28-day repeated dose response study of diglycolic acid: Renal and hepatic effects

Sprando, Robert L.; Mossoba, Miriam E.; Black, T.N.; Keltner, Zachary; Vohra, Sanah; Olejnik, Nicholas; Toomer, Howard; Stine, Cynthia B.; Evans, Eric; Sprando, Jessica; Ferguson, Martine

doi:10.1016/j.fct.2017.03.047

Cited by 13 publications

(12 citation statements)

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“…In addition to changes in beating rate, we also observed that DGA could negatively affect Ca 2+ signal amplitude of the beating iCells (data not shown), which is consistent with DGA's ability to chelate divalent metal ions as an additional potential mechanism of toxicity as it has been described in the renal system [21]. By investigating the in vitro effects of DGA, we gained the opportunity to compare our findings to that of a recent in vivo rat study that was also recently performed by members of our research group [10]. In that study, rats were orally dosed on a daily basis with DGA dose solution ranging in strength from 0 to 300 mg/kg BW for a total of up to 30 days.…”

Section: Discussionsupporting

confidence: 61%

“…The identification and characterization of DGA as a renal and hepatic toxicant has been unequivocally established using in vitro cellular, in vivo rat, and even human systems [3,[7][8][9][10]. A single case report of human exposure indicated that the heart could be negatively affected by DGA, but this effect has never been previously captured in vitro or in vivo animal models.…”

Section: Discussionmentioning

confidence: 99%

“…In a tragic case report of unintentional human DGA oral exposure, not only were the kidneys and liver severely damaged, but there was some evidence of heart injury as well [9]. Our rat in vivo study, for example, revealed that after daily gavage dosing of different concentrations of DGA ranging up to 300 mg/kg BW, creatine kinase levels doubled or tripled in the animals that were treated with high doses of DGA, but no direct findings of gross or microscopic cardiac pathology [10]. These preliminary findings may suggest the possibility that the heart is vulnerable to the primary or secondary effects of DGA.…”

Section: Introductionmentioning

confidence: 96%

“…In the absence of published in vivo dose-response and lethal dose (LD)50 data on DGA, we sought out to begin investigating the potential for DGA to engender toxicity. Human in vitro and rat in vivo studies by our group and others have established that DGA is an acute renal and hepatic toxin, with the potential of also being a cardiotoxin [5][6][7][8][9][10]. In a tragic case report of unintentional human DGA oral exposure, not only were the kidneys and liver severely damaged, but there was some evidence of heart injury as well [9].…”

Section: Introductionmentioning

confidence: 99%

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

Calvert¹,

Mossoba²,

Bailey³

et al. 2017

J Toxicol Health

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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.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Calvert¹,

Mossoba²,

Bailey³

et al. 2017

J Toxicol Health

Self Cite

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show abstract

“…As our second goal, we sought to determine whether our in vitro model correlated with a rat in vivo model of DGA toxicology. As a subset of a recent in vivo study [17] , we measured the same kidney-specific biomarker measured in the HK-2 system in the urine of rats exposed to DGA. Our in vitro and in vivo findings yielded strikingly similar findings.…”

Section: Introductionmentioning

confidence: 99%