Faculty Bibliography

Chromium is a human carcinogen primarily by inhalation exposure in occupational settings. Although lung cancer has been established as a consequence of hexavalent chromium exposure in smokers and nonsmokers, some cancers of other tissues of the gastrointestinal and central nervous systems have also been noted. Except for a few reports from China, little is known about the health risks of environmental exposures to chromium. Likewise, there has been a lack of epidemiological studies of human exposure to hexavalent Cr by drinking water or ingestion, and it has been suggested that humans can perhaps tolerate hexavalent Cr at higher levels than the current drinking water standard of 50 ppb. This review highlights the most recent data on the induction of skin tumors in mice by chronic drinking-water exposure to hexavalent chromium in combination with solar ultraviolet light. This experimental system represents an important new animal model for chromate-induced cancers by ingestion of drinking water, and it suggests by extrapolation that chromate can likely be considered a human carcinogen by ingestion as well. The potential use of this animal model for future risk assessment is discussed

Arsenic is an established human carcinogen. However, there has been much controversy about the shape of the arsenic response curve, particularly at low doses. This controversy has been exacerbated by the fact that the mechanism(s) of arsenic carcinogenesis are still unclear and because there are few satisfactory animal models for arsenic-induced carcinogenesis. Recent epidemiological studies have shown that the relative risk for cancer among populations exposed to 10 muM), As induces down-regulation of DNA repair, oxidative DNA damage and apoptosis. This low dose adaptive (protective) response by a toxic agent is known as hormesis and is characteristic of many agents that induce oxidative stress. A mechanistic model for arsenic carcinogenesis based on these data would predict that the low dose risk for carcinogenesis should be sub-linear. The threshold dose where toxicity outweighs protection is hard to predict based on in vitro dose response data, but might be estimated if one could determine the form (metabolite) and concentration of arsenic responsible for changes in gene regulation in the target tissues.

Epigenetic gene silencing by aberrant DNA methylation of gene promoter regions is a nonmutagenic but heritable epigenetic mechanism that may mistakenly cause the silencing of important cancer-related tumor suppressor genes. Using a transgenic, V79-derived, mammalian cell line (G12) that contains a bacterial gpt reporter gene in its DNA, we can study carcinogen-induced gene inactivation by mutagenic as well as epigenetic DNA methylation mechanisms. Whereas numerous carcinogens have previously been shown to be mutagenic in these cells, a few carcinogens, including nickel, diethylstilbestrol, and X-rays, are also capable of silencing the G12 cell gpt transgene by aberrant DNA methylation. Here we report for the first time that carcinogenic potassium chromate salts can also induce aberrant DNA methylation in this system. In contrast insoluble barium chromate produced significant level of mutations in these cells but did not cause DNA methylation changes associated with transgene expression

Mutagenesis assays in mammalian cells are frequently used to complement bacterial mutagenesis assays. This unit describes a mutagenesis assay using either Chinese hamster V79 cells or V79-derivative gpt transgenic cell line to assess the effects of chemical agents on mammalian cells