Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms

Eum, Ki-Do; Seals, Ryan; Taylor, Kathryn M.; Grespin, Matthew; Umbach, David M.; Hu, Howard; Sandler, Dale P.; Kamel, Freya; Weisskopf, Marc G.

doi:10.3109/21678421.2014.964259

Cited by 27 publications

(24 citation statements)

References 34 publications

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“…The hemochromatosis gene encodes a protein that is in part responsible for iron sensing and regulation and HFE variant homozygosity results in clinical hemochromatosis, which is characterized by iron overload. The presence of one or more polymorphism of the HFE gene (either H63D or C282Y) has been shown to exacerbate the detrimental effects of lead on cognitive function in elderly men (Wang et al, 2007), and has been associated with increased susceptibility to neurodegenerative disease (Eum et al, 2014, Mariani et al, 2013, Nandar and Connor, 2011). Interestingly, variant HFE gene expression has also been associated with lower blood and bone lead in the NAS cohort (Wright et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: The Normative Aging Study

Grashow

Sparrow

et al. 2015

NeuroToxicology

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Introduction Olfactory dysfunction has been identified as an early warning sign for Alzheimer’s disease, Parkinson’s disease, dementia and more. A few occupational and environmental exposures have also been associated with reduced olfactory function, although the effects of long term environmental exposure to lead on olfactory dysfunction have not been explored. Here we performed olfactory recognition testing in elderly men in a community-dwelling cohort and examined the association with cumulative lead exposure, as assessed by lead in tibial and patellar bone. Methods Olfactory recognition was measured in 165 men from the Normative Aging Study (NAS) who had previously taken part in bone lead measurements using K-X-Ray fluorescence (KXRF). Olfactory recognition was measured using the University of Pennsylvania Smell Identification Test (UPSIT). Associations between olfactory recognition, global cognition and cumulative lead exposure were estimated using linear regression, with additional adjustment for age, smoking, and functional polymorphism status for hemochromatosis (HFE), transferrin (TfC2), glutathione-s-transferase Pi1 (GSTP1) and apolipoprotein E (APOE) genotypes. Sensitivity analyses explored olfactory recognition in men with high global cognitive function as measured using the Mini-Mental Status Exam (MMSE). Results The average age of the NAS participants at the time of olfactory recognition testing was 80.3 (standard deviation or SD = 5.7) years. Mean tibia lead was 16.3 (SD = 12.0) μg/g bone, mean patella lead was 22.4 (SD = 14.4) μg/g bone, and mean UPSIT score was 26.9 out of 40 (SD = 7.0). Consistent with previous findings, age at olfaction testing was negatively associated with UPSIT score. Tibia (but not patella) bone lead was negatively associated with olfaction recognition (per 15 μg/g tibia lead: β = −1.57; 95% CI: −2.93, −0.22; p = 0.02) in models adjusted for smoking and age. Additional adjustment for education did not significantly change results. Of all the genes explored, only the presence of one or more HFE variant alleles was significantly associated with olfaction recognition (HFE β = 2.26; 95% CI: 0.09, 4.43; p = 0.04). In a model containing the HFE term and a lead term, the tibia lead parameter estimate dropped by 21% (per 15 μg/g tibia lead: β = −1.25; 95% CI: −2.64, 0.14; p = 0.08) while the HFE term dropped 15% (β = 1.91; 95% CI: −0.28, 4.10; p=0.09). None of the other gene terms were associated with olfactory recognition in this cohort, nor were any gene-lead interaction terms significant. Additional sensitivity analysis in men with MMSE scores of 25 or higher (n = 149) showed a similar but slightly attenuated association between lead and olfactory recognition (per 15 μg/g tibia lead β = −1.39; 95% CI: −3.00, 0.22; p = 0.09) Conclusion Cumulative exposure to lead is associated with reduced olfactory recognition in a cohort of elderly men. The association was similar but not significant in men with better cognitive function as measured by the MMSE. Iron metabolism gene sta...

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Section: Introductionmentioning

confidence: 99%

Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: The Normative Aging Study

Grashow

Sparrow

et al. 2015

NeuroToxicology

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“…Multiple lines of evidence suggest that lead exposure plays a significant role in the aetiology of MND. These lines of evidence include the meta-analysis between MND and occupational lead exposure [ 11 ], previous bone lead studies [ 23 , 24 , 25 , 26 ] and studies that have found positive associations between MND and lead in human biological samples [ 13 , 14 , 16 ], questionnaires [ 12 , 20 , 21 , 22 ] and the results from this study. Lead is also known to cause oxidative stress [ 69 , 70 ].…”

Section: Discussionmentioning

confidence: 64%

“…Eum et al (2015) [ 26 ] measured bone lead, a biomarker of cumulative lead exposure, using K-shell-X-ray fluorescence in 100 neurologist-confirmed MND cases and 194 controls. They further examined the interaction with haemachromatosis genotype and found that the OR per 15.6 μg/g patella lead (interquartile range—IQR) was 8.24 (95% CI = 0.94–72.19) times larger among C282Y variant carriers, and 0.34 (95% CI = 0.15–0.78) times smaller among H63D variant carriers; results however were weaker for tibia lead.…”

Section: Introductionmentioning

confidence: 99%

A Temporal Association between Accumulated Petrol (Gasoline) Lead Emissions and Motor Neuron Disease in Australia

Laidlaw

Rowe

Ball

et al. 2015

IJERPH

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Background: The age standardised death rate from motor neuron disease (MND) has increased from 1.29 to 2.74 per 100,000, an increase of 112.4% between 1959 and 2013. It is clear that genetics could not have played a causal role in the increased rate of MND deaths over such a short time span. We postulate that environmental factors are responsible for this rate increase. We focus on lead additives in Australian petrol as a possible contributing environmental factor. Methods: The associations between historical petrol lead emissions and MND death trends in Australia between 1962 and 2013 were examined using linear regressions. Results: Regression results indicate best fit correlations between a 20 year lag of petrol lead emissions and age-standardised female death rate (R2 = 0.86, p = 4.88 × 10−23), male age standardised death rate (R2 = 0.86, p = 9.4 × 10−23) and percent all cause death attributed to MND (R2 = 0.98, p = 2.6 × 10−44). Conclusion: Legacy petrol lead emissions are associated with increased MND death trends in Australia. Further examination of the 20 year lag between exposure to petrol lead and the onset of MND is warranted.

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“…Moreover, H63D was noted to affect patella and tibia lead levels, associated with ALS. Specifically, in sALS patients, C282Y was associated with patella and tibia lead levels, while GSTP1 was related to blood lead levels (Eum et al, 2015). Additionally, there is strong evidence that H63D polymorphism has a protective role against AD risk (Lin et al, 2012), while there is only mild indication that the C282Y polymorphism protects against PD (Duan et al, 2016;Xia et al, 2015).…”

Section: Sod1 Hfe Transferrin Gsts Pgc-1α and Nrf2mentioning

confidence: 99%

Genetic polymorphisms in amyotrophic lateral sclerosis: Evidence for implication in detoxification pathways of environmental toxicants

Dardiotis

Siokas

Sokratous

et al. 2018

Environment International

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease of the central nervous system, characterized by progressive loss of motor neurons, and occurring in both sporadic and familial form. The origin of the disease is unknown, though increasing evidence suggests that the interaction between genetic and environmental factors may increase susceptibility to ALS, including its sporadic form. Although genetic mutations have been correlated to the familial type of ALS, relatively little is known about the sporadic type (sALS). Genetic factors concerning pesticide metabolism and heavy metal detoxification are increasing the susceptibility to sALS. This review focuses on the genes implicated in metabolic detoxification pathways of environmental toxicants and their potential role in ALS susceptibility.

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Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms

Cited by 27 publications

References 34 publications

Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: The Normative Aging Study

Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: The Normative Aging Study

A Temporal Association between Accumulated Petrol (Gasoline) Lead Emissions and Motor Neuron Disease in Australia

Genetic polymorphisms in amyotrophic lateral sclerosis: Evidence for implication in detoxification pathways of environmental toxicants

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