Arsenic metabolites; selenium; and AS3MT, MTHFR, AQP4, AQP9, SELENOP, INMT, and MT2A polymorphisms in Croatian‐Slovenian population from PHIME‐CROME study
Arsenic metabolites; selenium; and AS3MT, MTHFR, AQP4, AQP9, SELENOP, INMT, and MT2A polymorphisms in Croatian‐Slovenian population from PHIME‐CROME study
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DOI：
10.1016/j.envres.2018.11.045
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发表时间：
2019-03
影响因子：
8.3
通讯作者：
A. Stajnko;Z. Šlejkovec;D. Mazej;A. France-Štiglic;A. Briški;I. Prpić;Z. Špirić;M. Horvat;I. Falnoga
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文献类型：
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作者：
A. Stajnko;Z. Šlejkovec;D. Mazej;A. France-Štiglic;A. Briški;I. Prpić;Z. Špirić;M. Horvat;I. Falnoga
无机砷（iAs）代谢，硒（Se）的状态，和各种基因的遗传多态性之间的关系，通常在人群中暴露于高水平的iAs从饮用水中研究，研究了在更广泛的PHIME-CROME项目的斯洛文尼亚-斯洛文尼亚人口。人群包括136名妊娠晚期孕妇和176名非孕妇及其子女（n = 176，8-9岁）。根据生物样品的As（形态）分析，他们对iAs的接触程度很低。孕妇、非孕妇和儿童的生物活性代谢物（亚砷酸盐+砷酸盐+甲基化As形式）的总和分别为：3.23（2.84-3.68）、1.83（1.54-2.16）和2.18（1.86-2.54）ng/mLSG; GM（95 CI）。相应的血浆硒水平分别为：54.8（52.8-56.9）、82.3（80.4-84.0）和65.8（64.3-67.3）ng/mL; GM（95 CI）。作为甲基化效率指标，证实了妊娠/儿童期与更好的甲基化效率之间的关系。使用存档的血液和/或唾液样本进行砷（3+）甲基转移酶-AS 3 MT的单核苷酸多态性（SNP）基因分型（rs7085104、rs3740400、rs3740393、rs3740390、rs 11191439、rs 10748835、rs 1046778和相应的AS 3 MTha体型）;亚甲基四氢叶酸还原酶（rs 1801131，rs 1801133）;水通道蛋白-AQP 4和9（rs 9951307和rs 2414539）;硒蛋白P1 -SELENOP（rs7579，rs3877899）;吲哚乙胺N-甲基转移酶-INMT（rs6970396）;和金属硫蛋白2A-MT 2A（rs 28366003）。SNPs与As参数和尿Se的关联通过使用适当的混杂因素（血As、血浆Se、曾经吸烟等）调整的多元回归分析来确定。SNPs对As甲基化的影响，特别是由次级甲基化指数（SMI）定义，证实了sixAS 3 MTSNPs的次要等位基因及其单倍型仅在非妊娠妇女中的“保护”作用。在其他研究的基因中，AQP 9的携带者（rs 2414539）与非妊娠妇女中更有效的As甲基化和更高的As和Se尿浓度相关;观察到AQP 4携带者甲基化较差（rs 9951307）和非妊娠女性中的SELENOP（rs7579）; MT 2A（rs 28366003）与较高的尿As III浓度相关，而与妊娠状态无关; INMT（rs6970396）与非妊娠妇女中较高的As和Se浓度相关。在混杂因素中，观察到最强的影响是血浆硒，它降低了妊娠期间尿AsIII浓度，并增加了非妊娠妇女的次级甲基化指数。在本研究中，低砷暴露的人群，我们观察到一些新的As基因协会（特别是与AQPs）。更可靠的解释后，他们的确认在更大的人群与更高的作为暴露水平将是可能的。
The relationships between inorganic arsenic (iAs) metabolism, selenium (Se) status, and genetic polymorphisms of various genes, commonly studied in populations exposed to high levels of iAs from drinking water, were studied in a Croatian-Slovenian population from the wider PHIME-CROME project. Population consisted of 136 pregnant women in the 3rdtrimester and 176 non-pregnant women with their children (n = 176, 8–9 years old). Their exposure to iAs, defined by As (speciation) analyses of biological samples, was low. The sums of biologically active metabolites (arsenite + arsenate + methylated As forms) for pregnant women, non-pregnant women, and children, respectively were: 3.23 (2.84–3.68), 1.83 (1.54–2.16) and 2.18 (1.86–2.54) ng/mLSG; GM (95 CI). Corresponding plasma Se levels were: 54.8 (52.8–56.9), 82.3 (80.4–84.0) and 65.8 (64.3–67.3) ng/mL; GM (95 CI). As methylation efficiency indexes confirmed the relationship between pregnancy/childhood and better methylation efficiency. Archived blood and/or saliva samples were used for single nucleotide polymorphism (SNP) genotyping of arsenic(3+) methyltransferase -AS3MT(rs7085104, rs3740400, rs3740393, rs3740390, rs11191439, rs10748835, rs1046778 and the correspondingAS3MThaplotype); methylene tetrahydrofolate reductase -MTHFR(rs1801131, rs1801133); aquaporin -AQP4 and 9 (rs9951307 and rs2414539); selenoprotein P1 -SELENOP(rs7579, rs3877899); indolethylamine N-methyltransferase -INMT(rs6970396); and metallothionein 2A -MT2A(rs28366003). Associations of SNPs with As parameters and urine Se were determined through multiple regression analyses adjusted using appropriate confounders (blood As, plasma Se, ever smoking, etc.). SNPs’ influence on As methylation, defined particularly by the secondary methylation index (SMI), confirmed the ‘protective’ role of minor alleles of sixAS3MTSNPs and their haplotype only among non-pregnant women. Among the other investigated genes, the carriers ofAQP9(rs2414539) were associated with more efficient As methylation and higher urine concentration of As and Se among non-pregnant women; poorer methylation was observed for carriers ofAQP4(rs9951307) among pregnant women andSELENOP(rs7579) among non-pregnant women;MT2A(rs28366003) was associated with higher urine concentration of AsIII regardless of the pregnancy status; andINMT(rs6970396) was associated with higher As and Se concentration in non-pregnant women. Among confounders, the strongest influence was observed for plasma Se; it reduced urine AsIII concentration during pregnancy and increased secondary methylation index among non-pregnant women. In the present study of populations with low As exposure, we observed a few new As–gene associations (particularly withAQPs). More reliable interpretations will be possible after their confirmation in larger populations with higher As exposure levels.