Co-exposure to multiple metals, TERT-CLPTM1L variants, and their joint influence on leukocyte telomere length

https://doi.org/10.1016/j.envint.2020.105762Get rights and content
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Highlights

  • Increased plasma manganese level is positively associated with telomere length.

  • Multipollutant associations suggest manganese as a sole predictor for telomere length.

  • Manganese has joint effects with TERT-CLPTM1L variants on increasing telomere length.

  • This study offered clues for the early prevention of telomere shortening related diseases.

Abstract

Objective

Telomere is required for maintaining chromosome stability and genome integrity, while telomere length is sensitive to environmental stressors. We aimed to identify the effects of multiple metals co-exposure as well as their joint effects with TERT-CLPTM1L variants on leukocyte telomere length (LTL).

Methods

This study included 842 workers from a coke-oven plant, of whom plasma concentrations of 23 metals and LTL were determined. Genetic variations in TERT-CLPTM1L were genotyped by using the Global Screening Array. Multipollutant-based statistical methods, including the Bonferroni-correction, backward elimination procedure, and LASSO penalized regression analysis, were used to select the LTL-associated metals. Generalized linear regression models were used to evaluate the joint effects of TERT-CLPTM1L variants with positive metal on LTL.

Results

Each 1% increase in plasma concentration of manganese (Mn) was significantly associated with a 0.153% increase in LTL [β(95%CI) = 0.153(0.075, 0.230), P < 0.001] in single-metal models after Bonferroni-correction. The multiple-metal models and the LASSO penalized regression analysis both indicated Mn as the sole significant predictor for LTL. Furthermore, 5 tagSNPs (rs33954691, rs6554759, rs465498, rs2455393, and rs31489) in TERT-CLPTM1L with high plasma Mn (>4.21 μg/L) showed joint effects on increasing LTL.

Conclusions

Our study revealed the independent and positive association between plasma Mn and LTL when accounting for co-exposure to other metals. This effect can be further enhanced by TERT-CLPTM1L variants. These results may advance our understanding of the complex interplay between genetic and environmental factors on telomere length. Further experimental studies are warranted to elucidate the underlying mechanisms.

Keywords

Telomere length
Multiple metals
TERT-CLPTM1L
Genetic variants

Abbreviations

Al
aluminum
As
arsenic
Ba
barium
Cd
cadmium
Co
cobalt
Cr
chromium
Cu
copper
Fe
iron
Mn
manganese
Mo
molybdenum
Ni
nickel
Pb
lead
Rb
rubidium
Sb
antimony
Se
selenium
Sn
tin
Sr
strontium
Ti
titanium
Tl
thallium
U
uranium
V
vanadium
W
tungsten
Zn
zinc
BMI
body mass index
BPDE-Alb
benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin adducts
CIs
confidence intervals
CLPTM1L
cleft lip and palate transmembrane protein 1-like
CV
coefficient of variation
eQTL
the expression Quantitative Trait Loci
GC–MS
gas chromatography-mass spectrometry
GTEx
Genotype-Tissue Expression
GWAS
genome-wide association study
HWE
Hardy-Weinberg equilibrium
ICP-MS
inductively coupled plasma-mass spectrometry
LASSO
least absolute shrinkage and selection operator
LD
linkage disequilibrium
LOD
limit of detection
LTL
leukocyte telomere length
MAF
minor allele frequency
Mn-SOD
manganese superoxide dismutase
MSE
mean squared error
OH-PAHs
monohydroxy polycyclic aromatic hydrocarbons
ΣOH-PAHs
the sum concentrations of OH-PAHs
PAH
polycyclic aromatic hydrocarbons
Q
quartile
QC
quality control
SD
standard deviation
STE
standard error
SNP
single nucleotide polymorphism
TERT
telomerase reverse transcriptase

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1

These authors contributed equally to this work.