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Initial CDAS Request Approval
Jan 19, 2023
Perfluorooctanoic acid (PFOA) exposure, DNA methylation patterns, and renal cell carcinoma
Per- and polyfluoroalkyl substances (PFAS), especially perfluorooctanoic acid (PFOA), have been associated with increased risk of kidney cancer, but the mechanisms underlying this association are not well understood. Given its adverse health effects, PFOA, one of the most studied PFAS, has been banned across many industries in the U.S. and E.U. in the past few years. Exposure to PFAS is widespread in the U.S. and Europe, with detectable serum levels of PFAS found in over 98% of the general U.S. population. Given the persistence of these substances in the environment and their extended half-life in humans, PFAS constitute a significant public health threat with poorly understood biology. A previous nested-case control study in PLCO found a strong positive association between PFOA and renal cell carcinoma. In order to better understand the biological mechanisms underlying this association, we propose to study the relationship between PFAS exposure and DNA methylation in kidney cancer cases from PLCO in combination with a controlled exposure study in mice. Our proposed study will utilize 291 cases and 310 controls with PFAS measurements included in the previous PLCO study. We will profile genome-wide DNA methylation using a validated transmammalian array and assess associations with PFOA measurements in both species. This distinctive study design combining a prospective kidney cancer study with a controlled exposure mouse study will offer us the opportunity to understand the underlying mechanisms of PFAS exposure and uncover key gene targets.
Primary aim 1: To investigate the relationship between DNA methylation patterns and PFOA exposure in an experimentally-controlled exposure study in mice. Hypothesis: PFOA exposure in mice will be associated with altered DNA methylation patterns.
Primary aim 2: To investigate the relationship between serum levels of PFOA and DNA methylation profiles in humans and compare with PFOA associations observed in mice. Hypothesis: Altered DNA methylation at conserved sites observed in mice will also be seen in humans, providing evidence of a potential biological relationship.
Charles Breeze (National Cancer Institute)
Sonja Berndt (National Cancer Institute)
Jonathan Hofmann (National Cancer Institute)
Mark Purdue (National Cancer Institute)
Steve Horvath (UCLA)
Suzanne Fenton (National Institute of Environmental Health Sciences)
Jianxin Shi (National Cancer Institute)