Toward a Mechanistic Understanding of Poly- and Perfluoroalkylated Substances and Cancer

Abstract

Poly- and perfluoroalkylated substances (PFAS) are chemicals that persist and bioaccumulate in the environment and are found in nearly all human populations through several routes of exposure. Human occupational and community exposure to PFAS has been associated with several cancers, including cancers of the kidney, testis, prostate, and liver. While evidence suggests that PFAS are not directly mutagenic, many diverse mechanisms of carcinogenicity have been proposed. In this mini-review, we organize these mechanisms into three major proposed pathways of PFAS action—metabolism, endocrine disruption, and epigenetic perturbation—and discuss how these distinct but interdependent pathways may explain many of the proposed pro-carcinogenic effects of the PFAS class of environmental contaminants. Notably, each of the pathways is predicted to be highly sensitive to the dose and window of exposure which may, in part, explain the variable epidemiologic and experimental evidence linking PFAS and cancer. We highlight testicular and prostate cancer as models to validate this concept.

PFAS: forever chemicals—persistent, bioaccumulative and mobile. Reviewing the status and the need for their phase out and remediation of contaminated sites

“…A number of reviews report the numerous and varying biological effects of PFAS on experimental animals as well as on human beings [176][177][178][179][180][181][182][183][184]. The mechanisms that may be responsible for the pro-carcinogenic effects of PFAS are described by Boyd et al in a review [185].…”

The Relationship between Typical Environmental Endocrine Disruptors and Kidney Disease

“…Recently, studies are beginning to emerge on the effect of PFAS in select cancers (liver, prostate, kidney, etc.) [ 105 ], but mechanistic studies on the role of PFAS are sparse. Although epidemiological evidence points to kidney cancer as one of the cancers triggered by PFAS, very few studies have examined the role of PFAS in kidney disease or renal cell carcinoma.…”

How the Structure of Per- and Polyfluoroalkyl Substances (PFAS) Influences Their Binding Potency to the Peroxisome Proliferator-Activated and Thyroid Hormone Receptors—An In Silico Screening Study

“…PFAS are recognized by their hydrophobic carbon backbone, which is fully or partially saturated with fluorine atoms, and by possessing a hydrophilic functional group. PFAS, because of the C-F bonds, are very stable [ 2 ] and highly persistent in the environment, which can have a huge impact on humans and living organisms [ 5 , 6 ]. Continuous usage of PFAS leads to their accumulation in the environment and simultaneously increases the likelihood of harmful effects [ 2 ].…”

“…These substances may act as agonists or antagonists of nuclear hormone receptors (NHRs). One of the groups of NHRs with which PFAS compounds may interact is peroxisome proliferator-activated receptors (PPAR) alpha, beta, and gamma [ 6 , 21 ]. They are members of the nuclear receptor superfamily which plays a significant role in the regulation of lipid, glucose metabolism, and cellular growth [ 22 ].…”