Setting the Stage for Illness
Mercury Exposure and Autoimmune Disease
The current scientific literature abounds with studies of the strongly suspected link between exposure to inorganic mercury (iHg) and autoimmune disease, a family of often debilitating and sometimes fatal conditions. Although no human association has been documented, the connection is well known in animal models. A great deal of work continues to characterize the complex physiologic mechanisms involved and thereby shed light on the role of environmental mercury exposures in the etiology of these illnesses. Now a team of Maryland investigators has found that even brief, low-level environmental mercury exposure may increase susceptibility to autoimmune disease in mice [EHP 111:1273-1277].
iHg experiments often use mice bred for susceptibility to various autoimmune diseases. In this study, however, the team used healthy, genetically nonsusceptible mice. The researchers injected treatment groups of 6- to 8-week-old female B6D2F1 mice with iHg doses of 20 or 200 micrograms per kilogram dissolved in water. The mice were dosed every other day for 15 days, for a total of 8 doses. Control animals were injected with an equal total volume of sodium chloride. Five days after cessation of the iHg injections, both case and control mice were intravenously administered spleen cells from another mouse strain to induce chronic graft-versus-host disease (GVHD), a well-established murine model of acquired autoimmunity.
This study involved very low exposures compared to those commonly used in studies of iHg immunotoxicity (typically 500-2,000 micrograms per kilogram). These low doses helped avoid confounding of the subsequent results by the toxic effects of iHg exposure itself or by directly causing iHg-associated autoimmune disease.
The dose of parental donor cells was set just above the threshold for consistent induction of chronic GVHD, and under normal conditions would be expected to induce a mild case of the lupuslike condition, as it did in the controls. In the case mice, however, the scientists determined that the iHg pretreatment clearly accelerated and exacerbated the course of the disease.
Unlike the control mice, the iHg-exposed mice experienced glomerulonephritis (an inflammatory kidney disease) and elevated urine protein, evidence of accelerated GVHD. The glomerulonephritis, in turn, resulted in accelerated mortality in the iHg-treated groups. Upon reexamination 2-3 months after disease induction, autoantibodies characteristic of chronic GVHD were found to have become significantly elevated in surviving iHg-treated mice, but no markers characteristic of iHg-associated autoimmunity were seen. These results imply that the iHg treatment affected the acquired autoimmune disease itself--that the disease was not caused by delayed effects of the iHg exposure, but that its course was worsened by the exposure.
The results of the study, the first of its kind, support the hypothesis that low-level environmental exposure to mercury is a potential factor in the development of autoimmune disease in humans. Disturbingly, these results further suggest that "low-level exposure . . . may lower the threshold for disease development in susceptible individuals who later encounter the appropriate infectious or toxic triggers of disease." If these findings are confirmed by replication and further research, the implications regarding safe thresholds for environmental mercury exposure could be profound.
Ernie Hood
ALS and Lead
The Polymorphism Possibility
Although the etiology of amyotrophic lateral sclerosis (ALS), an often fatal neurodegenerative disease, is still largely unexplained, research suggests that lead exposure may be a risk factor. Freya Kamel of the NIEHS earlier led a group that identified a potential role of lead exposure in the etiology of ALS. Now she and her colleagues have taken that work a step further, examining the possible association of ALS risk with specific genetic polymorphisms known to affect lead toxicokinetics [EHP 111:1335-1339].
Origins of disease? A gene polymorphism that promotes the migration of lead from bone to blood and the retention of lead in blood may increase the risk of ALS.
image credit: Getty Images, Matt Ray/EHP
The researchers used data from a case-control study conducted in New England between 1993 and 1996 that involved more than 100 ALS patients and 38 control subjects. The study participants completed questionnaires on demographic and lifestyle characteristics, and were invited to provide tissue samples for measurement of blood and bone lead concentrations. For this analysis, DNA genotyping was performed using blood samples from the original study.
In many adults with no known recent environmental exposure (including most of the subjects in the study), internal lead exposure--that is, the migration of stored lead from bone into the blood--is the major source of blood lead. The researchers speculated that polymorphisms of two genes--ALAD (which codes for �-aminolevulinic acid dehydratase, an enzyme involved in heme synthesis in red blood cells) and VDR (which codes for the vitamin D receptor)--might confer increased susceptibility to ALS through their previously confirmed impact on lead retention or mobilization in bone and blood.
Kamel and colleagues found that the variant allele (ALAD 2) of the polymorphism denoted as ALAD K59N was positively associated with an approximate twofold increase in risk of ALS after adjustment for age, sex, region, education, and physical activity. In the course of their analysis, they also identified a previously unknown polymorphism, denoted as ALAD IVS2+299G>A. The variant allele of that polymorphism (ALAD I2-2) was found, after similar adjustment, to be negatively associated with ALS risk. Both alleles were positively associated with decreased bone lead concentrations, and neither affected the relationship of blood or bone lead to ALS. No ALS risk associations were found with the alleles of the VDR polymorphism, nor did it appear to be associated with blood or bone lead concentrations.
The researchers theorize that although ALAD alleles did not modify the relationship of ALS to lead in this cross-sectional study, genetic susceptibility conferred by these polymorphisms might still affect risk through a mechanism related to internal lead exposure. ALAD 2 appears to promote retention of lead in blood and migration of lead from bone to blood. The current findings are consistent with the hypothesis that this increased retention of lead in blood relative to bone increases its availability to target tissues and hence its toxicity. The authors speculate that "alterations in lead toxicokinetics conferred by the presence of the ALAD 2 allele may subtly increase exposure to lead throughout a person's lifetime, thereby elevating risk."
The authors point out that the study is limited by a low participation rate of control subjects (41%) in providing tissue samples, although a much higher percentage completed the questionnaire, leading to concerns about selection bias and contributing to imprecision in the statistical evaluation of relationships. They conclude that because the study is small and the observation unique, further research is necessary to confirm or refute the hypothesis. Considering that the frequency of the ALAD 2 allele is approximately 10% in Caucasian populations, if this study's conclusions are confirmed, it will be an important contribution to identifying a large number of people who could be at elevated risk for developing a devastating, incurable disease.
Mercury Exposure and Autoimmune Disease
The current scientific literature abounds with studies of the strongly suspected link between exposure to inorganic mercury (iHg) and autoimmune disease, a family of often debilitating and sometimes fatal conditions. Although no human association has been documented, the connection is well known in animal models. A great deal of work continues to characterize the complex physiologic mechanisms involved and thereby shed light on the role of environmental mercury exposures in the etiology of these illnesses. Now a team of Maryland investigators has found that even brief, low-level environmental mercury exposure may increase susceptibility to autoimmune disease in mice [EHP 111:1273-1277].
iHg experiments often use mice bred for susceptibility to various autoimmune diseases. In this study, however, the team used healthy, genetically nonsusceptible mice. The researchers injected treatment groups of 6- to 8-week-old female B6D2F1 mice with iHg doses of 20 or 200 micrograms per kilogram dissolved in water. The mice were dosed every other day for 15 days, for a total of 8 doses. Control animals were injected with an equal total volume of sodium chloride. Five days after cessation of the iHg injections, both case and control mice were intravenously administered spleen cells from another mouse strain to induce chronic graft-versus-host disease (GVHD), a well-established murine model of acquired autoimmunity.
This study involved very low exposures compared to those commonly used in studies of iHg immunotoxicity (typically 500-2,000 micrograms per kilogram). These low doses helped avoid confounding of the subsequent results by the toxic effects of iHg exposure itself or by directly causing iHg-associated autoimmune disease.
The dose of parental donor cells was set just above the threshold for consistent induction of chronic GVHD, and under normal conditions would be expected to induce a mild case of the lupuslike condition, as it did in the controls. In the case mice, however, the scientists determined that the iHg pretreatment clearly accelerated and exacerbated the course of the disease.
Unlike the control mice, the iHg-exposed mice experienced glomerulonephritis (an inflammatory kidney disease) and elevated urine protein, evidence of accelerated GVHD. The glomerulonephritis, in turn, resulted in accelerated mortality in the iHg-treated groups. Upon reexamination 2-3 months after disease induction, autoantibodies characteristic of chronic GVHD were found to have become significantly elevated in surviving iHg-treated mice, but no markers characteristic of iHg-associated autoimmunity were seen. These results imply that the iHg treatment affected the acquired autoimmune disease itself--that the disease was not caused by delayed effects of the iHg exposure, but that its course was worsened by the exposure.
The results of the study, the first of its kind, support the hypothesis that low-level environmental exposure to mercury is a potential factor in the development of autoimmune disease in humans. Disturbingly, these results further suggest that "low-level exposure . . . may lower the threshold for disease development in susceptible individuals who later encounter the appropriate infectious or toxic triggers of disease." If these findings are confirmed by replication and further research, the implications regarding safe thresholds for environmental mercury exposure could be profound.
Ernie Hood
ALS and Lead
The Polymorphism Possibility
Although the etiology of amyotrophic lateral sclerosis (ALS), an often fatal neurodegenerative disease, is still largely unexplained, research suggests that lead exposure may be a risk factor. Freya Kamel of the NIEHS earlier led a group that identified a potential role of lead exposure in the etiology of ALS. Now she and her colleagues have taken that work a step further, examining the possible association of ALS risk with specific genetic polymorphisms known to affect lead toxicokinetics [EHP 111:1335-1339].
Origins of disease? A gene polymorphism that promotes the migration of lead from bone to blood and the retention of lead in blood may increase the risk of ALS.
image credit: Getty Images, Matt Ray/EHP
The researchers used data from a case-control study conducted in New England between 1993 and 1996 that involved more than 100 ALS patients and 38 control subjects. The study participants completed questionnaires on demographic and lifestyle characteristics, and were invited to provide tissue samples for measurement of blood and bone lead concentrations. For this analysis, DNA genotyping was performed using blood samples from the original study.
In many adults with no known recent environmental exposure (including most of the subjects in the study), internal lead exposure--that is, the migration of stored lead from bone into the blood--is the major source of blood lead. The researchers speculated that polymorphisms of two genes--ALAD (which codes for �-aminolevulinic acid dehydratase, an enzyme involved in heme synthesis in red blood cells) and VDR (which codes for the vitamin D receptor)--might confer increased susceptibility to ALS through their previously confirmed impact on lead retention or mobilization in bone and blood.
Kamel and colleagues found that the variant allele (ALAD 2) of the polymorphism denoted as ALAD K59N was positively associated with an approximate twofold increase in risk of ALS after adjustment for age, sex, region, education, and physical activity. In the course of their analysis, they also identified a previously unknown polymorphism, denoted as ALAD IVS2+299G>A. The variant allele of that polymorphism (ALAD I2-2) was found, after similar adjustment, to be negatively associated with ALS risk. Both alleles were positively associated with decreased bone lead concentrations, and neither affected the relationship of blood or bone lead to ALS. No ALS risk associations were found with the alleles of the VDR polymorphism, nor did it appear to be associated with blood or bone lead concentrations.
The researchers theorize that although ALAD alleles did not modify the relationship of ALS to lead in this cross-sectional study, genetic susceptibility conferred by these polymorphisms might still affect risk through a mechanism related to internal lead exposure. ALAD 2 appears to promote retention of lead in blood and migration of lead from bone to blood. The current findings are consistent with the hypothesis that this increased retention of lead in blood relative to bone increases its availability to target tissues and hence its toxicity. The authors speculate that "alterations in lead toxicokinetics conferred by the presence of the ALAD 2 allele may subtly increase exposure to lead throughout a person's lifetime, thereby elevating risk."
The authors point out that the study is limited by a low participation rate of control subjects (41%) in providing tissue samples, although a much higher percentage completed the questionnaire, leading to concerns about selection bias and contributing to imprecision in the statistical evaluation of relationships. They conclude that because the study is small and the observation unique, further research is necessary to confirm or refute the hypothesis. Considering that the frequency of the ALAD 2 allele is approximately 10% in Caucasian populations, if this study's conclusions are confirmed, it will be an important contribution to identifying a large number of people who could be at elevated risk for developing a devastating, incurable disease.