NEHA December 2023 Journal of Environmental Health

ADVANCEMENT OF THE SCIENCE

FIGURE 1

Possible Activation of Genotoxic Endpoints and DNA Damage-Induced Dysregulation of p53 Pathways After Exposure to Metals

Metal Exposure

Oxidativ e Stress

L ipid Peroxidation

Protein Modif ication Adduct F ormation

ROS/ RNS

ATM/ ATR

Apoptosis

Genotoxicity

DNA- Metal Interaction

p53

DNA Damage

DNA Repair

Telomere Elongation

Telomere Shortening

DNA Strand Breaks DNA- Methylation/ Acetylation DNA– Protein Cross- L inking DNA Repair Inhibition Chromosomal Aberration Sister- Chromatid Exchange Micronuclei F ormation

Dysregulated Replication and Transcription F actors Tumor F ormation

Bypass Senescence

Cell Cycle Arrest Senescence

Note. ATM = ataxia telangiectasia mutated; ATR = ATM and Rad3-related; ROS = reactive oxygen species; RNS = reactive nitrogen species.

ris, Bishop, Meighan, Salmen, Eye, Friend, et al., 2017; Shoeb, Kodali, Farris, Bishop, Meighan, Salmen, Eye, Roberts, et al., 2017; Shoeb et al., 2020, 2021). Elevated Ni con- centrations in welders’ blood have been found to result in significantly increased DNA damage, DNA–protein cross-linking, and DNA strand breaks (Danadevi et al., 2004; Popp et al., 1991). Discussion and Conclusion By profiling and comparing genotoxic end- points reported in the toxicological profiles, we provide insight into genotoxic endpoints aug- menting genome stability for various metals. We provide a guide to compare DNA damage from exposures to six dierent metals. Table 2 presents the most investigated endpoints asso- ciated with exposure to these metals.

The genotoxic eects of exposure to Zn clearly contrast with other genotoxic met- als, as many of the eects associated with Zn exposure are beneficial. Dierences among the other genotoxic metals are apparent to a lesser degree, with Cr and As (NTP classification 1, known human carcinogens) having a greater number of studies finding adverse genotoxic eects, including telomere alteration. Yet each of the highly toxic metals (including Hg) pres- ent diering genotoxic eects due to dier- ences in their mechanism pathways. Metals such as Ni, Cr, As, Pb, and Hg cause minor to severe DNA damage and telo- mere alteration by activating DNA damage response machinery (Figures 1 and 2). In some instances, the damage can be repaired by cellular repair mechanisms. If it is not repaired, or if the damage is repaired inappro-

priately, then genomic instability, epigenetic alterations, and several disease conditions can occur. For example, activation of DNA damage response might result in inflamma- tory responses and activation or mutation of p53, which could activate anti- or pro-apop- totic pathways (Figures 1 and 2). Some of these metals can also bind directly with DNA and proteins, causing direct genotoxic eects (Figure 1). Further, metal ions can catalyze reactive oxidative stress, and then form toxic lipid aldehydes, also known as by-products of lipid peroxidation (Shoeb, Kodali, Farris, Bishop, Meighan, Salmen, Eye, Friend, et al., 2017; Shoeb, Kodali, Farris, Bishop, Meighan, Salmen, Eye, Roberts, et al., 2017). Metal- induced (Ni, Pb, Hg, Cr, and As) epigenetic modifications have been reported, including inhibition of tumor suppressor genes by DNA

Volume 86 • Number 5