Synergistic effect of 2,2',4,4',5,5'-hexachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic porphyrin levels in the rat.

Abstract

We studied the effect of polychlorinated biphenyls (PCBs) on hepatic porphyrin accumulation in female Sprague-Dawley rats by feeding them diets containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), or combinations of the single PCB congeners with TCDD for 13 weeks. A dose-dependent increase in hepatic porphyrin accumulation occurred after TCDD, PCB 126, or PCB 156 administration, reaching maximal levels of about twice control values. The lowest dose levels for which a significant increase in hepatic porphyrin accumulation was found were 0.7 microgram TCDD/kg diet, 50 micrograms PCB 126/kg diet, or 6 mg PCB 156/kg diet. These doses are equivalent to 47 ng TCDD/kg/day, 3.2 micrograms PCB 126/kg/day, and 365 micrograms PCB 156/kg/day. Relative potencies for hepatic porphyrin accumulation, using TCDD as a reference, ranged from 0.015 to 0.06 for PCB 126 and from 0.0001 to 0.0003 for PCB 156. CYP1A2 activities significantly correlated with hepatic porphyrin levels, with coefficients of 0.629, 0.483, or 0.808 for TCDD, PCB 126, or PCB 156, respectively. Administration of PCB 153 alone did not result in hepatic porphyrin accumulation. Co-administration of PCB 153 and TCDD revealed a strong synergistic effect on porphyrin accumulation (about 800 times control levels). This synergistic effect was significant in rats fed diets containing any combination of PCB 153 with TCDD. Uroporphyrin III and heptacarboxylic porphyrin were accumulated in porphyrinogenic livers. These results suggest that TCDD induction of CYP1A2 may be involved, leading to oxidation of uroporphyrinogen III to uroporphyrin III, in combination with an increase in delta-aminolevulinic acid synthetase induced by PCB 153. Under porphyrinogenic conditions, an inhibitor of CYP1A2 activity may also be formed. The interactive effects on porphyrin accumulation after co-administration of dioxinlike and non-dioxinlike compounds may have significant implications for the risk assessment of these chemicals.ImagesFigure 1.Figure 1.Figure 1.Figure 2.

Interactive Effects between 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,2′,4,4′,5,5′-Hexachlorobiphenyl in Female B6C3F1 Mice: Tissue Distribution and Tissue-Specific Enzyme Induction

“…This phenomenon has been reported before in female Sprague-Dawley rats and male C57BL/6J mice (Bager et al, 1995;De Jongh et al, 1995a). However, this induction was not observed in a 13-week feeding study in female Sprague-Dawley rats exposed to PCB 153 up to 6000 jzg/kg/day (Van der Kolk et al, 1992;Van Birgelen et al, 1996a). The increase in EROD and MROD activity by PCB 153 was not confirmed by the CYPl A1 and CYPl A2 protein levels.…”

Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife.

“…The apparent antagonism by PCB 153 of the TCDD-induced immunosupression is due to the enhanced immune response induced by PCB 153 (198). In addition, synergistic interactions have also been reported between PCBs and dioxins in the development of porphyria in rats (199) and mice (89), the induction of CYPIAI (152,178) and thyroid hormone levels and associated enzyme activities (200,201). These multiple nonadditive interactions between dioxinlike and nondioxinlike HAHs require further investigation to establish the extent to which they compromise the TEF concept.…”

Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…For example, PCB153 (a non-dioxin-like PCB congener) and TCDD produced a remarkable synergism in the EROD enzyme activity and hepatic porphyrin level, respectively (Bannister and Safe, 1987;van Birgelen et al, 1996). A synergistic decrease in the serum total thyroxine concentrations was found when using a mixture of 18 polyhalogenated aromatic hydrocarbons (dioxins, dibenzofurans, and dioxin-like and non-dioxin-like PCB congeners) (Crofton et al, 2005).…”