Abstract

Background:

Germline 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.

Objectives:

A 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.

Results:

Cadmium 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 $\mathrm{A}:\mathrm{T}\to \mathrm{G}:\mathrm{C}$ mutation rates and a lower overall $\mathrm{C}:\mathrm{G}\to \mathrm{G}:\mathrm{C}$ 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 $\mathrm{A}:\mathrm{T}\to \mathrm{G}:\mathrm{C}$ rate, whereas the lower exon mutation rate in cadmium was the result of a complete loss of exonic $\mathrm{C}:\mathrm{G}\to \mathrm{G}:\mathrm{C}$ mutations—mutations that are known to be enriched at 5-hydroxymethylcytosine. We experimentally show that cadmium exposure significantly reduced 5-hydroxymethylcytosine levels.

Discussion:

These 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

中文翻译：

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长期水蚤突变积累实验中镉诱导的种系突变的全基因组分析

摘要

背景：

种系突变为所有进化过程提供了原材料，并导致自发性人类疾病和紊乱的发生。然而，尽管人类和其他生物每天都与越来越多的可能致突变的化学物质相互作用，但仍缺乏对化学诱导的全基因组速率和种系突变谱变化的精确测量。

目标：

在存在和不存在与环境相关的镉浓度的情况下传播了大规模的Daphnia pulex突变积累实验，以量化镉对种系突变率和光谱的影响。

结果：

镉暴露极大地改变了种系突变的全基因组比率和区域谱。与对照条件相比，暴露于镉的水蚤总体$\mathrm{一种}：\mathrm{吨}\to \mathrm{G}：\mathrm{C}$突变率和较低的总体$\mathrm{C}：\mathrm{G}\to \mathrm{G}：\mathrm{C}$突变率。暴露于镉的水蚤具有较高的基因间突变率和较低的外显子突变率。镉暴露下较高的基因间突变率是基因间升高的结果$\mathrm{一种}：\mathrm{吨}\to \mathrm{G}：\mathrm{C}$率，而镉中较低的外显子突变率是外显子完全丧失的结果$\mathrm{C}：\mathrm{G}\to \mathrm{G}：\mathrm{C}$突变——已知富含 5-羟甲基胞嘧啶的突变。我们通过实验表明，镉暴露显着降低了 5-羟甲基胞嘧啶水平。

讨论：

这些结果提供了镉改变区域突变率的证据，并且可以通过干扰水蚤种系中的表观遗传过程来影响区域突变率。我们进一步表明，这些观察到的镉诱导的水蚤种系突变率变化可能是由镉对含锌结构域的抑制来解释的。我们报告的镉引起的种系突变率和光谱变化提供了镉致突变危险的全面视图，并深入了解其对人类健康的潜在影响。https://doi.org/10.1289/EHP8932