透過氫譜核磁共振代謝體學分析無機砷暴露與年輕成人血清代謝特徵的關聯性

Abstract

在自然的地殼環境中存在有廣泛分布的有毒類金屬-砷，無機砷暴露已被證實與多種慢性疾病相關。孕期為敏感的關鍵發育時期，流行病學證據顯示，子宮內及早期生命階段(如兒童期)的砷暴露會與後續生命階段的血脂及葡萄糖代謝異常相關，並可能增加青少年時期心血管疾病風險。然而，早期砷暴露對成年人影響之分子流行病學證據仍然不足。砷暴露造成脂質代謝異常不僅為心血管疾病的重要風險因子，亦與非酒精性脂肪肝疾病的發展密切相關，砷暴露與心血管疾病的關聯已有較多研究支持，然而，產前及早期生命砷暴露是否促進成年期脂肪肝形成及分子效應的研究相對有限。 本研究利用了來自臺灣母嬰環境暴露世代研究（TMICS-Taichung）追蹤至21歲的97位年輕成人，其血清藉由核磁共振儀測量其血清代謝體。砷暴露依不同年齡階段之尿砷濃度進行分群，並利用多變量分析視覺化探討砷暴露與代謝體表現之關係。另透過線性迴歸分析評估產前以及當下砷暴露與個別血清代謝物及肝臟脂肪化指標之關聯。此外，進一步以中介分析探索代謝物在砷暴露與脂肪肝之間可能扮演的角色。 結果顯示，較高的產前砷暴露與21歲血清中之VLDL及不飽和脂肪酸上升顯著相關，並且與多個胺基酸下降顯著相關。我們推論產前砷暴露可能導致肝臟比較偏向製造和輸出脂質，而不是清除或保護血管，脂質合成與輸出造成能量需求增加可能會消耗胺基酸作為能量提供來源。雖然在多變量分析中代謝體分群與有無脂肪肝有關，但是再使用中介效應分析探討是否有特定代謝物顯著影響砷暴露與脂肪肝之間關連時，結果未發現顯著影響砷暴露與脂肪肝的代謝物。 綜合上述，本研究探討早期砷暴露與年輕成年期之血清代謝體之關係，結果顯示產前砷暴露可能與成年期脂質運輸及代謝與能量相關之特徵改變有關。此研究提供初步流行病學證據，支持早期生命暴露對後續代謝健康具有長期影響，並凸顯產前暴露時期在生命歷程研究中的重要性，為未來進一步進行大型世代研究及機制性探討提供研究方向與基礎。

Arsenic is an environmentally ubiquitous toxic metalloid, and exposure to its inorganic forms has been associated with a greater risk of developing chronic diseases. Previous epidemiological studies showed that prenatal and early-life arsenic exposure is a critical window of susceptibility and has been associated with later-life disturbances in lipid and glucose metabolism and increased cardiovascular disease risk. However, the long-term consequences and underlying molecular mechanisms associated with arsenic exposure during early life remain poorly understood. Although disturbances in lipid metabolism play a central role in the pathogenesis of cardiovascular disease and non-alcoholic fatty liver disease, the biochemical linking arsenic exposure to hepatic steatosis development is still limited. Using NMR-based metabolomics, we investigated serum metabolic alterations associated with early-life arsenic exposure among 97 participants aged 21 years from Taiwan mother infant cohort study (TMICS)-Taichung. Arsenic exposure was categorized according to urinary arsenic concentrations measured at different life stages. The clustering patterns of serum metabolomic profiles according to arsenic exposure were evaluated using multivariate statistical analyses. In addition, to investigate the associations of prenatal and concurrent arsenic exposure with serum metabolites and hepatic steatosis indicators, linear regression models were constructed. Furthermore, mediation analysis was performed to investigate whether serum metabolites potentially mediated the relationship between arsenic exposure and fatty liver. The result showed that higher prenatal arsenic exposure was positively associated with increased very-low-density lipoprotein (VLDL) and unsaturated fatty acids and decreased of multiple amino acids in the serum of 21-year-old adults. Prenatal arsenic exposure appears to favor hepatic lipid synthesis and export over lipid clearance and vascular protective functions, according to the present findings. Moreover, increased amino acid utilization was suspected to meet energetic demands of hepatic lipid synthesis and secretion. Although fatty liver status was associated with distinct metabolic clustering in multivariate analyses, mediation analysis did not identify any metabolites with a significant indirect effect linking arsenic exposure to hepatic steatosis. In summary, this study examined serum metabolic profiles in young adults with early-life arsenic exposure. We found that prenatal arsenic exposure is associated with alterations in serum metabolites related to lipid transport and energy metabolism in adulthood. These findings provided preliminary epidemiological evidence supporting long-term metabolic effects of early-life arsenic exposure and highlighted the importance of prenatal exposure windows in life-course research, informing future large-scale cohort and mechanistic studies.