TCDD TERATOGENICITY--MODULATION IN MIXTURES

TCDD（2,3,7,9-四氯二苯并-对二恶英）是一种强效的发育致病菌

TCDD (2,3,7,9-tetrachlorodibenzo-p-dioxin) is a potent developmental toxin in all species examined, causing fetal toxicity at doses well below the maternal LD. However, teratogenic effects have only been demonstrated in sensitive strains of mice where TCDD causes hydronephrosis and cleft palate at extremely low doses. Compounds which are approximate isostereomers of TCDD also cause these malformations and exhibit parallel dose response curves. Thus, the potency of four different polychlorinated dibenzofurans and at least one PCB can be expressed as dilutions of the toxicity of TCDD. Combination treatment with these chemicals also results in an additive response. however, a PCB such as 2,4,5,2'4'5'-hexachloro- biphenyl (HCB) can antagonize the teratogenic effects of TCDD over a very narrow window of concentrations. HCB by itself can cause hydronephrosis, but it does not appear to cause cleft palate even at doses as high as 1g/kg. In combination with TCDD, it can block the induction of cleft palate and hydronephrosis, but the ratios for these antagonistic effects are different. The mechanism of this antagonism remains to be determined. The brominated dioxins and furans, which are also environmental and occupational hazards, are closely related in structure to the chlorinated congeners. The developmental toxicity and teratogenicity of 2,3,7,8-TBDD, 2,3,7,8-TBDF, 2,3,4,7,8-PeBDF, and 1,2,3,7,8,-PeBDF were examined in C57BL/6N mice. These compounds produced the same spectrum of effects as observed with TCDD, specifically cleft palate and hydronephrosis. At high doses, fetal thymic atrophy was also noted. TBDD was approximately 1/5 as potent as TCDD, while TBDF was equipotent to TBDD. This is in contrast to the relative teratogenicity of TCDF which is 1/20-1/30 as potent as TCDD. The two PeBDFs are approximately equiteratogenic and are 1/20 as potent as TBDD. Thus, the presence of the larger bromine atom appears to enhance the toxicity of TBDF, relative to TCDF, but decrease the toxicity of 2,3,4,7,8-PeBDF relative to its chlorinated congener.