Increase in Cardiovascular Pathology in Female Sprague-Dawley Rats Following Chronic Treatment with 2,3,7,8-Tetrachlorodibenzop- Dioxin and 3,3',4,4',5-Pentachlorobiphenyl

Abstract

The effects of chronic exposure to dioxin (2,3,7,8,-tetrachlorodibenzo-pdioxin [TCDD]) and a dioxin-like compound (3,3',4,4',5-pentachlorobiphenyl [PCB126]) on the cardiovascular system were evaluated in female Harlan Sprague-Dawley rats as part of an ongoing National Toxicology Program investigation. The animals were gavage treated 5 d per week with up to 1000 ng of PCB126 per kilogram of body weight per day or up to 100 ng of TCDD per kilogram of body weight per day for up to 2 yr. The control animals received only a corn oil/acetone vehicle (99:1 mixture). The corresponding stop-study groups received the highest doses for 31 wk and then received only the vehicle for the remainder of the study. After a full necropsy of all animals, a complete set of tissues was examined microscopically. Administration of each compound was associated with treatment-related increases in the incidences of degenerative cardiovascular lesions. Cardiomyopathy and chronic active arteritis increased in a dose-related manner in all groups treated with PCB126 or with TCDD. Increased incidences were also observed in the stop-study groups, indicating that a shorter term exposure may produce some effects. The average severity of cardiomyopathy was minimal or slightly greater in all dose groups, including the controls. Chronic active arteritis occurred primarily in the mesentery and pancreas, although the rectum, liver, heart, ovary, uterus, and glandular stomach in the PCB126 study and the liver and ovary in the TCDD study were affected in a few of the dosed animals. The authors' investigations indicate that the rat cardiovascular system is a target for dioxin toxicity, which increases the incidence of spontaneous cardiomyopathy and arteritis.

Dietary exposure to polychlorinated biphenyls and risk of myocardial infarction — A population-based prospective cohort study

“…In cell cultures, PCBs cause endothelial cell dysfunction through altered gene expression, inflammation and oxidative stress [2,6,7], supporting the hypothesis that exposure to PCBs is associated with atherosclerosis [53]. In animal experiments, chronic exposure to PCBs is associated with key events in the development of CVD including hypertension and hyperlipidemia as well as cardiovascular toxicity including cardiomyopathy [3][4][5].…”

“…Experimental studies indicate that PCBs cause endothelial cell dysfunction, hyperlipidemia and hypertension that are corner stones in the development of atherosclerosis [2][3][4][5][6][7]. In humans, PCB exposure has been associated with several intermediate risk factors for CVD such as hypertension [8][9][10][11], hyperlipidemia [9,12,13], atherosclerosis [14], and type 2 diabetes [15,16].…”

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

“…Similarly, in female Sprague-Dawley rats treated 5 days per week with up to 100 ng/kg/day TCDD for 2 years, cardiomyopathy and chronic active arteritis increased in a dose dependent manner. However the severity of cardiomyopathy did not increase in a dose-responsive manner and only became evident in the later treatment groups (Jokinen et al, 2003) …”

Comparison of chronic toxicity and carcinogenicity of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) in 2‐year bioassays in female Sprague‐Dawley rats

“…Increased incidences of minimal to mild multifocal cardiomyopathy were seen in rats of the NTP 2-year study, administered 10 ng/kg or greater [23]. The incidence of cardiomyopathy was lower in the 100-ng/kg stop-exposure groups compared to the 100-ng/kg core study group, but was greater than in the vehicle controls.…”

“…The incidence of cardiomyopathy was lower in the 100-ng/kg stop-exposure groups compared to the 100-ng/kg core study group, but was greater than in the vehicle controls. Cardiomyopathy had the typical microscopic appearance of spontaneous cardiomyopathy as seen in aging F344/N rats [23]. The heart was also considered a target organ in the Dow study, reporting an increase above the background incidence of myocardial degenerative changes.…”