Abstract
Though clinical trials for medical applications of dimethyl sulfoxide (DMSO) reported toxicity in the 1960s, later, the FDA classified DMSO in the safest solvent category. DMSO became widely used in many biomedical fields and biological effects were overlooked. Meanwhile, biomedical science has evolved towards sensitive high-throughput techniques and new research areas, including epigenomics and microRNAs. Considering its wide use, especially for cryopreservation and in vitro assays, we evaluated biological effect of DMSO using these technological innovations. We exposed 3D cardiac and hepatic microtissues to medium with or without 0.1% DMSO and analyzed the transcriptome, proteome and DNA methylation profiles. In both tissue types, transcriptome analysis detected >2000 differentially expressed genes affecting similar biological processes, thereby indicating consistent cross-organ actions of DMSO. Furthermore, microRNA analysis revealed large-scale deregulations of cardiac microRNAs and smaller, though still massive, effects in hepatic microtissues. Genome-wide methylation patterns also revealed tissue-specificity. While hepatic microtissues demonstrated non-significant changes, findings from cardiac microtissues suggested disruption of DNA methylation mechanisms leading to genome-wide changes. The extreme changes in microRNAs and alterations in the epigenetic landscape indicate that DMSO is not inert. Its use should be reconsidered, especially for cryopreservation of embryos and oocytes, since it may impact embryonic development.
Highlights
Dimethyl sulfoxide (DMSO) is an organic polar aprotic molecule with an amphipathic nature that is ideal for dissolving poorly soluble polar and non-polar molecules
Our analysis clearly demonstrated that dimethyl sulfoxide (DMSO) cannot be considered biologically inert but induces large alterations in microRNAs and epigenetic landscape, especially in the maturing cardiac model
In order to obtain a first overview of DMSO-induced cross-omics effects, amounts of differentially changed entities are summarized for each platform
Summary
Dimethyl sulfoxide (DMSO) is an organic polar aprotic molecule with an amphipathic nature that is ideal for dissolving poorly soluble polar and non-polar molecules. Research from the 1960’s till 1990’s pinpointed a lot of biologically relevant effects of DMSO It was even actively investigated for medical use, but because of adverse effects especially affecting the eyes, most clinical trials were halted in 1965 by the United States Food and Drug Administration (FDA). LD50 values gained from monkeys indicated that 880 grams applied on the skin or 320 grams injected intravenously would result in 50% mortality in 80 kg humans[7] This relatively high dose changed the view on DMSO toxicity and the FDA classified DMSO in the same class as ethanol, namely class 3 solvent, which is the safest category with low toxic potential at levels normally accepted in pharmaceuticals[8]. This relatively high concentration of DMSO in topological applications is necessary because the skin is harder to penetrate than cell membranes
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