Effects of methyl and inorganic mercury exposure on genome homeostasis and mitochondrial function in Caenorhabditis elegans

Abstract

Mercury toxicity mechanisms have the potential to induce DNA damage and disrupt cellular processes, like mitochondrial function. Proper mitochondrial function is important for cellular bioenergetics and immune signaling and function. Impacts of mercury on the nuclear genome (nDNA) are conflicting and inconclusive, and mitochondrial DNA (mtDNA) impacts are relatively unknown. In this study, we assessed genotoxic (mtDNA and nDNA), metabolic, and innate immune impacts of inorganic and organic mercury exposure in Caenorhabditis elegans. Genotoxic outcomes measured included DNA damage, DNA damage repair (nucleotide excision repair, NER; base excision repair, BER), and genomic copy number following MeHg and HgCl2 exposure alone and in combination with known DNA damage-inducing agents ultraviolet C radiation (UVC) and hydrogen peroxide (H2O2), which cause bulky DNA lesions and oxidative DNA damage, respectively. Following exposure to both MeHg and HgCl2, low-level DNA damage (~0.25 lesions/10 kb mtDNA and nDNA) was observed. Unexpectedly, a higher MeHg concentration reduced damage in both genomes compared to controls. However, this observation was likely the result of developmental delay. In co-exposure treatments, both mercury compounds increased initial DNA damage (mtDNA and nDNA) in combination with H2O2 exposure, but had no impact in combination with UVC exposure. Mercury exposure both increased and decreased DNA damage removal via BER. DNA repair after H2O2 exposure in mercury-exposed nematodes resulted in damage levels lower than measured in controls. Impacts to NER were not detected. mtDNA copy number was significantly decreased in the MeHg-UVC and MeHg-H2O2 co-exposure treatments. Mercury exposure had metabolic impacts (steady-state ATP levels) that differed between the compounds; HgCl2 exposure decreased these levels, while MeHg slightly increased levels or had no impact. Both mercury species reduced mRNA levels for immune signaling-related genes, but had mild or no effects on survival on pathogenic bacteria. Overall, mercury exposure disrupted mitochondrial endpoints in a mercury-compound dependent fashion.

Predictors of mitochondrial DNA copy number and damage in a mercury‐exposed rural Peruvian population near artisanal and small‐scale gold mining: An exploratory study

“…The lack of a direct impact of Hg exposure on mtDNA CN or damage is the first report of effect or lack thereof in a human population. We note that the potential for interactive effects with genotoxicants (as has been observed in laboratory models: Wyatt et al, , b) or with dietary limitations (as in the current study) remains important. The average lesion values for some groups in this study are in the range of 0.4–0.6 lesions/10 kb, compared to previously reported values of 0.75/10 kb for patients with Friedreich's ataxia (Haugen et al, ), and 0.17/10 kb for veterans with Gulf War Illness (Chen et al, ).…”

“…MeHg exposure led to increased mtDNA damage at 1 μM, but surprisingly, decreased damage at 5 μM. Perhaps most strikingly, the amount of mtDNA damage after hydrogen peroxide exposure was significantly increased by pre‐exposure to either inorganic or organic mercury (Wyatt et al ).…”

Cell Biology of the Mitochondrion

“…The results were mixed with sensitization to arsenite and ultraviolet radiation, protection from rotenone, and no effects on the toxicity of other compounds. Closely related work measuring the effects of organic and inorganic mercury on C. elegans documented that mitochondrial endpoints (mtDNA copy number and ATP levels) were susceptible to mercury (Wyatt et al 2017). The precise changes depended on coexposure to other secondary toxins (UVC and hydrogen peroxide), and whether the mercury was presented in organic or inorganic form.…”

Caenorhabditis elegans as an emerging model system in environmental epigenetics

“…As with P450 genes, such differences may be intentionally employed as part of experimental design. For example, although humans have both innate and adaptive immune systems, because C. elegans lacks an adaptive immune system, we were able to isolate effects of inorganic mercury and methylmercury on the innate immune system (Wyatt et al, ). Similarly, although humans rapidly methylate inorganic arsenic after absorption and often have mixtures of parent chemical and metabolites in circulation, because C. elegans lacks an arsenic methyltransferase, we were able to isolate the effect of inorganic arsenic on mitochondrial function (Luz et al, ).…”