Benzo[a]pyrene Exposure Reduces Cell-Type Diversity and Stimulates Sex-Biased Damage Pathways in End Organs of Lupus-Prone Mice.
Benzo[a]pyrene Exposure Reduces Cell-Type Diversity and Stimulates Sex-Biased Damage Pathways in End Organs of Lupus-Prone Mice.
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DOI：
10.3390/ijms24076163
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发表时间：
2023-03-24
影响因子：
5.6
通讯作者：
Liang, Yun
中科院分区：
文献类型：
--
作者：
Zhu, Runqi;Kennicott, Kameron;Liang, Yun
研究表明，遗传因素仅占所有自身免疫性疾病的大约百分之三十，而其余的自身免疫发病机制则归因于包括有毒化学物质在内的环境因素。为了了解环境污染物是否以及如何触发自身免疫，我们研究了苯并[a]芘 (BaP) 暴露对狼疮易发 MRL 菌株中自身免疫表型发展的影响。在狼疮发病前 8 周内，将 MRL 小鼠暴露于 BaP 会导致雄性小鼠总体体重减轻，同时抗 dsDNA 水平发生微小变化。对 BaP 处理和对照 MRL 小鼠的多器官分析表明，肾脏是直接受含苯化合物代谢影响的主要器官，BaP 靶基因（包括 Cyp4b1 和hao2）的表达增加。有趣的是，空间转录组数据表明 BaP 导致 MRL 小鼠肾脏和脾脏细胞类型多样性急剧减少。对受影响的分子途径的进一步分析表明，BaP 治疗具有性别偏见效应，雄性小鼠肺部血管生成基因表达上调，肾脏中 C3 沉积增加。虽然系统性红斑狼疮在女性中更为常见，但该疾病在男性患者中更为严重，疾病进展为肾衰竭和肺癌的风险增加。我们的结果揭示了 BaP 刺激的性别偏向分子途径，这可能有助于解释患有狼疮的男性终末器官损伤的可能性增加。
Studies indicate that genetic factors only account for approximately thirty percent of all autoimmune diseases, while the rest of autoimmune pathogenesis is attributed to environmental factors including toxic chemicals. To understand if and how environmental pollutants trigger autoimmunity, we investigated the effect of benzo[a]pyrene (BaP) exposure on the development of autoimmune phenotypes in the lupus-prone MRL strain. The exposure of MRL mice to BaP over the course of 8 weeks before lupus onset resulted in total body weight loss in males, while marginal changes in anti-dsDNA levels occurred. Multi-organ analyses of BaP-treated and control MRL mice suggested that the kidney is a major organ directly affected by the metabolism of benzene-containing compounds, with increased expression of BaP-target genes including Cyp4b1 and Hao2. Intriguingly, spatial transcriptomic data showed that BaP caused a drastic reduction in cell-type diversity in both the kidneys and spleen of MRL mice. Further analysis of the molecular pathways affected suggested a sex-biased effect of BaP treatment, with the upregulated expression of angiogenesis genes in the lungs and an increased deposition of C3 in the kidneys of male mice. While SLE is more common in women, the disease is more severe in male patients, with an increased risk of disease progression to renal failure and lung cancer. Our results reveal sex-biased molecular pathways stimulated by BaP which may help explain the increased likelihood of end organ damage in males with lupus.
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影响因子：
19.6
作者：
Gailly, P.;Jouret, F.;Devuyst, O.
通讯作者：
Devuyst, O.
影响因子：
9.8
作者：
Jung, Chau-Ren;Chung, Wan-Ting;Hwang, Bing-Fang
通讯作者：
Hwang, Bing-Fang
影响因子：
4
作者：
Hart, TC;Gorry, MC;Bleyer, AJ
通讯作者：
Bleyer, AJ
影响因子：
158.5
作者：
Arbuckle, MR;McClain, MT;Harley, JB
通讯作者：
Harley, JB
影响因子：
4.8
作者：
BUCHLI, R;ALBERATIGIANI, D;CESURA, AM
通讯作者：
CESURA, AM