Abstract
Induction of heart disease can be related to exposure to a number of agents, including environmental chemicals. Studies with laboratory rodents are commonly use to identify cardiotoxic agents and to investigate mechanisms of toxicity. This study was conducted to characterize spontaneous and chemically-induced rodent heart lesions. A retrospective light-microscopic evaluation was performed on the hearts of F344 rats and B6C3F1 mice from National Toxicology Program studies of six chemicals in which chemically-induced myocardial toxicity was present: oxymetholone, monochloroacetic acid, 3,3′–4,4′-tetrachoroazoxybenzene, diethanolamine, urethane, and methylbromide. Two myocardial lesions were observed: cardiomyopathy (multifocal myofiber degeneration that could occur spontaneously or as a treatment effect) and degeneration (diffuse myofiber degeneration that was clearly related to treatment). Oxymetholone produced cardiotoxicity that was apparent as an increase in the incidence and average severity of cardiomyopathy. The remaining five chemicals produced degeneration, which appeared morphologically similar with each of the chemicals. Based on available information concerning possible mechanisms by which each of these chemicals may induce cardiotoxicity, this evaluation indicated it may be possible to place the chemicals into two main categories: (1) those that primarily affected the coronary vasculature with secondary effects on the myocardium (oxymetholone), and (2) those that had a direct toxic effect on the myocardial cells (the remaining five chemicals). Beyond this, however, light-microscopic findings did not indicate any specific mechanisms. Additional morphologic evaluations, such as electron microscopy or special histochemical or immunostains, may help identify specific subcellular sites of toxic damage, which in turn can indicate appropriate types of molecular mechanistic studies.
Similar content being viewed by others
References
Greaves P. (2000). Cardiovascular system. In Histopathology of Preclinical Toxicity Studies (Greaves, P., ed), Elsevier, Amsterdam, pp. 254–311.
Mone, S.M., Gillman, M.W., Miller, R.L., Herman, E.H., and Lipshultz, S. E. (2004). Effects of environmental exposures on the cardiovascular system: Prenatal period through adolescence. Pediatrics 113:1058–1069.
Virmani, R. (1991). Cocaine-associated cardiovascular disease: Clinical and pathological aspects. NIDA Res. Monogr. 108:220–229.
Patel, V.B., Why, H.J., Richardson, P.J., and Preedy, V.R. (1997). The effects of alcohol on the heart. Adverse Drug React. Toxicol. Rev. 16:15–43.
Brook, R.D., Franklin, B., Cascio, W., Hong, Y., Howard, G., Lipsett, M., Luepker, R., et al. (2004). Air pollution and cardiovascular disease. A statement for healthcare professionals from the expert panel on population and prevention science of the American Heart Association. Circulation 109:2655–2671.
Benowitz, N.L. (1992). Cardiotoxicity in the workplace. Occup. Med. 7:465–478.
Deng, J.-F. (2002). Clinical and laboratory investigations in herbal poisonings. Toxicology 181–182:571–576.
Samenuk, D., Link, M.S., Hamoud, M.K., Contreras, R., Theohardes, T.C., Wang, P.J., and Estes, M.E. III. (2002). Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin. Proc. 77:12–16.
Lindsay B.D. (2002). Are serious adverse cardiovascular events an unintended consequence of the Dietary Supplement Health and Education Act of 1994? Mayo Clin. Proc. 77:7–9.
Kodavanti, U.P., Moyer, C.F., Ledbetter, A.D., Schladweiler, M.C., Costa, D.L., Hauser, R., et al. (2003). Inhaled environmental combustion particles cause myocardial injury in the Wistar Kyoto rat. Toxicol. Sci. 71:237–245.
Moyer, C.F., Kodavanti, U.P., Haseman, J. K., Costa, D.L., and Nyska, A. (2002). Systemic vascular disease in male B6C3F1 mice exposed to particulate matter by inhalation: Studies conducted by the National Toxicology Program. Toxicol. Pathol. 30:427–434.
Calvert, G.M., Wall, D.K., Sweeney, M.H., and Fingerhut, M.A. (1998). Evaluation of cardiovascular outcomes among U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environ. Health Perspect. 106:S635-S643.
Jokinen, M.P., Walker, N., Brix, A.E., Sells, D.M., Haseman, J.K., and Nyska, A. (2003). Increase in cardiovascular pathology in female Sprague-Dawley rats following chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3,3′,4,4′,5-pentachlorobiphenyl. Cardiovasc. Toxicol. 3:299–310.
Nyska, A., Murphy, E., Foley, J.F., Collins, B.J., Petranka, J., Howden, R., et al., (2004). Acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine. Toxicol. Sci. 83(2): 388–396.
National Toxicology Program (NTP) (1999). NTP Technical Report on Toxicology and Carcinogenesis Studies of Oxymetholone in F344/N Rats and Toxicology Studies of Oxymetholone in B6C3F1 Mice. Technical Report Series No. 485. NIH Publication No. 99-3975. U.S. Department of Health and Human Services. Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (1992). NTP Technical Report on Toxicology and Carcinogenesis Studies of Monochloroacetic Acid in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 396. NIH Publication No. 92-2851. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (1999). NTP Technical Report on the Toxicity Studies of 3,3′,4,4′-Tetrachloroazoxybenzene Administered by Gavage to F344/N Rats and B6C3F1 Mice. Toxicity Report Series No. 66. NIH Publication No. 99-3846. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (1999). NTP Technical Report on Toxicology and Carcinogenesis Studies of Diethanolamine in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 478. NIH Publication No. 99-3968. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (2003). NTP Technical Report on Toxicology and Carcinogenesis Studies of Urethane. Ethanol, and Urethane/Ethanol in B6C3F1 Mice. Technical Report Series No. 510. NIH Publication No. 04-4444, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (1992). NTP Technical Report on the Toxicology and Carcinogenesis Studies of Methyl Bromide in B6C3F1 Mice. Technical Report Series No. 385. NIH Publication No. 92-2840. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. Research Triangle Park, NC
Ruben, Z., Arceo, R.J., Bishop, S.P., Elwell, M.R., Kerns, W.D., Mesfin, G.M., et al. (2000). Non-proliferative lesions of the heart and vasculature in rats. in Guides for Toxicologic Pathology, STP/ARP/AFIP, Washington, DC.
MacKenzie, W.F. and Alison, R.H. (1990). Heart. In Pathology of the Fischer Rat (Boorman, G.A., Eustis, S.L., Elwell, M.R., Montgomery, C.A. Jr., and Mackenzie, W.F., eds) Academic Press, San Diego, CA, pp. 461–471.
Elwell, M.R., Mahler, J.F., and Ruecker, F.A (2004). Proliferative and non-proliferative lesions in the heart and vasculature in mice. In Guides for Toxicologic Pathology, STP/ARP/AFIP, Washington, DC.
Eustis, S.L., Haber, S.B., Drew, R. T., and Yang, R.S.H. (1988). Toxicology and pathology of methyl bromide in F344 rats and B6C3F1 mice following repeated inhalation exposure. Fun. Appl. Toxicol. 11:594–610.
Kato, N., Morinobu, S., and Ishizu, S. (1986). Subacute inhalation experiment for methyl bromide in rats. Ind. Health 24:87–103.
Reuzel, P.G.J., Dreef-Van Der Meulen, H. C., Hollanders, V.M.H., Kuper, C.F., Feron, V.J., and Van Der Heijden, C.A. (1991). Clironic inhalation toxicity and carcinogenicity study of methyl bromide in Wistar rats. Food Chem. Toxicol. 29:31–39.
Ayers, K.M. and Jones, S.R. (1978). The cardiovascular system. In Pathology of Laboratory Animals (Benirschke, K., Garner, F.M., and Jones, T.C., eds). Springer-Verlag, New York, pp. 1–69.
Combs, A.B. and Acosta, D. (1990). Toxic mechanisms of the heart: a review. Toxicol. Pathol. 18:583–596.
Sullivan, M.L., Martinez, C.M., Gennis, P., and Gallagher, E.J. (1998). The cardiactoxicity of anabolic steroids. Prog. Cardiovasc. Dis. 41:1–15.
Welder, A.A., Robertson, J.W., Fugate, R.D., and Melchert, R.B. (1995). Anabolic-androgenic steroid-induced toxicity in primary neonatal rat myocardial cell cultures. Toxicol. Appl. Pharmacol. 133;328–342.
Vesselinovitch, S.D., and Mihailovich, N. (1968). The development of neurogenic neoplasms, embryonal kidney tumors, Harderian gland adenomas, Anitschkow cell sarcomas of the heart, and other neoplasms in urethan-treated newborn rats. Cancer Res. 28:888–897.
Dunnick, J., Johnson, J., Horton, J., and Nyska, A. (2004). Bis(2-chloroethoxy)methane-induced mitochondrial and myofibrillar damage: short-term time-course study. Toxicol. Sci., 81: 243–252.
Visarius, T.M., Bahler, H., Kupfer, A., Cerny, T., and Lauterburg, B.H. (1998). Thiodiglycolic acid is excreted by humans receiving ifosfamide and inhibits mitochondrial function in rats. Drug Metab. Dispos. 26:193–196.
Dunnick, J.K., Lieuallen, W., Moyer C., Orzech, D. and Nyska, A. (2004). Cardiac damage in rodents after exposure to bis(2-chloroethoxy)methane. Toxicol. Pathol. 32: 309–317.
Draminski, W. and Trojanowska, B. (1981). Chromatographic determination of thiodiglycolic acid—a metabolite of vinyl chloride. Arch. Toxicol. 48:289–292.
Loqueviel, C., Malet-Martino, M., and Martino, R. (1997). A 13C NMR study of 2-(13)C-chloroacetaldehyde, a metabolite of ifosfamide and cyclophosphamide, in the isolated perfused rabbit heart model. Initial observations on its mitochondrial function in rats. Drug Metab. Dispos. 26: 193–196.
Barbee, S.J., and Hartung, R. (1979). The effect of diethanolamine on hepatic and renal phospholipid metabolism in the rat. Toxicol. Appl. Pharmacol. 47:421–430.
Barbee, S.J. and Hartung, R. (1979). Diethanolamine-induced alteration of hepatic mitochondrial function and structure. Toxicol. Appl. Pharmacol. 47:431–440.
Melnick, R.L., Mahler, J., Bucher, J.R., Hejtmancik, M., Singer, A., and Persing, R.L., (1994). Toxicity of diethanolamine. 2. Drinking water and topical application exposures in B6C3F1 mice. J. Appl. Toxicol. 14:11–19.
Melnick, R.L., Mahler, J., Bucher, J.R., Thompson M., Hejtmancik, M., Ryan, M.J., and Mezza, L. E. (1994). Toxicity of diethanolamine. 1. Drinking water and topical application exposures in F344 rats. J. Appl. Toxicol. 14:1–9.
Milei, J. and Bolomo, N. J. (1983). A routine method for diagnosis of early myocardial infarction. Int. J. Cardiol. 4, 319–321.
Milei, J. and Storino, R. (1986). Early myocardial infarction. A feasible histologic diagnostic procedure. Jp. Heart. J. 27, 307–319.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jokinen, M.P., Lieuallen, W.G., Johnson, C.L. et al. Characterization of spontaneous and chemically induced cardiac lesions in rodent model systems. Cardiovasc Toxicol 5, 227–244 (2005). https://doi.org/10.1385/CT:5:2:227
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/CT:5:2:227