Cardiotoxicity testing of diglycolic acid using In Vitro and In Vivo models

Abstract

Background: Renal and hepatotoxicity of diglycolic acid (DGA) has been described with in vitro cellular models as well as in vivo animal and human systems. The possibility of DGA being toxic to other organs, such as the heart, has not been well investigated. A human case report identified the heart as a potential target organ of DGA, but an in-house in vivo rat study neither found gross nor microscopic pathological changes following repeated oral DGA exposure. Methods: To better understand the potential of DGA to adversely affect the heart, we focused our current study on evaluating cardiac effects of DGA by treating rat H9c2 cardiomyocytes and human induced pluripotent stem cells (iPSCs) that were differentiated into beating cardiomyocytes (iCells) with increasing concentrations of DGA in cell culture media. We investigated the effects, mechanisms, and value of our in vitro cellular cardiac models. Results: We measured mild effects of DGA on cytotoxicity and the cellular production of reactive oxygen species in H9c2 cells. Cardiomyocyte beat rate (BPM) was also mildly affected by transient treatment with DGA. Conclusions: Our study indicates that DGA cardiotoxicity in vitro correlates with the preliminary findings in our in vivo study where rats treated with daily doses of up to 300 mg/kg of DGA orally for 5 days did not show any major signs of abnormal cardiac pathology.

Comparison of diglycolic acid exposure to human proximal tubule cells in vitro and rat kidneys in vivo

“…It should be noted that although our study focused on the effects of DGA on renal systems, the potential for DGA to target other organ systems, exists. As such, we have also investigated the toxicity of direct exposure of DGA on the liver (manuscript submitted) and the heart [28] . Other publications have also demonstrated DGA-induced liver toxicity in animal models (Robinson et al, 2017, [17] ).…”