无论是组织驻留巨噬细胞还是从骨髓中招募并转化为组织驻留细胞的单核细胞，它们在调节体内稳态以及发炎性疾病的病理过程中起着关键作用。砷（iAs）是全球最常见的饮用水污染物之一，也是一个重大的公共卫生问题。巨噬细胞在多种疾病中的参与与iAs的暴露有关，包括心血管疾病、癌症以及感染性疾病的风险增加。因此，了解iAs暴露对巨噬细胞的影响，有助于更好地理解砷引起的免疫毒性的全面范围，并为特定暴露人群中iAs诱导疾病的治疗靶点设计提供帮助。在本研究中，我们分析了经低剂量iAs暴露的雄性和雌性小鼠骨髓来源的巨噬细胞（BMDMs）在M0、M1或M2刺激下的转录组。我们通过性别和刺激依赖的方式确定了iAs调节的差异表达基因，并使用生物信息学工具预测了蛋白质相互作用、转录调控网络以及相关的生物过程。总体而言，我们的数据表明，M1刺激的巨噬细胞，尤其是雌性来源的BMDMs，对iAs的暴露最敏感。值得注意的是，我们观察到了主要的促炎转录因子（如IRF8）及其下游靶基因的显著下调，以及参与模式识别和抗原呈递的蛋白质编码基因（如TLR7、TLR8和H2-D1）的显著下调，这可能提供了关于砷在干扰免疫对感染性疾病应答中作用的因果洞察。我们还观察到了参与协调促炎反应的关键过程的基因的显著下调，包括白细胞迁移、分化以及细胞因子和趋化因子的生成和响应。最后，我们发现，对于被iAs暴露的雌性刺激组，有24个X连锁基因的表达失调，而在iAs暴露的雄性刺激组中只有3个。这些发现阐明了性别差异在与iAs相关的免疫相关疾病风险中的潜在机制。

Both tissue-resident macrophages and monocytes recruited from the bone marrow that transform into tissue-resident cells play critical roles in mediating homeostasis as well as in the pathology of inflammatory diseases. Inorganic arsenic (iAs) is the most common drinking water contaminant worldwide and represents a major public health concern. Several diseases that macrophages have implicated involvement in are caused by iAs exposure, including cardiovascular disease, cancer, and increased risk of infectious disease. Therefore, understanding the effects of iAs exposure on macrophages can help us better grasp the full range of arsenic immunotoxicity and better design therapeutic targets for iAs-induced diseases particularly in exposed populations. In this study, we analyzed the transcriptome of low dose iAs-exposed male and female murine bone marrow-derived macrophages (BMDMs) with either M0, M1, or M2 stimulation. We identified differentially expressed genes by iAs in a sex- and stimulation-dependent manner and used bioinformatics tools to predict protein-protein interactions, transcriptional regulatory networks, and associated biological processes. Overall, our data suggest that M1-stimulated, especially female-derived, BMDMs are most susceptible to iAs exposure. Most notably, we observed significant downregulation of major proinflammatory transcription factors, like IRF8, and its downstream targets, as well as genes encoding proteins involved in pattern recognition and antigen presentation, such as TLR7, TLR8, and H2-D1, potentially providing causal insight regarding arsenic's role in perturbing immune responses to infectious diseases. We also observed significant downregulation of genes involved in processes crucial to coordinating a proinflammatory response including leukocyte migration, differentiation, and cytokine and chemokine production and response. Finally, we discovered that 24 X-linked genes were dysregulated in iAs-exposed female stimulation groups compared to only 3 across the iAs-exposed male stimulation groups. These findings elucidate the potential mechanisms underlying the sex-differential iAs-associated immune-related disease risk.