PO.PR02.03 · 预防研究
叶酸稳态的营养性破坏触发一种内源性遗传毒性致癌物
Nutritional disruption of folate homeostasis triggers an endogenous genotoxic carcinogen
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：甲醛是一种存在于工业化学品中的人类致癌物，也由哺乳动物代谢产生。内源性甲醛的毒性在患有甲醛解毒酶（ALDH2/ADH5）先天性缺陷的儿童中最为严重，可通过甲醛-DNA损伤导致早发性骨髓衰竭和白血病。虽然内源性甲醛存在于所有健康组织中，但控制其产生的营养和代谢因素仍属未知。既往体外研究表明叶酸可自发分解释放甲醛。然而，叶酸代谢对体内内源性甲醛的贡献从未被研究过。鉴于叶酸补充的广泛使用以及全球20亿叶酸不足人群，我们在小鼠模型中研究了叶酸过量和缺乏如何影响内源性甲醛。
方法：对于叶酸过量，给野生型和Adh5-/-小鼠喂食高叶酸饮食（每日推荐摄入量的10倍）8周。对于缺乏：1）SLC46A1缺失导致叶酸吸收不良，2）叶酸缺乏饮食8-12周。我们开发了超灵敏质谱法，以定量甲醛-DNA加合物作为组织甲醛暴露的生物标志物。
结果：与体外预测相反，组织叶酸积累并未升高内源性甲醛。引人注目的是，叶酸缺乏显著增加了肝脏、脾脏和骨髓中的甲醛。在甲醛清除受损的叶酸缺乏Adh5-/-小鼠中，肝脏甲醛增加35倍，伴随DNA损伤升高、严重贫血（红细胞减少50%）和造血干细胞丢失。代谢组学显示叶酸缺乏的肝脏上调胆碱氧化以生成一碳单位，该通路产生甲醛作为毒性副产物。
结论：我们确立叶酸代谢是防止内源性甲醛积累的关键保护机制，缺乏则通过代偿性胆碱氧化触发甲醛产生。我们的发现有三大意义：第一，通过证明过量叶酸不产生甲醛，验证了叶酸补充（数百万人用于产前保健和癌症治疗）的安全性。第二，我们提出了一种机制，用以解释全球叶酸缺乏个体的癌症风险，尤其是5亿无法解毒甲醛的ALDH2缺陷者。第三，我们发现胆碱是一种意料之外的内源性甲醛来源，凸显了在低叶酸状态下补充胆碱需谨慎的必要性。这些发现支持将靶向叶酸补充作为ALDH2缺陷高危人群的癌症预防策略。
查看英文原文 English abstract
Background: Formaldehyde, a human carcinogen found in industrial chemicals, is also produced by mammalian metabolism. The toxicity of endogenous formaldehyde is most severe in children with inborn errors in formaldehyde detoxification enzymes (ALDH2/ADH5), causing early-onset bone marrow failure and leukemia through formaldehyde-DNA damage. While endogenous formaldehyde exists in all healthy tissues, the nutritional and metabolic factors controlling its production remain unknown. Prior in vitro studies showed folate can spontaneously decompose to release formaldehyde. However, folate metabolism's contribution to endogenous formaldehyde in vivo has never been studied. Given widespread folate supplementation and the 2 billion people with folate insufficiency worldwide, we investigated how folate excess and deficiency affect endogenous formaldehyde in mouse models.
Methods: For folate excess, wildtype and Adh5 -/- mice received high-folate diet (10x recommended daily allowance) for 8 weeks. For deficiency: 1) SLC46A1 deletion causing folate malabsorption, and 2) folate-depleted diet for 8-12 weeks. We developed ultra-sensitive mass spectrometry to quantify formaldehyde-DNA adducts as biomarkers of tissue formaldehyde exposure.
Results: Contrary to in vitro predictions, tissue folate accumulation did not elevate endogenous formaldehyde. Strikingly, folate deficiency significantly increased formaldehyde in liver, spleen, and bone marrow. In folate-deficient Adh5 -/- mice with impaired formaldehyde clearance, hepatic formaldehyde increased 35-fold with elevated DNA damage, severe anemia (50% reduction in red cells), and hematopoietic stem cell loss. Metabolomics revealed folate-deficient livers upregulated choline oxidation to generate one-carbon units, a pathway that produces formaldehyde as a toxic byproduct.
Conclusions: We establish folate metabolism as a critical safeguard against endogenous formaldehyde accumulation, with deficiency triggering formaldehyde production through compensatory choline oxidation. Our findings have three major implications: First, they validate the safety of folate supplementation, used by millions for prenatal care and cancer treatment, by proving excess folate does not generate formaldehyde. Second, we hypothesize a mechanism underlying cancer risk in folate-deficient individuals worldwide, particularly the 500 million with ALDH2 deficiency who cannot detoxify formaldehyde. Third, we identify choline as an unexpected endogenous formaldehyde source, highlighting the need for caution with choline supplementation during low-folate status. These findings support targeted folate supplementation as a cancer prevention strategy for high-risk populations with ALDH2 deficiency
利益披露 Disclosure
C. Mellor, None..
S. Azad, None..
N. Cheng, None..
B. James, None..
V. A. Simon, None..
O. V. Malysheva, None..
G. Burgos Barragan, None..
M. S. Field, None..
M. Wang, None.