Induction of genetic damage in human lymphocytes and mutations in Salmonella by trihalomethanes: role of red blood cells and GSTT1-1 polymorphism

The brominated trihalomethanes (THMs) are mutagenic and carcinogenic disinf ection by-products frequently found in chlorinated drinking water. They can be activated to mutagens by the product of the glutathione S-transferase-t heta (GSTT1-1) gene in Salmonella RSJ100, which has been transfected with t his gene. To evaluate this phenomenon in humans, we have examined the genot oxicity of a brominated THM, bromoform (BF), using the Comet assay in human whole blood cultures exposed in vitro. No differences were found in the co met tail length between cultures from GSTT1-1(+) versus GSTT1-1(-) individu als (1.67 +/- 0.40 and 0.74 +/- 0.54 mu m/mM, respectively, P = 0.28). The high variability was due to the relatively weak induction of comets by BF, Combining the data from both genotypic groups, the genotoxic potency of BF was 1.20 +/- 0.34 mu m/mM (P = 0.003). GSTT1-1 is expressed in red blood ce lls but not in the target cells (lymphocytes), and expression within the ta rget cell las in Salmonella RSJ100) may be necessary for enhanced mutagenes is in GSTT1-1(+) relative to GSTT1-1(-) cultures. To examine this, we expos ed Salmonella RSJ100 and a control strain not expressing the gene (TPT100) to the most mutagenic brominated THM detected in Salmonella, dibromochlorom ethane (DBCM), either in the presence or absence of S9 or red blood cells f rom GSTT1-1(+) or GSTT1-1(-) individuals. S9 did not activate DBCM in the n on-expressing strain TPT100, and it did not affect the ability of the expre ssing strain RSJ100 to activate DBCM, As with S9, red cells from either gen otypic group were unable to activate DBCM in TPT100, However, red cells (wh ole or lysed) from both genotypic groups completely repressed the ability o f the expressing strain RSJ100 to activate DBCM to a mutagen. Such results suggest a model in which exposure to brominated THMs may pose an excess gen otoxic risk in GSTT1-1(+) individuals to those organs and tissues that both express this gene and come into direct contact with the brominated THM, su ch as the colon. In contrast, those organs to which brominated THMs would b e transported via the blood might be protected by erythrocytes, Such a prop osal is reasonably consistent with the organ specificity of drinking water- associated cancer in humans, which shows slightly elevated risks for cancer of the colon and bladder but not of the liver.