Polychlorinated biphenyls (PCBs) as initiating agents in hepatocellular carcinoma

Abstract

PCBs are carcinogens, but for many decades it was assumed that PCBs may not possess initiating activity. Initiation is a process that involves changes in the DNA sequence, often, but not exclusively produced through DNA adduction by a reactive compound or reactive oxygen species (ROS). DNA adducts can be detected by 32P-postlabeling, a method that Dr. Ramesh Gupta co-developed and refined. Today these types of assays together with other mechanistic studies provide convincing evidence that specific PCB congeners can be biotransformed to genotoxic and therefore potentially initiating metabolites. This review will provide an overview of our current knowledge of PCBs genotoxic potential and mechanism of action, emphasizing the contributions of Dr. Ramesh Gupta during his tenures at the Universities of Kentucky and Louisville.

Hepatocellular carcinoma and the risk of occupational exposure

“…The contamination occurs by skin contact or inhalation, which also allows the possibility of developing vapors for equipment containing PCB overheating [185] . Studies in animal models have shown that these chemical compounds can cause chronic hepatitis as well as cancers, such as HCC and cholangiocarcinoma, especially if there is high exposure and a prolonged time.…”

“…In one case, exposure to olive oil accidentally contaminated with PCB resulted in death from hepatic cirrhosis. Other studies in workers exposed to the PCB have reported an increased incidence of liver tumors [185][186][187][188] . Some possible mechanisms by which PCB can cause cancer have been assumed: Reactive oxygen species (ROS) is produced through the enzymatic oxidation or autoxidation of PCB; PCB determines the increased expression of genes responsible for inflammation and apoptosis in the liver; and PCB has "toxic" effects on certain genes, such as the loss of part of a chromosome and chromosome breakage [189][190][191][192][193][194][195][196][197][198][199] .…”

Carcinogenicity of polychlorinated biphenyls and polybrominated biphenyls

“…Low-chlorinated PCBs are readily metabolised into highly reactive electrophilic species (ie, arene oxides, quinones) which, in addition to producing DNA adducts and reactive oxygen species, are directly genotoxic and mutagenic. 2 By contrast, highly chlorinated PCBs are poorly metabolised but, through induction of xenobiotic-metabolising enzymes, can also generate reactive oxygen species, lipid peroxidation, oxidative and alkylating DNA adducts, and can eventually cause genotoxic eff ects.…”

Lactational exposure to low levels of the six indicator non-dioxin-like polychlorinated biphenyls induces DNA damage and repression of neuronal activity, in juvenile male mice

“…Health effects associated with exposure to PCBs include carcinogenicity (Ludewig and Robertson, 2013;Porta et al, 2007), genotoxicity (Viganò et al, 2002;Jacobus et al, 2010), neurotoxicity (Crinnion, 2009;Forns et al, 2012;Ribas-Fitó et al, 2001), and reproductive toxicity (Nieminen et al, 2013). In the past, the toxic effects of PCBs have been mostly attributed to the coplanar or dioxin-like (DL-PCBs) compounds that bind to AhR (Kafafi et al, 1993).…”