Dataset Information

Resistance of mitochondrial DNA to cadmium and Aflatoxin B1 damage-induced germline mutation accumulation in C. elegans.

ABSTRACT: Mitochondrial DNA (mtDNA) is prone to mutation in aging and over evolutionary time, yet the processes that regulate the accumulation of de novo mtDNA mutations and modulate mtDNA heteroplasmy are not fully elucidated. Mitochondria lack certain DNA repair processes, which could contribute to polymerase error-induced mutations and increase susceptibility to chemical-induced mtDNA mutagenesis. We conducted error-corrected, ultra-sensitive Duplex Sequencing to investigate the effects of two known nuclear genome mutagens, cadmium and Aflatoxin B1, on germline mtDNA mutagenesis in Caenorhabditis elegans. Detection of thousands of mtDNA mutations revealed pervasive heteroplasmy in C. elegans and that mtDNA mutagenesis is dominated by C:G → A:T mutations generally attributed to oxidative damage. However, there was no effect of either exposure on mtDNA mutation frequency, spectrum, or trinucleotide context signature despite a significant increase in nuclear mutation rate after aflatoxin B1 exposure. Mitophagy-deficient mutants pink-1 and dct-1 accumulated significantly higher levels of mtDNA damage compared to wild-type C. elegans after exposures. However, there were only small differences in mtDNA mutation frequency, spectrum, or trinucleotide context signature compared to wild-type after 3050 generations, across all treatments. These findings suggest mitochondria harbor additional previously uncharacterized mechanisms that regulate mtDNA mutational processes across generations.

SUBMITTER: Leuthner TC

PROVIDER: S-EPMC9410910 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Resistance of mitochondrial DNA to cadmium and Aflatoxin B1 damage-induced germline mutation accumulation in C. elegans.

Leuthner Tess C TC Benzing Laura L Kohrn Brendan F BF Bergemann Christina M CM Hipp Michael J MJ Hershberger Kathleen A KA Mello Danielle F DF Sokolskyi Tymofii T Stevenson Kevin K Merutka Ilaria R IR Seay Sarah A SA Gregory Simon G SG Kennedy Scott R SR Meyer Joel N JN

Nucleic acids research 20220801 15

Mitochondrial DNA (mtDNA) is prone to mutation in aging and over evolutionary time, yet the processes that regulate the accumulation of de novo mtDNA mutations and modulate mtDNA heteroplasmy are not fully elucidated. Mitochondria lack certain DNA repair processes, which could contribute to polymerase error-induced mutations and increase susceptibility to chemical-induced mtDNA mutagenesis. We conducted error-corrected, ultra-sensitive Duplex Sequencing to investigate the effects of two known nu ...[more]

PMID: 35947695

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Project description:BackgroundGermline mutations provide the raw material for all evolutionary processes and contribute to the occurrence of spontaneous human diseases and disorders. Yet despite the daily interaction of humans and other organisms with an increasing number of chemicals that are potentially mutagenic, precise measurements of chemically induced changes to the genome-wide rate and spectrum of germline mutation are lacking.ObjectivesA large-scale Daphnia pulex mutation-accumulation experiment was propagated in the presence and absence of an environmentally relevant cadmium concentration to quantify the influence of cadmium on germline mutation rates and spectra.ResultsCadmium exposure dramatically changed the genome-wide rates and regional spectra of germline mutations. In comparison with those in control conditions, Daphnia exposed to cadmium had a higher overall A:T→G:C mutation rates and a lower overall C:G→G:C mutation rate. Daphnia exposed to cadmium had a higher intergenic mutation rate and a lower exonic mutation rate. The higher intergenic mutation rate under cadmium exposure was the result of an elevated intergenic A:T→G:C rate, whereas the lower exon mutation rate in cadmium was the result of a complete loss of exonic C:G→G:C mutations-mutations that are known to be enriched at 5-hydroxymethylcytosine. We experimentally show that cadmium exposure significantly reduced 5-hydroxymethylcytosine levels.DiscussionThese results provide evidence that cadmium changes regional mutation rates and can influence regional rates by interfering with an epigenetic process in the Daphnia pulex germline. We further suggest these observed cadmium-induced changes to the Daphnia germline mutation rate may be explained by cadmium's inhibition of zinc-containing domains. The cadmium-induced changes to germline mutation rates and spectra we report provide a comprehensive view of the mutagenic perils of cadmium and give insight into its potential impact on human population health. https://doi.org/10.1289/EHP8932.

Dataset Information

Resistance of mitochondrial DNA to cadmium and Aflatoxin B1 damage-induced germline mutation accumulation in C. elegans.

Publications

Resistance of mitochondrial DNA to cadmium and Aflatoxin B1 damage-induced germline mutation accumulation in C. elegans.

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