Environmental cadmium exposure facilitates mammary tumorigenesis via reprogramming gut microbiota-mediated glutamine metabolism in MMTV-Erbb2 mice

作者全名："Yue, Yang; Zhang, Huadong; Deng, Ping; Tan, Miduo; Chen, Chengzhi; Tang, Bo; Li, Jingdian; Chen, Fengqiong; Zhao, Qi; Li, Ling; Hao, Rongrong; Wang, Hui; Luo, Yan; Tian, Li; Xie, Jia; Chen, Mengyan; Yu, Zhengping; Zhou, Zhou; Pi, Huifeng"

作者地址："[Yue, Yang; Deng, Ping; Li, Jingdian; Li, Ling; Hao, Rongrong; Wang, Hui; Luo, Yan; Tian, Li; Xie, Jia; Chen, Mengyan; Yu, Zhengping; Pi, Huifeng] Third Mil Med Univ, Dept Occupat Hlth, Key Lab Electromagnet Radiat Protect, Minist Educ, Chongqing 400038, Peoples R China; [Zhang, Huadong; Chen, Fengqiong; Zhao, Qi] Chongqing Municipal Ctr Dis Control & Prevent, Chongqing 400042, Peoples R China; [Tan, Miduo] Cent South Univ, Affiliated Zhuzhou Hosp, Dept Breast Surg, Xiang Ya Sch Med, Zhuzhou 412000, Hunan, Peoples R China; [Chen, Chengzhi] Chongqing Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Chongqing 400016, Peoples R China; [Tang, Bo] Third Mil Med Univ, Xinqiao Hosp, Dept Gastroenterol, Chongqing 400037, Peoples R China; [Zhou, Zhou] Chongqing Univ, Ctr Neurointelligence, Sch Med, Chongqing 400030, Peoples R China"

通信作者："Pi, HF (通讯作者)，Third Mil Med Univ, Dept Occupat Hlth, Key Lab Electromagnet Radiat Protect, Minist Educ, Chongqing 400038, Peoples R China.; Zhou, Z (通讯作者)，Chongqing Univ, Ctr Neurointelligence, Sch Med, Chongqing 400030, Peoples R China."

来源：SCIENCE OF THE TOTAL ENVIRONMENT

ESI学科分类：ENVIRONMENT/ECOLOGY

WOS号：WOS:001047383900001

JCR分区：Q1

影响因子：8.2

年份：2023

卷号：897

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Gut dysbiosis; MMTV-Erbb2 mice; Breast cancer; Cadmium; Glutamine metabolism

摘要："Cadmium (Cd) isa heavy metal that has been widely reported to be linked to the onset and progression of breast cancer (BC). However, the mechanism of Cd-induced mammary tumorigenesis remains elusive. In our study, a transgenic mouse model that spontaneously develops tumors through overexpression of wild-type Erbb2 (MMTV-Erbb2) was constructed to investigate the effects of Cd exposure on BC tumorigenesis. The results showed that oral exposure to 3.6 mg/L Cd for 23 weeks dramatically accelerated tumor appearance and growth, increased Ki67 density and enhanced focal necrosis and neovascularization in the tumor tissue of MMTV-Erbb2 mice. Notably, Cd exposure enhanced glutamine (Gln) metabolism in tumor tissue, and 6-diazo-5-oxo-L-norleucine (DON), a Gln metabolism antagonist, inhibited Cd-induced breast carcinogenesis. Then our metagenomic sequencing and mass spectrometrybased metabolomics confirmed that Cd exposure disturbed gut microbiota homeostasis, especially Helicobacter and Campylobacter abundance remodeling, which altered the gut metabolic homeostasis of Gln. Moreover, intratumoralGln metabolism profoundly increased under Cd-elevated gut permeability. Importantly, depletion of microbiota with an antibiotic cocktail (AbX) treatment led to a significant delay in the appearance of palpable tumors, inhibition of tumor growth, decrease in tumor weight, reduction in Ki6 7 expression and low-grade pathology in Cd-exposed MMTV-Erbb2 mice. Also, transplantation of Cd-modulated microbiota decreased tumor latency, accelerated tumor growth, increased tumor weight, upregulated Ki67 expression and exacerbated neovascularization as well as focal ne-crosis in MMTV-Erbb2 mice. In summary, Cd exposure induced gut microbiota dysbiosis, elevated gut permeability and increased intratumoral Gln metabolism, leading to the promotion of mammary tumorigenesis. This study provides novel insights into environmental Cd exposure-mediated carcinogenesis."

基金机构："National Natural Science Foundation of China [82173473, 82173468]; Natural Science Foundation of Chongqing [CSTC2018JCYJAX0138]; Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) [2023DBXM006]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (82173473 and 82173468) , Natural Science Foundation of Chongqing (CSTC2018JCYJAX0138) and Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) (2023DBXM006) . Graphical abstract and protocols for animal experiments were created with BioRender. Com."