Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function
Introduction
In the United States, the population of persons aged 65 years and older is projected to increase twofold to 75 million in the next 30 years and a concomitant upsurge in the number of individuals with dementia is expected (US Census Bureau, 2000a, US Census Bureau, 2000b). Cognitive decline, a risk factor for dementia, may be a transition stage spanning normal cognition and onset of diseases associated with dementia, including Alzheimer's disease (Bischkopf et al., 2002, Burns and Zaudig, 2002, Pratico et al., 2002, Knopman et al., 2003, Palmer et al., 2003b).
Lead exposure has long been recognized to impair cognition. Numerous studies in children have found inverse associations between blood lead levels and tests of cognitive development (Schwartz, 1994, Lanphear et al., 2005). Workers in lead-related industries have been found to experience cognitive declines proportional to current blood lead and total lead burden levels (Shih et al., 2007). The few studies that have addressed cognitive function among non-occupationally exposed older adults have predominantly reported inverse associations between body lead levels and cognitive function (Muldoon et al., 1996, Nordberg et al., 2000, Wright et al., 2003, Weisskopf et al., 2004, Weisskopf et al., 2007, Shih et al., 2006, Shih et al., 2007, Weuve et al., 2006, Bandeen-Roche et al., 2009). Bone lead measures are biomarkers of body lead burden that have been found to correlate well with measures of cumulative external lead levels and integrated blood lead levels (Bleecker et al., 1997). With half-life estimates on the order of decades for cortical bone and several years for trabecular bone (Kim et al., 1997, Wilker et al., 2011), lead levels in bone are thought to better reflect long-term cumulative lead exposure than blood lead, which has a half-life of approximately 30 days (Rabinowitz, 1991).
Oxidative stress has been proposed as a mechanism by which lead affects cognition (Volicer and Crino, 1990, Feldman, 1999). Glutathione S-transferases (GST) are enzymes involved in the clearance of harmful electrophilic compounds, including redox radicals. Several polymorphisms in GST result in phenotypic variations in enzymatic activity. The GST pi class (GSTP1) isoenzymes are expressed in the brain and blood brain barrier (Hayes and Strange, 2000). Studies have reported that the Ile105Ā āĀ Val105 substitution in GSTP1 is a functional polymorphism that results in differential substrate clearance efficiencies by GSTP1 isoenzymes (Spiteri et al., 2000). Of the mu class of isoenzymes, glutathione S-transferase M1 (GSTM1) enzymes are the most widely expressed (Hayes and Strange, 1995). It has been estimated that 45% of most populations are homozygous for the GSTM1 deletion polymorphism and thus do not express the GSTM1 isoenzyme (Stroombergen and Waring, 1999); these GSTM1 null individuals may experience greater oxidative stress and, as a consequence, greater cognitive impairment associated with lead exposure because of their inability to clear particular reactive compounds.
Several studies have found associations between cumulative lead exposure and cognitive function in adults, but no study has yet evaluated the modifying roles of GST polymorphisms on this relation. Therefore, we examined the modifying roles of GSTP1 Ile105Val and GSTM1 null polymorphisms on the association between cumulative lead exposureāas measured by lead in boneāand cognition as measured by the Mini-Mental State Exam (MMSE), a test of global cognitive function, in a cohort of older men.
Section snippets
Materials and methods
Participants in the current study were drawn from the VA Normative Aging Study (NAS), a community-based, prospective cohort study initiated in 1963 at the Veterans Affairs (VA) Outpatient Clinic in Boston to examine factors related to healthy aging among men (Bell et al., 1966). Every 3ā5 years, study participants have undergone extensive in-person evaluations including medical and physical examinations and laboratory tests. They also completed questionnaires on smoking history, diet and other
Participants characteristics and bone lead
Median concentrations of lead biomarkers in our study population were 19 (interquartile range [IQR], 13ā28) Ī¼g/g, 25 (IQR, 17ā36) Ī¼g/g, and 5(IQR, 3ā6) Ī¼g/dL for tibia, patella, and blood lead respectively. On average, participants were 69 years of age at first cognitive testing. Median MMSE score at first cognitive assessment was 27 (range: 16ā29). Participants who were younger, more educated, native English speakers, or had computer experience had lower bone lead levels on average (Table 1).
Discussion
In our study population of older men, the deleterious association between cumulative lead exposure and poorer cognitive function was significantly worse among men with GSTP1 Val105 polymorphisms than among GSTP1 wildtype participants. Moreover, the detrimental association of lead with cognition was greater among participants with more GSTP1 Val105 alleles. Although lead burden was associated with slightly worse cognition among men with the GSTM1 deletion polymorphism, the interaction between
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by grants 5-P42-ES05947, R01-ES05257, and ES-00002 from the National Institutes of Health. F. Wang was partially supported by National Institute for Occupational Safety and Health (NIOSH) Grant T42/CCT110421 and T32 ES007155 from the National Institutes of Health.
The Cognition and Health in Aging Men Project (CHAMP) has been supported by the Research Services of the US Department of Veterans Affairs, the National Institutes of Health (grants R01-AA08941, R01-AG13006,
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