維生素D受體、金屬硫蛋白1A及2A之基因多型性對慢性鉛暴露工人的感覺神經系統毒性的影響

The influence of Vitamin D receptor, Metallothionein 1A and 2A gene polymorphisms on the lead toxicity to the sensory nervous system in chronic lead – exposed workers

劉信良(Hsin-Liang Liu)

指導教授 ： 莊弘毅

高雄醫學大學/健康科學院/公共衛生學系職業安全衛生碩士班/碩士(2015年)

https://doi.org/10.6832/KMU.2015.00146

摘要

鉛會對人體產生神經、心血管、造血等等全身的毒性，隨著現在科學對基因的了解，基因多型性對鉛暴露工人對鉛毒性的易感性也越來越重要，其中維生素D受體、金屬硫蛋白1A及2A之基因多型性在之前的研究中提到可以跟鉛毒性有關連，但對神經毒性方面從未提到。本篇研究是第一篇研究維生素D受體(Vitamin D receptor,VDR)、金屬硫蛋白(Metallothioneins,MT) 1A及2A之基因多型性對慢性鉛暴露工人的感覺神經系統毒性的影響。我們收集六年間181位鉛電池工廠工人，測量分析基本資料、血中時間加權鉛累積指數(Time-weighted index of cumulative blood lead,TWICL)、維生素D受體VDR(Bsm rs1544410, Apa rs7975232 and Taq rs731236)、金屬硫蛋白MT1A(rs11640851 and rs8052394)及2A(rs10636 and rs28366003)之基因多型性等，再以震動或電流剌激測量手指和腳趾的敏感閥值並加以分析。結果發現在某些基因多型性中，血中時間加權鉛累積指數TWICL至少要上升20μg/dL，才能等同於基因多型性對感覺神經系統毒性的影響。有AG基因型的MT2A rs28366003藉著增加神經敏感性而對鉛造成的神經毒性有保護作用.有CC 基因型的VDR Apa (rs7975232)和MT2A rs10636 會顯著增加手的神經毒性. MT1A rs8052394的GG 基因型能保護大型有髓鞘的神經， MT1A rs11640851的AA基因型是神經毒性的易感型，最後，鉛與鋅在感覺神經毒性的交互作用還需進一步的研究。

關鍵字

維生素D受體 ； 金屬硫蛋白1A及2A ； 基因多型性 ； 慢性鉛暴露 ； 感覺神經系統 ； 毒性

並列摘要

Background and objective:
Lead had neurotoxicity in peripheral sensory systems. Variant vitamin D receptor (VDR) genes and polymorphisms of Metallothioneins (MTs) were associated to lead toxicity. But no relationship between lead neurotoxicity and polymorphisms were discussed before. This study investigated the relationship among the polymorphisms of the VDR, MT1A, MT2A and lead toxicity to sensory nervous system in chronic lead – exposed workers
Methods:
We measured 181 workers’ vibration perception thresholds (VPT) and current perception thresholds (CPT) as neurological outcomes since 1990~1995. The outcome variables were then correlated to the subject’s index of long-term lead exposure that was calculated by the subject’s serial blood lead data in a period of working duration. The polymorphisms of VDR (Bsm rs1544410, Apa rs7975232 and Taq rs731236), MT1A (rs11640851 and rs8052394) and MT2A (rs10636 and rs28366003) are defined. The potential confounders, including age, gender, body height, smoking, alcohol consumption and working life span, were also collected and analyzed in linear regressions.
Results:
The regression coefficients of some gene polymorphisms were at lease 20 times larger than regression coefficients of TWICL. The regression analyses showed MT2A rs28366003(AG/AA) had significant different in all neurological outcomes except foot VPT and had the negative regression coefficients. All regression coefficients of TWICL mildly increased at the same time. MT1A rs11640851 (AA/CC) had significant difference in all neurological outcomes except hand and foot VPT. MT1A rs8052394 (GG/AA) had significant difference in hand and foot CPT 2000Hz. In MT2A rs10636, more C allele showed more influence in all three frequency of hand CPT. Among VDR, Apa rs7975232 (CC/AA) had most difference in all three frequency of hand CPT.
Conclusion:
TWICL needed to increase at lease 20μg/dL to have the same influence on neurotoxicity comparing with some different gene polymorphisms. Individuals with AG genotype for MT2A rs28366003 had neural protective effects by increasing sensitivity. CC genotype for Apa (rs7975232) of VDR and CC genotype for MT2A rs10636 increased the neurotoxicity on CPT more significant on hands. MT1A rs8052394 GG genotype has the protective effect on large myelinated nerve. MT1A rs11640851 AA genotype has susceptibilities to neurotoxicity. The interaction between zinc and lead to neurotoxicity needs further studies.

並列關鍵字

Vitamin D receptor ； Metallothionein 1A and 2A ； gene polymorphisms ； lead toxicity ； sensory nervous system

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