Several lines of evidence indicate that oxidative stress induces mutagenesis [33
]. Oxidation reactions produce deleterious effects on DNA by a variety of mechanisms, depending on the type of affected nucleotide [33
]. Indeed, the threat of oxidation reactions to DNA is so prevalent that most genetic material would be altered by reactive oxygen species (ROS), were it not for the cell’s natural defenses and capacity for DNA repair [33
]. Sperm cells appear to be more vulnerable to the mutagenic effects of oxidative stress than oocytes. Several features of sperm cells, including the unique membrane structure crucial to fertilization, provide greater opportunities for the production of ROS [35
]. In contrast, in oocytes there are multiple pathways to repair DNA damage caused by ROS [38
Mercury, nickel, and cadmium, like vinyl chloride and trichloroethylene, have been identified as significant mutagens by a variety of studies. These substances appear to exert their mutagenic effects in at least two ways. First, they contribute to oxidative stress, leading to oxidative DNA damage by free radicals [39
]. Second, they tend to inhibit DNA repair systems, thereby leading to the accumulation of mutations [40
]. To maintain intracellular redox balance and protect against oxidative stress, cells produce reducers such as glutathione and nicotinamide adenine dinucleotide phosphate (NADPH). Mercury, cadmium, and nickel become toxic to cells by depleting intracellular levels of glutathione and binding to sulfhydric groups of proteins [39
], leaving DNA vulnerable to the mutagenic effects of ROS.
For each of the heavy metals and industrial solvents discussed below, there has been extensive research involving dozens of studies confirming their mutagenic effects, in both in vitro and in vivo studies, and in research from different species, including humans. We briefly summarize examples of studies on each of the five factors; more comprehensive summaries of research on each factor are available online at the website of the Agency for Toxic Substances and Disease Registry (ATSDR), part of the U.S. Center for Disease Control.
there is evidence for mutagenicity from several dozen studies; many of these are summarized at the ATSDR [42
] webpage. For example, Ariza and Williams [43
] found low concentrations of mercury to be mutagenic in mammalian cells; the investigators found significantly more mutations in cells exposed to mercury acetate, even at levels too dilute to cause cytotoxicity. In a follow-up study, Ariza & Williams [44
] found a dose-dependent effect on type of mutation after mercury exposure; that is, at concentrations of 0.4 or fewer nanomoles, mercury tended to induce point mutations
, while higher concentrations mostly induced partial and complete deletions
in chromosomes. Silva-Pereira et al. [45
] found low concentrations of organic mercury compounds to have a significant mutagenic effect on chromosomes in cultured human lymphocytes.
, there is also evidence for mutagenicity from dozens of studies [46
]. For example, Filipic et al. [40
] found that low concentrations of cadmium induced oxidative DNA damage and also impaired the capacity of the cell for DNA repair. Coen et al [47
] demonstrated that exposure to cadmium can induce delayed effects in the progeny of exposed cells even after removal of the toxic substance. The investigators found significant increases of chromosomal aberrations in human lung tissue cells eight generations removed from the originally exposed ancestor cells.
has also been found to be mutagenic in many studies [48
]. Thus, for example, point mutations and chromosomal deletions have been detected in a number of mammalian cell lines exposed to nickel [48
], and DNA damage has been detected in the lymphocytes of nickel refinery workers [49
]. Nickel has been shown to have deleterious effects on DNA through several processes, such as potentiation of the effect of other mutagens [50
], production of ROS [51
], and inhibition of DNA repair [41
is a volatile industrial solvent and metal-cleaning agent. Again, many studies have indicated that it is mutagenic [52
]. Hu et al. [53
], for example, found that trichloroethylene induced DNA damage in human liver cells in a dose-dependent manner. The mutagenic effects were exacerbated in cells with depleted levels of the antioxidant glutathione, suggesting that trichloroethylene causes DNA damage via its application of oxidative stress to the cell.
is a known mutagen [54
] that is metabolized in the cell to products that react directly with DNA to create various DNA adducts, which then in turn have their own mutagenic effects, including, for example, chromosomal deletions and transversions [55