Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function

doi:10.1016/j.neuro.2013.08.002

NeuroToxicology

Volume 39, December 2013, Pages 65-71

https://doi.org/10.1016/j.neuro.2013.08.002 Get rights and content

Highlights

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Cognitive function was measure using Mini-Mental State Exam.
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Tibia and patella lead were measured using K-X-ray fluorescence.
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Effects of lead burden were greater among men carrying the GSTP1 Val105 variant.

Abstract

Background

Glutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association.

Methods

We used repeated measures analysis to compare the association between cumulative lead biomarkers—bone lead measured using K-shell X-Ray Fluorescence—and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses.

Results

A 15 μg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p = 0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead.

Conclusion

Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.

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 Ile105 → 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 exposure—as measured by lead in bone—and 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 3–5 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], 13–28) μg/g, 25 (IQR, 17–36) μg/g, and 5(IQR, 3–6) μg/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: 16–29). 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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Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function

Highlights

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Materials and methods

Participants characteristics and bone lead

Discussion

Conflict of interest statement

Acknowledgements

Toxicology

Lancet

Lancet Neurol

Ann Epidemiol

J Psychiatr Res

Environ Res

Mayo Clin Proc

Neurotoxicol Teratol

Neurotoxicol Teratol

Lancet

Free Radic Biol Med

Environ Res

Neurobiol Aging

Validation of K X-ray fluorescence bone lead measurements by inductively coupled plasma mass spectrometry in cadaver legs

Med Phys

Improvements in the calibration of 109Cd K X-ray fluorescence systems for measuring bone lead in vivo

Phys Med Biol

Cumulative lead dose and cognitive function in older adults

Epidemiology

The Veterans Administration longitudinal study of healthy aging

Gerontologist

Natural history of mild cognitive impairment in older persons

Neurology

Mild cognitive impairment – a review of prevalence, incidence and outcome according to current approaches

Acta Psychiatr Scand

Differential contribution of current and cumulative indices of lead dose to neuropsychological performance by age

Neurology

Interaction between 6-hydroxydopamine and transferrin: let my iron go

Biochemistry

Education and decline in cognitive performance: compensatory but not protective

Int J Geriatr Psychiatry

Population-based norms for the Mini-Mental State Examination by age and educational level

JAMA

Occupational and environmental neurotoxicology

GSTM1, GSTT1, and the risk of squamous cell carcinoma of the head and neck: a mini-HuGE review

Am J Epidemiol

The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance

Crit Rev Biochem Mol Biol

Potential contribution of the glutathione S-transferase supergene family to resistance to oxidative stress

Free Radic Res

Glutathione S-transferase polymorphisms and their biological consequences

Pharmacology

The relationship of bone and blood lead to hypertension. The Normative Aging Study

JAMA

Bone lead as a biological marker in epidemiologic studies of chronic toxicity: conceptual paradigms

Environ Health Perspect

Five-year outcomes for dementia defined solely by neuropsychological test performance

Neuroepidemiology

Three-year follow-up of Mini-Mental State Examination score in community residents aged 85 and over

Psychol Med