ADVANCEMENT OF THE SCIENCE
Profiling Metal-Induced Genotoxic Endpoints
Mohammad Shoeb, PhD Gregory M. Zarus, MS Henry E. Abadin, MSPH
Office of Innovation and Analytics, Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention
prioritize evidence of cancer, 3) identify data gaps, and 4) generate ideas that enable fur- ther research. For a genotoxic substance to cause an observable health eect, it must first damage genetic information within a cell and then not be repaired by the cell’s natural DNA repair processes. Genotoxic endpoints could serve as a first step in assessing the genotoxic risk of a corresponding health eect follow- ing hazardous exposures. In this initial analysis, we examine the genotoxic-endpoint data found in the toxi- cological profiles and published studies for chromium (Cr), arsenic (As), nickel (Ni), lead (Pb), mercury (Hg), and zinc (Zn; Table 2). These metals are among the most fre- quently found contaminants at hazardous waste sites—with As, Pb, and Hg ranking as the top three substances on the Substance Priority List. Table 2 also includes the can- cer classification of the National Toxicology Program (NTP, 2021) within the U.S. Depart- ment of Health and Human Services. The metals listed in Table 2 are ordered according to their NTP classification, from most to least carcinogenic (left to right, respectively) and top to bottom in order of the most generally investigated genotoxic endpoint. The genotoxic potential of these metals is based on several factors, including oxida- tion state, physiochemical properties, and target cell or organ interaction. Based on their genotoxic and mutagenic potential, As, Pb, Hg, and Cr are categorized as highly toxic (Arora & Chauhan, 2021). Unlike the other metals, Ni compounds are considered weak mutagens because of their inability to eciently induce base pair substitutions, frameshift mutations, or deletions in human cells (ATSDR, 2023b; International Agency for Research on Cancer, 2023; Stroebel et al., 1993). Studies have shown, however, a muta- genic response of Ni in vitro, mutation of the tumor suppressor p53 gene, and inhibition of
Abstract Many toxic metals are involved in the initiation and progression of DNA damage that can result in the activation of DNA damage response machinery at double- and single-stranded DNA; this response can result in global and gene-specific DNA alteration. The toxicological profiles from the Agency for Toxic Substances and Disease Registry (ATSDR) and several other studies have demonstrated the influence of metal exposure- induced genotoxic endpoints and epigenetic modifications. Our review systematically summarizes accumulating evidence from ATSDR toxicological profiles and the available literature that demonstrate a possible induction of various genotoxic endpoints and metal exposures. We include in this article studies on chromium, arsenic, nickel, lead, mercury, and zinc.
I ntroduction This article compiles information from several of the Agency for Toxic Substances and Disease Registry (ATSDR) toxicological profiles to summarize genotoxic endpoints associated with exposure to metals. Humans are exposed to various toxins and environmen- tal pollutants in our day-to-day lives. Some of these toxicants damage the genetic informa- tion within a cell and lead to genetic altera- tions. In general, genotoxicity is a temporary or permanent change to the genome that can be caused by exposure to specific chemicals. Genotoxicity can occur through exposure to toxicants found in air, food, water, and the workplace (Alloway & Ayres, 1993; Antonini et al., 2019; Boyce et al., 2020; Kodali et al., 2020; Langston, 1990; Shoeb, Kodali, Farris, Bishop, Meighan, Salmen, Eye, Friend, et al., 2017; Shoeb, Kodali, Farris, Bishop, Meighan, Salmen, Eye, Roberts, et al., 2017; Shoeb et al., 2020, 2021). ATSDR (2022a, 2022b) has developed detailed toxicological profiles for many hazardous substances. The agency uses its Substance Priority List to select substances based on their toxicity and frequency of
detection in the environment and then pre- pares toxicological profiles for highly ranked substances. Each peer-reviewed toxicological profile evaluates, summarizes, and interprets available toxicological and epidemiologi- cal information on a substance. The profiles provide insight into a substance’s occurrence, physiochemical properties, dierent expo- sures, potential health eects, mechanisms of action, and other topics (ATSDR, 2023a). Within the toxicological profiles, evidence of genotoxicity includes evidence of very spe- cific changes in some part of the processes of natural cell growth, division, and death. ATSDR defines genotoxicity as a specific adverse eect on the genome of living cells that, upon the duplication of aected cells, can be expressed as a mutagenic, clastogenic (i.e., chromosomal breakage-induced mutation), or carcinogenic event due to specific alteration of the molecular structure of the genome. Table 1 lists and defines some of the genotoxic terms used to analyze DNA alterations. ATSDR began to organize these varied markers and their eects across several toxic substances to 1) compare the eects, 2) cre- ate a hierarchy of genotoxic endpoints to help
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