Dataset Information

Molecular Basis for Endocrine Disruption by Pesticides Targeting Aromatase and Estrogen Receptor.

ABSTRACT: The intensive use of pesticides has led to their increasing presence in water, soil, and agricultural products. Mounting evidence indicates that some pesticides may be endocrine disrupting chemicals (EDCs), being therefore harmful for the human health and the environment. In this study, three pesticides, glyphosate, thiacloprid, and imidacloprid, were tested for their ability to interfere with estrogen biosynthesis and/or signaling, to evaluate their potential action as EDCs. Among the tested compounds, only glyphosate inhibited aromatase activity (up to 30%) via a non-competitive inhibition or a mixed inhibition mechanism depending on the concentration applied. Then, the ability of the three pesticides to induce an estrogenic activity was tested in MELN cells. When compared to 17?-estradiol, thiacloprid and imidacloprid induced an estrogenic activity at the highest concentrations tested with a relative potency of 5.4 × 10-10 and 3.7 × 10-9, respectively. Molecular dynamics and docking simulations predicted the potential binding sites and the binding mode of the three pesticides on the structure of the two key targets, providing a rational for their mechanism as EDCs. The results demonstrate that the three pesticides are potential EDCs as glyphosate acts as an aromatase inhibitor, whereas imidacloprid and thiacloprid can interfere with estrogen induced signaling.

SUBMITTER: Zhang C

PROVIDER: S-EPMC7459580 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Molecular Basis for Endocrine Disruption by Pesticides Targeting Aromatase and Estrogen Receptor.

Zhang Chao C Schilirò Tiziana T Gea Marta M Bianchi Silvia S Spinello Angelo A Magistrato Alessandra A Gilardi Gianfranco G Di Nardo Giovanna G

International journal of environmental research and public health 20200805 16

The intensive use of pesticides has led to their increasing presence in water, soil, and agricultural products. Mounting evidence indicates that some pesticides may be endocrine disrupting chemicals (EDCs), being therefore harmful for the human health and the environment. In this study, three pesticides, glyphosate, thiacloprid, and imidacloprid, were tested for their ability to interfere with estrogen biosynthesis and/or signaling, to evaluate their potential action as EDCs. Among the tested co ...[more]

PMID: 32764486

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Project description:Purpose:To explore the targeted therapy of estrogen-related receptor ? (ERR?) in endometrial cancer (EC) cells and its potential mechanisms. Methods:The mRNA and protein expression levels of ERR? and estrogen receptor ? (ER?) were detected by qPCR and Western blotting in RL-952, AN3-CA, HEC-1A, and HEC-1B EC cell lines. After treatment with the ERR?-specific antagonist XCT790 or infection with lentivirus-mediated small interfering RNA (siRNA) targeting the ERR? (siRNA-ERR?), cell proliferation and apoptosis were evaluated by MTS assay and flow cytometry. After treatment with siRNA-ERR?, the expression profiles of transcription factors (TFs) were analyzed by protein/DNA arrays in EC cells. Results:The relative mRNA levels of ERRa in RL-952 (1±0.0831) and AN3-CA (1.162±0.0325) were significantly higher than those in HEC-1A (0.3081±0.0339) and HEC-1B (0.1119±0.0091) (P<0.05), and similar results were observed for ERR? protein levels. A higher ratio of ERa/ERRa was observed in ER?-positive RL-952 (10-fold) and ANC-3A (8.5-fold) cells, whereas a lower ratio was observed in ER?-negative HEC-1A (3.75-fold) and HEC-1B cells (0-fold). Both - exogenous XCT790 and endogenous siRNA-ERR? - can decrease the expression of ERR?, thereby inhibiting proliferation but promoting apoptosis in both ER?-positive and -negative EC cells. The XCT790 presented higher proliferation-inhibition and apoptosis rates in the ER?-positive than ER?-negative cells, whereas the siRNA-ERR? exhibited higher proliferation-inhibition and apoptosis rates in the ER?-negative than in ER?-positive cells. In total, 3 upregulated and 17 downregulated TFs were screened out by knocked-down expression of ERR? in all EC cells. Among them, the upregulated TFs organic cation transporter 3/4(Oct3/4), hepatic nuclear factor 4 (HNF4), HNF4 and chicken ovalbumin upstream TF (COUP-TF) as well as downregulated transcription factor EB (TFEB) were found to be statistically significant (P<0.05). Conclusion:Targeting ERR? provides a promising novel endocrine therapeutic strategy.

Project description:The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype.Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n?=?67,932) and Fudan University Shanghai Cancer Center (n?=?2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated.Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta-analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P?=?0.61 for sufficient versus insufficient endocrine therapy).The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed to validate these findings.

Dataset Information

Molecular Basis for Endocrine Disruption by Pesticides Targeting Aromatase and Estrogen Receptor.

Publications

Molecular Basis for Endocrine Disruption by Pesticides Targeting Aromatase and Estrogen Receptor.

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