Researchers Identify Underlying Mechanisms that Help Explain Link Between PFAS Exposure and Testicular Cancer
Research Assistant Professor of Comparative Biosciences Ratnakar Singh (left) and Professor of Comparative Biosciences Michael Spinella. / Cancer Center at Illinois
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Ratnakar Singh, Research Assistant Professor of Comparative Biosciences, and Michael Spinella (ACPP/EIRH), Professor of Comparative Biosciences, collaborated in new research that fills in critical gaps of understanding in the relationship between testicular cancer growth and the presence of PFAS.
Per- and polyfluoroalkyl substances (PFAS), also known as “forever chemicals,” includes a host of synthetic chemicals broadly used in numerous consumer, commercial, and industrial products. PFAS break down very slowly, thereby stubbornly residing in biological and ecological environments for long periods of time.
“The key finding from our team’s research,” reported Singh, “is that PFAS can directly disrupt lipid and hormone metabolism in testicular cancer cells at exposure levels relevant to humans. And PFAS do so by interfering with the key metabolic regulator PPARy.”
This finding provides a biologically plausible mechanism to help explain why epidemiological studies consistently link PFAS exposure to testicular cancer risk.
“In other words, our work moves the conversation beyond ‘association’ toward how PFAS might promote cancer-related changes within cells,” said Singh, who has worked closely with Spinella on PFAS research. The research duo’s most recent paper is published in the journal of Environmental Toxicology and Pharmacology. This most recent research publication also includes lab members Doha Shokry, Brayden Rennels, Younan Adam , Christine Powell , Samantha Johnson, and first author Raya Boyd.
Given that the team’s study shows PFAS can antagonize PPARγ, a key regulator of lipid metabolism, it is critical to distinguish how this disruption potentially explains the link between PFAS exposure and testicular cancer development. “PPARγ plays a central role in lipid handling, steroid hormone balance, and cellular differentiation,” shared Singh. “By blocking PPARγ activity, PFAS can disturb these tightly controlled processes, creating conditions that may favor cancer development. Because testicular cancer is strongly influenced by developmental and hormonal signaling, this disruption offers a plausible explanation for how environmental PFAS exposure could contribute to disease risk.”
Critically, the team modeled PFAS concentrations based on real human exposure ranges. They found that different PFAS compounds—PFOS, HQ 115, and GenX—affect testicular tumor cells in distinct ways.
“The key message here is that PFAS are not interchangeable,” Singh said. “Even at similar exposure ranges, different PFAS compounds can perturb cellular metabolism in distinct but overlapping ways. Our data suggest PFOS, HQ-115, and GenX all disrupted PPAR signaling, but PPARγ antagonism was the most consistent effect across compounds.”
The team found that HQ-115, a PFAS associated with clean-energy technologies, strongly altered metabolites linked to steroid and lipid metabolism, even though it looks very different chemically from PFOS. They found that GenX, often considered a “safer” replacement, still showed biologically meaningful effects on PPAR signaling.
“For the general population, this suggests that replacement PFAS may not be entirely risk-free. Even low-level, chronic exposure can subtly alter biological pathways linked to cancer risk,” Singh shared.
A casual observer may wonder, what makes this study different from previous research on PFAS and cancer risk? The Illinois team’s research is an important building block in our understanding of the relationship between PFAS and cancer risk—and therefore critical for the American public.
“Most prior studies have shown associations between PFAS and cancer but have lacked mechanistic insight,” said Singh. “Our study directly identifies how PFAS alter cancer-relevant biology by combining human cancer cell models, metabolomics, and functional reporter assays at human-relevant doses. By pinpointing disruptions in lipid metabolism and PPAR signaling, the work strengthens the biological basis for epidemiological findings.”
What are the next steps needed to determine whether the metabolic changes you observed in TGCT cells translate into increased cancer risk in humans? What unanswered questions remain, and what research should come next to better understand PFAS chemicals and cancer risks?
The research team’s next steps include testing whether these metabolic disruptions occur in animal models and human tissues, particularly during sensitive developmental windows such as fetal life and puberty. Future studies will also need to examine PFAS mixtures, long-term exposure, and individual susceptibility, because people are exposed to mixtures rather than single compounds.
“Understanding how these chemicals interact biologically is essential. Together, this research will help clarify how environmental PFAS exposure may contribute to cancer risk and inform safer regulatory decisions,” Singh concluded.
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The paper, “The role of lipid metabolism and peroxisome proliferator activation in mediating pro-cancer phenotypes of poly- and perfluoroalkyl substances in testicular cancer,” is published in the Environmental Toxicology and Pharmacology journal, and is available here. DOI: https://doi.org/10.1016/j.etap.2025.104866
Ratnakar Singh and Michael Spinella are members of the Cancer Center at Illinois.