Heavy Metals Induce Decline of Derivatives of 5-Methycytosine in Both DNA and RNA of Stem Cells

Abstract

Toxic heavy metals have been considered to be harmful environmental contaminations. The molecular mechanisms of heavy-metals-induced cytotoxicity and carcinogenicity are still not well elucidated. Previous reports showed exposures to toxic heavy metals can cause a change of DNA cytosine methylation (5-methylcytosine, 5-mC). However, it is still not clear whether heavy metals have effects on the recently identified new epigenetic marks in both DNA and RNA, i.e., 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-foC), and 5-carboxylcytosine (5-caC). Here, we established a chemical labeling strategy in combination with liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) analysis for highly sensitive detection of eight modified cytidines in DNA and RNA. The developed method allowed simultaneous detection of all eight modified cytidines with improved detection sensitivities of 128-443-fold. Using this method, we demonstrated that the levels of 5-hmC, 5-foC, and 5-caC significantly decreased in both the DNA and RNA of mouse embryonic stem (ES) cells while exposed to arsenic (As), cadmium (Cd), chromium (Cr), and antimony (Sb). In addition, we found that treatments by heavy metals induced a decrease of the activities of 10-11 translocation (Tet) proteins. Furthermore, we revealed that a content change of metabolites occurring in the tricarboxylic acid cycle may be responsible for the decline of the derivatives of 5-mC. Our study shed light on the epigenetic effects of heavy metals, especially for the induced decline of the derivatives of 5-mC in both DNA and RNA.

Solidification and Biotoxicity Assessment of Thermally Treated Municipal Solid Waste Incineration (MSWI) Fly Ash

“…Higher concentrations of heavy metals, which were related to leaching capacity, implied stronger inhibition. In addition, exposure to heavy metals induced great DNA damage and mutagenesis [13,23]. Moreover, the pH of leachate from all samples reached a significantly high level of about 12.5, which also contributed to bactericidal activity through changing osmotic pressure of cell cytomembrane.…”

Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study

“…It is one of the most relevant heavy metals in terms of potentially explaining adverse health effects of smoking because it has been associated with tobacco-related health outcomes, including cardiovascular disease (CVD) and cancer (Agarwal et al 2011;Andersson et al 2018;García-Esquinas et al 2014;Navas-Acien et al 2004). Increased exposure to Cd has been associated with differences in global DNAm in human (Ruiz-Hernandez et al 2015) and animal (Nica et al 2017;Šrut et al 2017) studies, possibly related to Cd-induced alterations of DNA methyltransferases (Benbrahim-Tallaa et al 2007;Jiang et al 2008;Poirier and Vlasova 2002;Takiguchi et al 2003;Yuan et al 2013) and ten-eleven translocation (TET) (Ravichandran 2017;Xiong et al 2017) enzymes activity. Some reports have suggested that TETs activity is influenced by oxidative stress (Delatte et al 2015).…”

Modified nucleoside triphosphates exist in mammals

“…Introduction of an easily ionizable group to targeted analytes could enhance the ionization efficiency in mass spectrometry analysis. 33 , 34 Our group recently established chemical labeling methods for the sensitive detection of endogenous low-abundant compounds by LC-MS analysis. 35 – 38 Along this line, here we synthesized 8-DMQ that harbors a diazo group to efficiently react with the phosphate group of NTPs under mild condition ( Fig.…”