as an adult, and you decide to have kids, that exposure doesn’t end,” said UofL doctoral candidate, Jamie Young. “So it is passed on through the children.”

The UofL investigators used in utero��mouse models to look at how chronic exposure to the toxicants arsenic or cadmium in the womb would play out when those mice were grown. And, whether that exposure would exacerbate the negative health effects of a high-fat diet.

Dr. Chris States, associate dean for Research at the UofL School of Medicine and one of the lead investigators on this study, said chronic exposure can cause a variety of diseases in adults, including many cancers, cardiovascular disease and diabetes.��

Because arsenic and cadmium can find their way into ground water, he said one way people can be chronically exposed to arsenic is by drinking from contaminated wells.

“People who are using private wells are on their own to find out if there’s arsenic in their water,” States said. Contamination can be natural dependent on the type of rock, he said, or result from human activity and leach into the ground water.

According to estimated some 44 million people in the 48 contiguous U.S. states were on private wells in 2017. Of those, about 2.1 million people were potentially using wells that were contaminated with high concentrations of arsenic.��

To make things worse, the UofL research also showed those who are chronically exposed to toxicants in utero��could be more sensitive to the effects of a high-fat diet, such as diabetes and metabolic syndrome.

“The addition of arsenic actually causes more problems,” Young said. Combined with the negative side effects of high fat diet, she said, the outcomes are worse.

This study was to gather preliminary data to support a number of grant applications, which States hopes to use to continue studying the interaction of different health factors at the��UofL Center for Integrative and Environmental Health Sciences (CIEHS), where he’s also director.

The CIEHS is one of several Centers under the umbrella of . CIEHS research seeks to understand how life style factors interact with exposure to environmental toxicants in human health and disease and how life stage and gender influence these interactions.

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States received the award at the 2017 Society of Toxicology Annual Meeting and ToxExpo in Baltimore��earlier this month. The Career Achievement Award recognizes a senior investigator who has substantially advanced the understanding of metals toxicology through scientific contributions, training and mentorship of young scientists, leadership and service to the metals toxicology field, and influence in regulatory and risk assessment decisions related to metals toxicology.

“Chris is highly deserving of this honor, having made significant scientific contributions to the field of metal toxicology, serving as part of the leadership of the Metals Specialty Section, and mentoring a new generation of metal toxicologists,” said Koren Mann, PhD, associate professor of oncology at McGill University of Montreal and director of the Molecular and Regenerative Medicine Axis, Lady Davis Institute for Medical Research.

“He has made a significant impact on the field and on the next generation of metals toxicologists in his more than 35 years in research, education and administration,”��added Aaron Barchowsky, PhD, professor at the University of Pittsburgh Graduate School of Public Health. “Chris has a long held interest in the molecular mechanisms regulating DNA stability and DNA damage repair in response to metals such as arsenic and platinum. He made seminal discoveries identifying how the metals impact mitotic spindle formation and cell checkpoints that result in either promoting cancers in the case of arsenic, or can be targeted for therapeutic treatment of cancers in the case of platinum.”

States, vice chair for graduate education in the Department of Pharmacology and Toxicology, joined UofL in 1999 and was named a Distinguished University Scholar in 2007. States has served as a peer reviewer for the National Institutes of Health and the Medical Research Council of the United Kingdom, the United States Department of Energy, U.S. Department of Defense and other granting agencies. He is academic editor for “,” serves on the editorial board of three research journals and is a peer reviewer for more than 40 journals. He has published more than 100 articles in journals or books and more than 125 abstracts.��

At this month’s meeting, UofL faculty members and researchers John P. Wise Sr., PhD, Daniel Conklin, PhD, Shanice Hudson, PhD, and Petra Haberzettl, PhD, also led sessions and workshops. UofL graduate student Laila Al-Eryani received the Battelle Student Research Award from the Dermal Toxicology Specialty Section. Her award comes with $1,000 to use for her research project, “Differential mRNA and miRNA Expression in Arsenic-induced Skin Cancer In Vivo and in an In Vitro Model,” under the direction of States.