Sex‐Specific Adverse Effects of Chronic Dichloroacetate Administration in Mice

Abstract

Dichloroacetate (DCA) is a small, orally available inhibitor of pyruvate dehydrogenase kinase (PDK). Consequently, DCA stimulates the activity of the pyruvate dehydrogenase complex (PDC), leading to glucose oxidation in the mitochondria. Therapeutically, DCA is employed to decrease lactate production and has been used in the acute treatment of certain metabolic diseases, such as lactic acidosis. More recently, DCA has been reported to have anti‐cancer efficacy and has been suggested as a chemotherapeutic. However, DCA as a therapeutic agent may have adverse effects, as it has been reported to cause hepatocellular and peripheral nerve toxicity. As it may have further adverse effects when used chronically, there is a need for further investigation of the effects and mechanisms triggered by DCA. We aimed at assessing the effects of chronic DCA administration in the mouse heart. We hypothesized that long‐term treatment of mice with DCA will lead to cardiac toxicity, ultimately contributing to heart failure development, and that the severity of these effects will differ between the sexes. Fourteen‐month old male and female C57Bl6 mice (n = 12/group) were treated with vehicle or DCA (0.8 g/L in drinking water leading to 80 mg/kg/d, similar to clinically used dose) for 7 months. All mice underwent transthoracic 2D echocardiography under anesthesia (isoflurane 2%) following established procedures. The study was conducted in conformance with the FASEB Statement of Principles for the use of Animals in Research and Education. Following the 7‐mo DCA treatment, echocardiographic measurements revealed no major functional effect in female mice. In contrast, male mice treated with DCA exhibited a significant systolic dysfunction associated with impaired contractility compared with control mice (ejection fraction: 36% vs. 47% respectively, P < 0.001). Ultrastructural analysis of left ventricular samples by transmission electron microscopy revealed increased numbers of heavily damaged and swollen mitochondria in male mice treated with DCA, while female mice treated with DCA were not affected. Further cellular characterization revealed no major effects on apoptosis, as assessed by the TUNEL assay, or fibrosis, as assessed by Sirius‐red staining. Transcriptome analysis of left ventricles from vehicle‐ and DCA‐treated mice by genome‐wide expression profiling (n = 5/group, P < 0.001) revealed decreased levels of genes involved in ion channel activity and metabolism in male DCA‐treated mice. In contrast, the levels of genes with antioxidant activity were increased in female DCA‐treated mice. In conclusion, chronic DCA treatment leads to male‐specific cardiac toxicity and dysfunction. These findings highlight the role of biological sex in therapeutic and adverse effects of pharmacological agents.Support or Funding InformationDZHK (German Centre for Cardiovascular Research) and BMBF (Federal Ministry of Education and Research).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.