From a 1984 study by Rowland et al. Antibiotics and Milk play a role in the efficency of Hg Excretion. In this study rats were given high doses of oral antibiotics the half-life for excretion of mercury increased from 10 days to >100 days. If the rats were also on a milk diet the excretion half-life increased to over 300 days. These results are consistent with the theory that demethylation of methylmercury by intestinal microflora is a major factor determining the excretion rate of mercury.
Effects of Diet on Mercury Metabolism and Excretion in Mice Given Methylmercury: Role of Gut Flora
Mice fed either (1) a pelleted rodent diet, (2) evaporated milk, or (3) a synthetic diet (high protein, low fat) exhibited different rates of whole body mercury elimination and fecal mercury excretion after exposure (per os) to methylmercuric chloride. The percentage of the total mercury body burden present as mercuric mercury was highest (35.3%) in mice fed the synthetic diet (which had the highest rate of mercury elimination) and lowest (6.6%) in the animals having the lowest mercury elimination rate (milk-fed mice). Mice fed the syn-thetic diet had lower mercury concentrations and had a higher proportion of mercuric mer-cury in their tissues than the mice from the other dietary groups. Treatment of the mice with antibiotics throughout the experimental period to suppress the gut flora reduced fecal mer-cury excretion and the dietary differences in whole body retention of mercury. Tissue mercury concentrations and proportion of organic mercury in feces, cecal contents, liver, and kidneys were increased by antibiotic treatment of mice fed the pelleted or synthetic diets.
These results are consistent with the theory that demethylation of methylmercury by intestinal microflora is a major factor determining the excretion rate of mercury.
The marked diet-related differences in whole body retention of Hg after MeHg exposure confirm the re-sults of Landry et al. 3 In addition, the differences in whole body retention were reflected in the amount or concentration of Hg present in the carcass (the major site of deposition of Hg in the mice), brain, blood, liver, and kidneys. The effect of diet on Hg concentration in brain (a target organ for MeHg toxicity) suggests that diet may influence MeHg-induced neurotoxicity since the concentration of Hg in tissues, particularly the central nervous system, has been correlated with the inci-dence of neurotoxicity in rats and mice.· 19 20
The three diets used in this study have many differences which make it difficult to differentiate the effects of specific dietary components1 although it would appear that dietary fiber is not an important factor governing the rate of Hg excretion since both the milk and GIBCO diets contained little indigestible residues.
Although differences in concentrations of Se were found in the three diets, it is unlikely that these were responsible for the differences in Hg elimination rates since the RMH3000 diet contained by far the highest Se concentration, yet mice fed this diet had an intermediate rate of Hg elimination. These results agree with those of Stil-lings el al., 21 who found that though dietary Se reduced the toxicity of MeHg, it did not appear to influence Hg elimination in feces or urine.
Over short time periods (up to 5 hrl co-administration of MeHgCI and low-molecular-weight thiol compounds has been shown to decrease blood Hg concentration and increase Hg accumulation by various organs by comparison to MeHgCI given alone. 22-24
Thus, differences in thiol concentrations in the diets and tissues may be responsible for diet-related changes in HHg tissue concentrations. However, in the present study, the thiol concentrations of the three diets were similar, and although some differences were detected in concentration of nonprotein-bound thiols in liver, they could not be correlated with Hg excretion rates or tissue Hg levels since mice fed milk or GIBCO diets had almost identical hepatic thiol concentrations. The con-centration of sulfhydryl compounds in the small intes-tine was highest in those mice fed milk probably due to an increase in glutathione from bile, because the ma-jority of the sulfhydryl groups were not protein-bound. However, it seems unlikely that differences in intestinal thiol concentration significantly affect Hg excretion rate since the sulfhydryl concentrations were greatly in excess of the Hg concentration to which the mice were exposed. It is noteworthy that the administration of MeHgCI increased (by 1-2 JLmoles/g tissue) the concentration of nonprotein-bound thiols in the livers of mice in all dietary groups, presumably affecting an increased synthesis of glutathione in bile.
It is possible that diet may also affect the whole body elimination of Hg via an effect on excretion of Hg in bile, since age-related changes in Hg elimination, can be as-cribed, at least in part, to changes in biliary excretion. 25
The differences in the amount of mercuric Hg in the whole body (Table 2), in the various tissues (Tables 3 and 4), and in cecal and colon contents (Fig. 4) in the animals fed the different diets suggest that diet-induced differences in Hg elimination are related to the extent of MeHg demethylation by the animals. The mice with the highest rates of Hg elimination, namely those fed GIBCO diet, had the highest proportion of their Hg body burden as mercuric Hg.
The previously demonstrated ability of the intestinal microilora to demethylate MeHg6 and its capacity to alter its metabolic activity in response to dietary modifi-cation 13•16 suggest that diet-induced changes in demeth-ylating activity of the gut flora are responsible for the differences in Hg elimination seen. Tlw results of the present study lend support to this theory.
It is clear that in all dietary groups a large proportion of total Hg in the gut was present in the mercuric form, especially in the cecum and colon. In particular, the GIBCO-fed animals reatained very high levels of Hg in the cecum and colon. Furthermore, the major route of excretion of Hg was the feces with only small amounts emerging in the urine, and in the GIBCO-fed mice the increased Hg elimination occurred via the feces rather than the urine. This indicates that MeHg demethylation occurs at sites where the product, mercuric Hg, does not re-enter the general circulation since parenterally administered HgCI2 is excreted mainly in the urine (Landry et al., unpublished observation, 1982).
Treatment of the mice with antibiotics to sterilize the gut contents virtually eliminated the diet-related dif-ferences in whole body Hg retention, in Hg excretion in feces and urine, and in the amount of mercuric Hg in whole body, gut contents, and tissues (especially in liver and kidney). These results are consistent with the theory that demethylation by the gut flora is a major determinant of the rate of Hg excretion after MeHg ex-posure. The almost complete retention of the dose of MeHg (apparent elimination of half-times> 100 days) in the animals without a gut flora and the increase in MeHg concentration in blood and liver is also consis-tent with the theory since it would be expected that the greater proportion of MeHg relative to total Hg in the gut of antibiotic-treated animals would result in greater absorption of the administered mercury dose.
Landry et al. (unpublished observation), using mice give MeHgCI intramuscularly, have reproduced the dietary-related differences in Hg elimination seen in orally dosed animals, but the three diets had little effect on Hg retention after parenteral administration of HgCI,. It would appear, therefore, that if MeHg is demethylated, diet is unlikely to exert any differential effects on Hg … retention, suggesting that the differential effects of diet oc-cur on demethylation or on excretion of MeHg in bile.
In the mice given antibiotics, some residual formation November/December 1984 [Vol. 39, (No.6)] of mercuric Hg was apparent (Table 2) suggesting that sites of demethylation other than the gut flora exist. One possible site is the liver, although enzymatic demethyla-tion of MeHg by this organ has been little studied. It is also possible that the slow release of inorganic Hg from MeHg in the presence of thiol compounds17 contributes to inorganic Hg formation in vivo. 1€ have confirmed (unpublished observations, 1981) that this can occur in the presence of thiol concentrations found in bile and in the liver (approximately 5 ~-tmole/mll.
In conclusion, the results of this study confirm previous reports 10 that the gut flora is the major site of de-methylation of MeHg in the mouse and strongly suggest that dietary effects on Hg elimination rates are mediated by changes in demethylating activity of the flora. The result of a high demethylation rate would be the formation in the gut lumen of mercuric Hg which, being poorly absorbed, interrupts the enterohepatic recycling of MeHg. 4
Large variations have been reported in rates of elimi-nation of Hg in human populations exposed to MeHg.18 It is conceivable that this variation may be related to the wide variation in composition of gut flora among individuals.29 Furthermore, if the major differences in gut flora that have been observed in populations in different geographic areas 10 are reflected in their MeHg demethylation rates, it is possible that there are inter-individual as well as inter-regional differences in suscep-tibility to MeHg poisoning.
Effects of Diet on Mercury Metabolism and Excretion in Mice Given Methylmercury: Role of Gut Flora
I. R. ROWLAND, Ph.D. The British Industrial Biological Research Association Woodmansterne Road Carshalton, Surrvey, United Kingdom R. D. ROBINSON, M.S. R. A. DOHERTY, M.D. Department of Pediatrics Environmental Health Sciences Center University of Rochester Rochester, New York 14642
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