Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studies
Neonicotinoid insecticides (NIs) have been widely detected in environmental media and human body with concentrations reaching hundreds of nanomolar to micromolar levels. However, the information about their human health toxicology and mechanism is deficient. Previous studies have implied that NIs mi...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Environment International |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412022004950 |
| _version_ | 1811315917864304640 |
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| author | Xin Li Sen He Han Xiao Ting-Ting He Jia-Da Zhang Zi-Rui Luo Jie-Zhi Ma Yu-Long Yin Lin Luo Lin-Ying Cao |
| author_facet | Xin Li Sen He Han Xiao Ting-Ting He Jia-Da Zhang Zi-Rui Luo Jie-Zhi Ma Yu-Long Yin Lin Luo Lin-Ying Cao |
| author_sort | Xin Li |
| collection | DOAJ |
| description | Neonicotinoid insecticides (NIs) have been widely detected in environmental media and human body with concentrations reaching hundreds of nanomolar to micromolar levels. However, the information about their human health toxicology and mechanism is deficient. Previous studies have implied that NIs might exert estrogenic disruption and promote breast cancer progression, but the molecular mechanism is unclear, especially the molecular initiating event. G protein-coupled estrogen receptor (GPER), as a candidate therapeutic target, plays vital roles in the development of breast cancer. This work aimed to reveal the potential mechanism through GPER pathway. Firstly, we screened the activities of seven most common NIs on GPER signal pathway by calcium mobilization assay. Clothianidin, acetamiprid (ACE), and dinotefuran activated GPER most potently and ACE displayed the highest agonistic activity with the lowest observed effective concentration (LOEC) of 1 μM. The molecular docking and dynamics simulation showed favored interaction trend between the NIs and GPER. The three NIs with GPER activity induced 4T1 breast cancer cells migration and ACE showed the highest potency with LOEC of 100 nM. ACE also induced 4T1 cells proliferation at high concentration of 50 μM and up-regulated GPER expression in a dose-dependent manner. We speculated that both the induction effects of ACE on 4T1 cells proliferation and migration might be owing to the activation and up-regulation of GPER. By using 4T1-Luc cells injected orthotopic tumor model, we found that ACE also promoted in-situ breast cancer growth and lung metastasis in normal mouse dependent on GPER. However, ACE only promoted in-situ breast cancer growth through GPER but not lung metastasis in ovariectomized mice, implying that the ACE-induced lung metastasis should be related to endogenous estrogen from ovary. Overall, we demonstrated that NIs promoted breast cancer progression via GPER pathway at human related exposure levels and their female health risks need urgent concerns. |
| first_indexed | 2024-04-13T11:40:03Z |
| format | Article |
| id | doaj.art-a553b69aa00c44d99c683378620f4068 |
| institution | Directory Open Access Journal |
| issn | 0160-4120 |
| language | English |
| last_indexed | 2024-04-13T11:40:03Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj.art-a553b69aa00c44d99c683378620f40682022-12-22T02:48:20ZengElsevierEnvironment International0160-41202022-12-01170107568Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studiesXin Li0Sen He1Han Xiao2Ting-Ting He3Jia-Da Zhang4Zi-Rui Luo5Jie-Zhi Ma6Yu-Long Yin7Lin Luo8Lin-Ying Cao9College of Resources and Environment, Hunan Agricultural University, 1, Nongda Road, Furong District, Changsha 410128, ChinaCollege of Resources and Environment, Hunan Agricultural University, 1, Nongda Road, Furong District, Changsha 410128, ChinaState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, ChinaCollege of Resources and Environment, Hunan Agricultural University, 1, Nongda Road, Furong District, Changsha 410128, ChinaCollege of Resources and Environment, Hunan Agricultural University, 1, Nongda Road, Furong District, Changsha 410128, ChinaCollege of Resources and Environment, Hunan Agricultural University, 1, Nongda Road, Furong District, Changsha 410128, ChinaDepartment of Obstetrics and Gynecology, Xiangya Third Hospital, Central South University, Changsha 410013, ChinaCollege of Resources and Environment, Hunan Agricultural University, 1, Nongda Road, Furong District, Changsha 410128, ChinaCollege of Resources and Environment, Hunan Agricultural University, 1, Nongda Road, Furong District, Changsha 410128, China; Corresponding authors.College of Resources and Environment, Hunan Agricultural University, 1, Nongda Road, Furong District, Changsha 410128, China; Corresponding authors.Neonicotinoid insecticides (NIs) have been widely detected in environmental media and human body with concentrations reaching hundreds of nanomolar to micromolar levels. However, the information about their human health toxicology and mechanism is deficient. Previous studies have implied that NIs might exert estrogenic disruption and promote breast cancer progression, but the molecular mechanism is unclear, especially the molecular initiating event. G protein-coupled estrogen receptor (GPER), as a candidate therapeutic target, plays vital roles in the development of breast cancer. This work aimed to reveal the potential mechanism through GPER pathway. Firstly, we screened the activities of seven most common NIs on GPER signal pathway by calcium mobilization assay. Clothianidin, acetamiprid (ACE), and dinotefuran activated GPER most potently and ACE displayed the highest agonistic activity with the lowest observed effective concentration (LOEC) of 1 μM. The molecular docking and dynamics simulation showed favored interaction trend between the NIs and GPER. The three NIs with GPER activity induced 4T1 breast cancer cells migration and ACE showed the highest potency with LOEC of 100 nM. ACE also induced 4T1 cells proliferation at high concentration of 50 μM and up-regulated GPER expression in a dose-dependent manner. We speculated that both the induction effects of ACE on 4T1 cells proliferation and migration might be owing to the activation and up-regulation of GPER. By using 4T1-Luc cells injected orthotopic tumor model, we found that ACE also promoted in-situ breast cancer growth and lung metastasis in normal mouse dependent on GPER. However, ACE only promoted in-situ breast cancer growth through GPER but not lung metastasis in ovariectomized mice, implying that the ACE-induced lung metastasis should be related to endogenous estrogen from ovary. Overall, we demonstrated that NIs promoted breast cancer progression via GPER pathway at human related exposure levels and their female health risks need urgent concerns.http://www.sciencedirect.com/science/article/pii/S0160412022004950Neonicotinoid insecticidesG protein-coupled receptorEstrogenic disruption effectBreast cancerSignal pathwayMolecular initiation event |
| spellingShingle | Xin Li Sen He Han Xiao Ting-Ting He Jia-Da Zhang Zi-Rui Luo Jie-Zhi Ma Yu-Long Yin Lin Luo Lin-Ying Cao Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studies Environment International Neonicotinoid insecticides G protein-coupled receptor Estrogenic disruption effect Breast cancer Signal pathway Molecular initiation event |
| title | Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studies |
| title_full | Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studies |
| title_fullStr | Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studies |
| title_full_unstemmed | Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studies |
| title_short | Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studies |
| title_sort | neonicotinoid insecticides promote breast cancer progression via g protein coupled estrogen receptor in vivo in vitro and in silico studies |
| topic | Neonicotinoid insecticides G protein-coupled receptor Estrogenic disruption effect Breast cancer Signal pathway Molecular initiation event |
| url | http://www.sciencedirect.com/science/article/pii/S0160412022004950 |
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