Depleted uranium induces sex- and tissue-specific methylation patterns in adult zebrafish

• This study demonstrates a sex-related effect of DU exposure on DNA methylation patterns.
• Impacts on DNA methylation patterns revealed a tissue-specific effect of DU exposure.
• The MS–AFLP and HPLC–MS/MS sensitively and complementarily demonstrated the responses to environmental concentrations of DU.

We examined the effects of chronic exposure to different concentrations (2 and 20 μg L−1) of environmentally relevant waterborne depleted uranium (DU) on the DNA methylation patterns both at HpaII restriction sites (5′-CCGG-3′) and across the whole genome in the zebrafish brain, gonads, and eyes. We first identified sex-dependent differences in the methylation level of HpaII sites after exposure. In males, these effects were present as early as 7 days after exposure to 20 μg L−1 DU, and were even more pronounced in the brain, gonads, and eyes after 24 days. However, in females, hypomethylation was only observed in the gonads after exposure to 20 μg L−1 DU for 24 days. Sex-specific effects of DU were also apparent at the whole-genome level, because in males, exposure to 20 μg L−1 DU for 24 days resulted in cytosine hypermethylation in the brain and eyes and hypomethylation in the gonads. In contrast, in females, hypermethylation was observed in the brain after exposure to both concentrations of DU for 7 days. Based on our current knowledge of uranium toxicity, several hypotheses are proposed to explain these findings, including the involvement of oxidative stress, alteration of demethylation enzymes and the calcium signaling pathway. This study reports, for the first time, the sex- and tissue-specific epigenetic changes that occur in a nonhuman organism after exposure to environmentally relevant concentrations of uranium, which could induce transgenerational epigenetic effects.