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

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

  • Sci Total Environ. 2023 Jul 8;165348. doi: 10.1016/j.scitotenv.2023.165348.
Yang Yue 1,  Huadong Zhang 2,  Ping Deng 1,  Miduo Tan 3,  Chengzhi Chen 4,  Bo Tang 5,  Jingdian Li 1,  Fengqiong Chen 2,  Qi Zhao 2,  Ling Li 1,  Rongrong Hao 1,  Hui Wang 1,  Yan Luo 1,  Li Tian 1,  Jia Xie 1,  Mengyan Chen 1,  Zhengping Yu 1,  Zhou Zhou 6,  Huifeng Pi 7
Affiliations

Affiliations

  • 1 Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Medical University, Chongqing 400038, China.
  • 2 Chongqing Municipal Center for Disease Control and Prevention, Chongqing 400042, China.
  • 3 Department of Breast Surgery, The Affiliated Zhuzhou Hospital of Xiang Ya School of Medicine, Central South University, Zhuzhou 412000, Hunan, China.
  • 4 Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
  • 5 Department of Gastroenterology, Xinqiao Hospital, Third Medical University, Chongqing 400037, China.
  • 6 Center for Neurointelligence, School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: lunazhou00@cqu.edu.cn.
  • 7 Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Medical University, Chongqing 400038, China. Electronic address: pihuifeng@tmmu.edu.cn.
PMID: 37429473 DOI: 10.1016/j.scitotenv.2023.165348
Abstract

Cadmium (Cd) is a 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 spectrometry-based metabolomics confirmed that Cd exposure disturbed gut microbiota homeostasis, especially Helicobacter and Campylobacter abundance remodeling, which altered the gut metabolic homeostasis of Gln. Moreover, intratumoral Gln 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 Ki67 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 necrosis 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.

Keywords

Breast cancer; Cadmium; Glutamine metabolism; Gut dysbiosis; MMTV-Erbb2 mice.

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