Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway

Abstract

Background:Aromatase (CYP19) is a key enzyme in estrogens biosynthesis. In the mammary gland, CYP19 gene is expressed at low levels under the regulation of its I.4 promoter. In hormone-dependent breast cancer, fibroblast cells surrounding the tumor express increased levels of CYP19 mRNA due to a decrease of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter activity. Little is known about the effects of environmental chemicals on the promoter-specific CYP19 expression.Objective:We aimed to determine the effects of two neonicotinoids (thiacloprid and imidacloprid) on promoter-specific CYP19 expression in Hs578t breast cancer cells and understand the signaling pathways involved.Methods:Hs578t cells were exposed to various signaling pathway stimulants or neonicotinoids for 24 h. Promoter-specific expression of CYP19 was determined by real-time quantitative polymerase chain reaction and catalytic activity of aromatase by tritiated water release assay.Results:To our knowledge, we are the first to demonstrate that the normal I.4 promoter and the breast cancer-relevant PII, I.3, and I.7 promoters of CYP19 are active in these cells. We found that the expression of CYP19 via promoters PII, I.3, and I.7 in Hs578t cells was, in part, dependent on the activation of two VEGF signaling pathways: mitogen-activated protein kinase (MAPK) 1/3 and phospholipase C (PLC). Exposure of Hs578t cells to environmental concentrations of imidacloprid and thiacloprid resulted in a switch in CYP19 promoter usage, involving inhibition of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter-mediated CYP19 expression and aromatase catalytic activity. Greater effects were seen at lower concentrations. Our results suggest that thiacloprid and imidacloprid exert their effects at least partially by inducing the MAPK 1/3 and/or PLC pathways.Conclusions:We demonstrated in vitro that neonicotinoids may stimulate a change in CYP19 promoter usage similar to that observed in patients with hormone-dependent breast cancer. https://doi.org/10.1289/EHP2698

Trends in neonicotinoid pesticide residues in food and water in the United States, 1999–2015

“…Average DFs over the entire study period, 1999–2015, for domestic and imported commodities were also low at 4.5% Neonicotinoids were mainly detected in fruits and vegetables, with imidacloprid and acetamiprid residues as the more frequently detected neonicotinoids. Although the majority of commodities had neonicotinoid residue levels well below the US EPA’s tolerances, the detection of multiple neonicotinoids on fruits and vegetables in our study, including on commodities frequently consumed by children, the worldwide commercial expansion of neonicotinoids, systematic properties and environmental persistence of neonicotinoids coupled with limited information about their mixtures toxicity for developmental, neurological and possible endocrine disruption effects among humans [10, 38] underscores the need to further evaluate cumulative exposures and the potential health risks resulting from dietary intakes of neonicotinoids, especially among children and pregnant women. The implications of neonicotinoid exposures may be better understood if a national biomonitoring surveillance was in place.…”

“…Acute and chronic exposures to neonicotinoids have resulted in measurable health effects on multiple organ systems in rodents, perhaps most notable on the neurological system and on developing pups in utero [31–36]. Emerging evidence raises concerns that neonicotinoids may also act as endocrine disruptors; testicular developmental effects of thiamethoxam have been reported in a 2-generational reproductive rat study and thiacloprid and imidacloprid may activate excess estrogen production in breast tissue by altering promoter activity [37, 38]. Both acetamiprid and imidacloprid exposure in utero is reported to adversely affect neuron development in rat brains.…”

Preclinical evaluation of exemestane as a novel chemotherapy for gastric cancer

“…The third mechanism is off-target inhibition; for example, Ar activity could increase prostaglandin E2 (PGE2) binding to the G-protein-coupled PGE2 receptor to stimulate cyclic AMP production. 43,44 Whether the consequential PGE2 ablation with ARI-II inhibits cell growth requires further examination. The fourth mechanism is the epigenetic modification of Ar by ARI-II.…”

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

“…Insecticides such as thiacloprid, thiamethoxam, and imidacloprid affect aromatase expression and activity in a co-culture model of fetoplacental steroidogenesis, increasing estrone and estradiol production, while estriol production is decreased [36]. Thiacloprid, imidacloprid, and thiamethoxam have also been demonstrated to increase aromatase expression and activity in H295R and Hs578t cells [37,38].…”