Role of the Ah Receptor and the Dioxin-Inducible [Ah] Gene Battery in Toxicity, Cancer, and Signal Transduction

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Abstract

1. On the basis of our current knowledge about the evolution of drug-metabolizing enzymes, it appears to be extremely likely that these enzymes play a critical role in maintaining steady-state levels of the ligands involved in ligand-modulated transcription of genes effecting growth, differentiation, homeostasis, and neuroendocrine functions. 2. The original observations about genetic differences in CYP1A1 (cytochrome P1-450) induction by TCDD or benzo[a]pyrene in the mouse have led to an appreciation for a similar polymorphism in the human and the recent cloning of the murine Ah receptor (Ahr) and human Ah receptor nuclear translocator (ARNT) genes. It is most likely that the correlation between genetic differences in human or murine CYP1A1 inducibility by polycyclic hydrocarbons or TCDD and increased risk of cancer will be explained by differences in the AHR gene, leading to enhanced tumor promotion (rather than in the CYP1A1 structural gene). Perhaps the same will be found for birth defects, immunotoxicity, and other forms of toxic damage caused by these environmental chemicals. 3. In a manner similar to that of the phorbol ester tumor promoter, TCDD induces intracellular Ca2+ changes, accumulation of FOS and JUN mRNAs, and large increases in AP-1 transcription factor activity. Interestingly, these early effects of TCDD, and also of benzo[a]pyrene, appear not to require the Ah receptor. 4. Many genes are induced by TCDD, and many others are induced by electrophilic metabolites such as quinones and H2O2; using several mouse experimental systems, we have defined a subset of six of these genes as constituting the [Ah] battery by the sole criterion that a functional CYP1A1 or CYP1A2 enzyme is able to repress the expression of genes that are members of this gene battery.

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Cancer mortality among workers in chemical plant contaminated with dioxin.

Rudolf A Manz, Benjamin Dwyer, S Nagel … (1991)

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD) can arise as a contaminant in the production of herbicides. It causes chloracne in those exposed to it but its human carcinogenicity has been a matter of dispute. We report here a mortality follow-up of 1583 workers (1184 men, 399 women) employed in a chemical plant in Germany that produced herbicides, including processes contaminated with TCDD. Production of TCDD was reduced from 1954 after an outbreak of chloracne. Vital status up to 1989 was determined for 97.1% of workers hired between 1952 and 1984, and 367 deaths (313 men, 54 women) were recorded. A malignant neoplasm was the underlying cause of death in 93 men and 20 women. Standardised mortality ratios (SMR) were calculated with, as references, national mortality statistics for West Germany and deaths in a cohort of male gas workers; for total cancer mortality they were 1.24 (95% confidence interval 1.00-1.52) and 1.39 (1.10-1.75), respectively, among men. Cancer mortality was increased among men with 20 or more years of employment (SMR = 1.87 [Germany] and 1.82 [gas workers]) and among men who began employment before 1955 (SMR = 1.61 and 1.87). The group with suspected highest exposure to TCDD had SMRs of 1.42 and 1.78. Only 7% of cohort women worked in the high exposure locations in the plant, compared with 39.6% of men, and no increased risk of cancer mortality was observed among women; but breast cancer mortality was raised (SRM = 2.15). These results, together with a US occupational study and a German investigation of accidental exposure, support the hypothesis that TCDD is a human carcinogen.