Subcellular Localization of TCDD Differs between the Liver, Lungs, and Kidneys after Acute and Subchronic Exposure: Species/Dose Comparisons and Possible Mechanism

Abstract

Subcellular localization of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds has been examined only in the liver. The objective of this study was (1) to examine and compare the subcellular distribution of TCDD within hepatic and nonhepatic (lungs/kidneys) tissues of female Sprague-Dawley rats acutely exposed to TCDD, (2) to analyze species comparisons in the subcellular localization of TCDD in multiple tissues, (3) to investigate the effect of dose on subcellular distribution of TCDD, (4) to analyze the effect of subchronic exposure on the subcellular distribution of TCDD, and (5) to examine one possible mechanism for subcellular localization of TCDD. Female Sprague-Dawley rats and B6C3F1 mice received a single oral dose of 0.1, 1.0, or 10 microg [3H]TCDD/kg body weight and subcellular fractions of the liver, lungs, and kidneys were prepared by differential centrifugation 3 days after exposure. Analysis of the rat subcellular fractions revealed that TCDD was equally distributed between the hepatic P9 (mitochondrial, lysosomal, and nuclear) and S9 (cytosol and microsomal) fractions at all doses tested. In contrast, TCDD was concentrated in the P9 of rat nonhepatic tissues at all doses studied. Differential centrifugation of the hepatic S9 showed that TCDD was localized within the hepatic P100 (microsomal) fraction at all doses tested. In contrast, TCDD localized in pulmonary and renal S100 (cytosolic) fractions at all doses. The subcellular distribution of TCDD in the liver and lungs of acutely exposed B6C3F1 mice was similar to that observed in the rats. Although TCDD was concentrated within the renal P9, the remainder of TCDD in the S9 was evenly distributed between the S100 and the P100 fractions of acutely exposed B6C3F1 mice. Subchronic exposure of B6C3F1 mice to 1.5 or 150 ng [3H]TCDD/kg/day revealed that increasing dose resulted in equal distribution of TCDD between the hepatic S9 and P9 versus concentration in the renal P9. In addition, a dose-dependent increase in accumulation of TCDD in the hepatic P100 was accompanied by a dose-dependent increase in TCDD localization in the renal S100 of mice subchronically exposed to TCDD. TCDD exposure in rats resulted in a dose-dependent increase in the induction of CYP1A1 protein and associated enzyme activity in hepatic, pulmonary, and renal microsomes. TCDD-induced CYP1A2 protein levels and associated enzymatic activity were only present in hepatic microsomes. This is the first report to suggest that subcellular distribution of TCDD differs between hepatic and nonhepatic tissues and demonstrate that the liver-specific microsomal localization of TCDD in female Sprague-Dawley rats also occurs in the liver of female B6C3F1 mice acutely or subchronically exposed to TCDD. In addition, these data are consistent with the hypothesis that the hepatic sequestration of TCDD is due to an interaction with CYP1A2. Furthermore, the lack of pulmonary/renal sequestration coupled with the lack of localization of TCDD in pulmonary/renal microsomes also supports the r...

Dioxin-Dependent and Dioxin-Independent Gene Batteries: Comparison of Liver and Kidney in AHR-Null Mice

“…It is not clear, however, if these are primary effects of TCDD as these animals exhibited reduced activity, a 27% decline in food intake and a 28% decline in body-weight (feed-restricted controls were not included). On balance, then, it appears that adult kidney is not acutely responsive to TCDD, perhaps in part because TCDD is sequestered in liver and does not distribute to the kidney (Santostefano et al , 1996). It is known, however, that chronic low doses result in hypertension which may be due, in part, to effects on kidney (Kopf et al , 2008).…”

Physiologically Based Pharmacokinetic Model for Developmental Exposures to TCDD in the Rat

“…Acute exposure in nonpregnant rats. Female Sprague-Dawley rats (age, 8 weeks; 250 g) received a single dose of 10 mg 3 H-TCDD/kg of body weight (Santostefano et al, 1996). Tissue samples were collected at 0.5, 1, 3, 8, and 24 h, 7 days, 14 days, and 35 days after exposure.Three to five animals/group were used.…”

Induction of Lung Lesions in Female Rats Following Chronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

“…The respiratory tract in general and, more specifically, the lung were identified in these studies as targets with increased cancer risk. Al-though the lung appears to be a target organ for TCDD in people, there are only a few studies in experimental animals that attempt to investigate the pulmonary effects (2,3,25,32,33).…”