Synergistic and antagonistic effects between the halogenated aromatic hydrocarbons in C57BL/6J and DBA/2J mice

Abstract

The effects of a series of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) on the hepatic microsomal enzyme inducing activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in C57BL/6J (B6) and DBA/2J (D2) mice have been investigated. Treatment of B6 mice with 2,2',4,4',5,5'-hexachlorobiphenyl (HCB, 500 umol/kg) elevated hepatic cytosolic Ah receptor levels 82-178% for up to 14 days. Scatchard analysis of [³H]-2,3,7,8-TCDD-Ah receptor binding curves confirmed that treatment with the PCB did not significantly alter receptor-radioligand affinities. In contrast, cyctosolic Ah receptor was not detectable in D2 mice tissues either in corn oil treated animals or after treatrment with the PCB (100-3000 umol/kg). Cotreatment of B6 mice with 2,2',4,4',5,5'-HCB (500 umol/kg) and 2,3,7,8-TCDD (1 nmol/kg) resulted in significant synergistic induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) compared to animals treated only with 2,3,7,8-TCDD, whereas cotreatment with maximally inducing dose levels of 2,3,7,8-TCDD (100 or 500 nmol/kg) resulted in a slight, or no, difference in the induction of AHH and EROD. In contrast, cotreatment of D2 mice with 2,2',4,4',5,5'-HCB (500 umol/kg) and 2,3,7,8-TCDD resulted in significant synergistic induction of AHH and EROD at both submaximal (80-500 nmol/kg and maximal (5000 nmol/kg) inducing dose levels of 2,3,7,8-TCDD. However when the commercial PCB mixture, Aroclor 1254, and several individual PCDDs, PCDFs and PCBs were cotreated with 2,3,7,8-TCDD, significant antagonistic effects were found on the microsomal enzyme inducing activity of 2,3,7,8-TCDD in B6 and D2 mice liver. For example, cotreatment of B6 and D2 mice with a dose of 2,3,7,8-TCDD, which submaximally induced AHH and EROD, and doses of Aroclor 1254, which elicited little or no induction activity, resulted in up to 44% and 23% antagonism of EROD induction by 2,3,7,8-TCDD in D2 and B6 liver, respectively. Cotreatment of B6 and D2 mice with a higher dose of either the antagonist or 2,3,7,8-TCDD reversed the antagonistic effects of all the compounds studied. The results show that in D2 mice much lower molar ratios of antagonist: 2,3,7,8-TCDD resulted in greater antagonism of EROD and AHH induction by 2,3,7,8-TCDD compared to B6 mice, and that within specific antagonist:agonist dose ratios, many PCDDs, PCDFs and PCBs, which competitively bind to the Ah receptor, can antagonize two Ah receptor-mediated effects of 2,3,7,8-TCDD, namely AHH induction and thymic atrophy.