Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
EMBO Rep. 2022 Jun 7;23(6):e54147. doi: 10.15252/embr.202154147. Epub 2022 Apr 4.
Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.
发育性砷暴露与流行病学研究中的认知缺陷有关，但潜在机制仍知之甚少。在这里，我们建立了一个发育性砷暴露的小鼠模型，该模型在后代中表现出识别和空间记忆缺陷。这些缺陷与全基因组 DNA 低甲基化和海马中与认知相关基因的异常表达有关。砷原子直接与 DNA 甲基转移酶 3A（DNMT3A）的富含半胱氨酸的 ADD 结构域结合，在不同的细胞环境中触发泛素和蛋白酶体介导的 DNMT3A 降解。DNMT3A 降解导致小鼠胚胎成纤维细胞中的全基因组 DNA 低甲基化，但在非胚胎细胞系中则不会。一线抗糖尿病药物二甲双胍可增加 DNA 甲基化，用其治疗可改善砷暴露后代的行为缺陷，并使海马中与认知相关的基因和 DNA 甲基化的异常表达恢复正常。本研究确立了发育性砷暴露的 DNA 低甲基化效应，并提出了一种针对砷污染地区孕妇后代认知缺陷的潜在治疗方法。
