Effect of exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) on mitochondrial DNA (mtDNA) copy number in rats.

Mitochondria are intracellular organelles responsible for biological oxidation and energy production. These organelles are susceptible to damage from oxidative stress and compensate for damage by increasing the number of copies of their own genome, mitochondrial DNA (mtDNA). Cancer and environmental exposure to some pollutants have also been associated with altered mtDNA copy number. Since exposures to polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been shown to increase oxidative stress, we hypothesize that mtDNA copy number will be altered with exposure to these compounds. mtDNA copy number was measured in DNA from archived frozen liver and lung specimens from the National Toxicology Program (NTP) study of female Harlan Sprague Dawley rats exposed to TCDD (3, 10, or 100 ng/kg/day), dioxin-like (DL) PCB 126 (10, 100, or 1000 ng/kg/day), non-DL PCB 153 (10, 100, or 1000 µg/kg/day), and PCB 126 + PCB 153 (10 ng/kg/day + 10 µg/kg/day, 100 ng/kg/day + 100 µg/kg/day, or 1000 ng/kg/day + 1000 µg/kg/day, respectively) for 13 and 52 weeks. An increase in mtDNA copy number was observed in the liver and lung of rats exposed to TCDD and the lung of rats exposed to the mixture of PCB 126 and PCB 153. A statistically significant positive dose-dependent trend was also observed in the lung of rats exposed to PCB 126 and a mixture of PCB 153 and PCB 126, although in neither case was the control copy number significantly exceeded at any dose level. These exposures produced a range of pathological responses in these organs in the two-year NTP studies. Conversely, there was a significant decrease or no change in mtDNA copy number in the liver and lung of rats exposed to non-DL PCB 153. This is consistent with a general lack of PCB 153 mediated liver or lung injury in the NTP study, with the exception of liver hypertrophy. Together, the results suggest that an increase in mtDNA copy number may serve as a sensitive, early biomarker of mitochondrial injury and oxidative stress that contributes to the development of the toxicity of dioxin-like compounds.

Telomeres as targets for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) in rats.

Telomere length (TL) can be affected by various factors, including age and oxidative stress. Changes in TL have been associated with chronic disease, including a higher risk for several types of cancer. Environmental exposure of humans to PCBs and dioxins has been associated with longer or shorter leukocyte TL. Relative telomere length (RTL) may serve as a biomarker associated with neoplastic and/or non-neoplastic responses observed with chronic exposures to TCDD and PCBs. RTL was measured in DNA isolated from archived frozen liver and lung tissues from the National Toxicology Program (NTP) studies conducted in female Harlan Sprague Dawley rats exposed for 13, 30, and 52 weeks to TCDD, dioxin-like (DL) PCB 126, non-DL PCB 153, and a mixture of PCB 126 and PCB 153. RTL was assessed by quantitative polymerase chain reaction (qPCR). Consistent with literature, decreased liver and lung RTL was seen with aging. Relative to time-matched vehicle controls, RTL was increased in both the liver and lung tissues of rats exposed to TCDD, PCB 126, PCB 153, and the mixture of PCB 126 and PCB 153, which is consistent with most epidemiological studies that found PCB exposures were associated with increased leukocyte RTL. Increased RTL was observed at doses and/or time points where little to no pathology was observed. In addition to serving as a biomarker of exposure to these compounds in rats and humans, increases in RTL may be an early indicator of neoplastic and non-neoplastic responses that occur following chronic exposure to TCDD and PCBs.