Cancer Center at Illinois (CCIL) members Ratnakar Singh and Michael Spinella 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.
Learn more about PFAS chemicals here.
“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.
Ratnakar Singh
Research Assistant Professor, Comparative Biosciences
CCIL Research Program and Theme
- Program: Cancer Engineering and Biological Systems
- Theme: Comparative and Engineered Oncology Models
Research Focus
Singh studies testicular germ cell tumors to find the epigenetic mechanisms that regulate the chemoresponse in TGCTs. He seeks to understand the role of H3K27 methylation in chemo-resistance or chemo-sensitivity in germ cell lines, and the role of microRNAs in chemo-resistance or chemo-sensitivity in germ cell lines.
Michael Spinella
Professor, Comparative Biosciences
CCIL Research Program and Theme
- Program: Cancer Engineering and Biological Systems
- Theme: Anticancer Chemistry
Research Focus
Michael Spinella’s laboratory explores the molecular genetics of cancer, particularly mechanisms of tumorigenesis, cancer therapy, and drug resistance. One research focus is on uncovering mechanisms that account for the curability of metastatic testicular germ cell tumors in order to inform novel therapeutic strategies for advanced somatic solid tumors, including glioblastoma and breast cancer. Other interests include the concept of differentiation therapy and the identification of mechanistic links between stem cell pluripotency, cancer, and response to chemotherapy. Spinella has a strong background in anticancer target identification and in molecular mechanisms of carcinogenesis, cancer therapeutics, and chemoresistance. Learn more about Michael Spinella’s lab.
Editor’s notes:
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 is a research assistant professor of comparative biosciences. He can be reached at rsingh02@illinois.edu.
Michael Spinella is a professor of comparative biosciences and a professor of biomedical and translational sciences. He can be reached at Spinella@illinois.edu.
This story was written by Jonathan King, CCIL Communications Specialist.