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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Dietary Prevention of Obesity-related Disease Research » Research » Publications at this Location » Publication #159067
Title: DIETARY ARSENIC AFFECTS DIMETHYLHYDRAZINE-INDUCED ABERRANT CRYPT FORMATION AND HEPATIC GLOBAL DNA METHYLATION AND DNA METHYLTRANSFERASE ACTIVITY IN RATS

Author
item Uthus, Eric
item DAVIS, CINDY - NAT INST OF HEALTH

Submitted to: Biological Trace Element Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/20/2004
Publication Date: 2/1/2005
Citation: Uthus, E.O., Davis, C.D. 2005. Dietary arsenic affects dimethylhydrazine-induced aberrant crypt formation and hepatic global DNA methylation and DNA methyltransferase activity in rats. Biological Trace Element Research. 103:133-145.

Interpretive Summary: Through epidemiological studies, arsenic exposure has been associated with lung, skin, bladder, and liver cancer. The US Environmental Protection Agency has classified arsenic as a known human carcinogen. As a result, no threshold exists when determining health effects of arsenic. That is, arsenic is considered toxic at any intake. However, the carcinogenicity of arsenic remains an enigma because, on the one hand, epidemiological studies have associated it with human cancer, but on the other hand, carcinogenesis in rodent models has never been convincingly demonstrated. Furthermore, current research suggests that arsenic itself is not a carcinogen, but that it acts in conjunction with another cancer causing agent to promote or intensify that agent's cancinogenic effect. Also, there are a number of studies that strongly suggest that arsenic is an essential nutrient for the goat, minipig, rat, hamster and mouse. Taken together, these data suggest that there is a concentration of arsenic that is actually beneficial such that not only is it detrimental to be exposed to too much arsenic, but it is also detrimental to be exposed to too little arsenic. To test this hypothesis, we determined the effects of feeding various concentrations of arsenic in rats treated with a colon carcinogen, dimethylhydrazine. Our results showed that rats fed a diet high in arsenic had higher numbers of preneoplastic lesions in the colon compared to rats fed a small amount of arsenic. Also, DNA was hypomethylated (a state normally associated with cancer) in rats that had the increased number of colon lesions. Rats fed a diet devoid in arsenic tended to respond similarly as those fed the high-arsenic diet. These data suggest that there is a threshold for arsenic toxicity and that possibly too little dietary arsenic could also be detrimental.

Technical Abstract: Ingested arsenic is methylated in what is generally accepted as a detoxification mechanism; this methylation requires S-adenosylmethionine (SAM). There is evidence in cell culture studies that arsenic exposure results in decreased SAM resulting in DNA hypomethylation. Previously, we have shown that SAM is decreased and/or S-adenosylhomocysteine increased in liver of arsenic-deprived rats; these rats tended to have hypomethylated DNA. Hypomethylation of DNA has been associated with cancer including colon cancer. To determine the effect of dietary arsenic on dimethylhydrazine (DMH)-induced aberrant crypt formation in the colon, Fisher-344 male, weanling rats (N=20/group) were fed diets containing 0, 0.5, or 50 µg arsenic (as NaAsO2)/g; the basal diet contained <10 ng arsenic/g. DMH dosing occurred at wk 3 and 4 of the 12 wk experiment. The DMH-induced aberrant crypt model was used because numerous studies indicate that arsenic is not a direct carcinogen but a cocarcinogen. Dietary arsenic affected the number of aberrant crypts (p<0.02) and aberrant crypt foci (p<0.007) in colon and the amount of global DNA methylation (p<0.04) and activity of DNA methyltransferase (DNMT, p<0.003) in liver. In each case, there were more aberrant crypts and aberrant crypt foci, a relative DNA hypomethylation, and increased activity of DNMT in the rats fed 50 µg arsenic/g compared to those fed 0.5 µg arsenic/g. The same phenomenon, an increased number of aberrant crypts and aberrant crypt foci, DNA hypomethylation, and increased DNMT tended to hold when comparing rats fed the diet containing no supplemental arsenic to rats fed 0.5 µg arsenic/g. Aberrant crypts and aberrant crypt foci are preneoplastic lesions and are related to the number of tumors that ultimately develop. Also, DNA hypomethylation and increased DNMT have been associated with cancer. The data suggest that there is a threshold for arsenic toxicity and that possibly too little dietary arsenic could also be detrimental.