Mitochondrial toxin 3-nitropropionic acid induces cardiac and neurotoxicity differentially in mice

Kathleen L. Gabrielson, Barbara A. Hogue, Vilhelm A. Bohr, A. J. Cardounel, Waco Nakajima, Julia Kofler, Jay L. Zweier, E. Rene Rodriguez, Lee J. Martin, Nadja C. De Souza-Pinto, Joseph Bressler

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Abstract

We investigated the effects of 3-nitropropionic acid (3NPA), a previously characterized neurotoxin, in four strains of mice to better understand the molecular basis of variable host responses to this agent. Unexpectedly, we found significant cardiac toxicity that always accompanied the neurotoxicity in all strains of mice in acute and subacute/chronic toxicity testing. Caudate putamen infarction never occurred without cardiac toxicity. All mouse strains tested are sensitive to 3NPA although the C57BL/6 and BALB/c mice require more exposure than 129SVEMS and FVB/n mice. Cardiac toxicity alone was found in 50% of symptomatic mice tested and morphologically, the cardiac toxicity is characterized by diffuse swelling of cardiomyocytes and multifocal coagulative contraction band necrosis. In subacute to chronic exposure, atrial thrombosis, cardiac mineralization, cell loss, and fibrosis are combined with cardiomyocyte swelling and necrosis. Ultrastructurally, mitochondrial swelling occurs initially, followed by disruption of myofilaments. Biochemically, isolated heart mitochondria from the highly sensitive 129SVEMS mice have a significant reduction of succinate dehydrogenase activity, succinate oxygen consumption rates, and heart adenosine triphosphate after 3NPA treatment. The severity of morphological changes parallels the biochemical alterations caused by 3NPA, consistent with cardiac toxicity being a consequence of the effects of 3NPA on succinate dehydrogenase. These experiments show, for the first time, that 3NPA has important cardiotoxic effects as well as neurotoxic effects, and that cardiac toxicity possibly resulting from inhibition of the succinate dehydrogenase in heart mitochondria, contributes to the cause of death in 3NPA poisoning in acute and subacute/chronic studies in mice.

Original languageEnglish (US)
Article number62536
Pages (from-to)1507-1520
Number of pages14
JournalAmerican Journal of Pathology
Volume159
Issue number4
DOIs
StatePublished - Jan 1 2001

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Gabrielson, K. L., Hogue, B. A., Bohr, V. A., Cardounel, A. J., Nakajima, W., Kofler, J., Zweier, J. L., Rodriguez, E. R., Martin, L. J., De Souza-Pinto, N. C., & Bressler, J. (2001). Mitochondrial toxin 3-nitropropionic acid induces cardiac and neurotoxicity differentially in mice. American Journal of Pathology, 159(4), 1507-1520. [62536]. https://doi.org/10.1016/S0002-9440(10)62536-9