Endocrine disrupting potential of neonicotinoids: impacts on aromatase (CYP19) expression and activity in cellular models of breast cancer and fetal development
Neonitocinoids are widely used pesticides that exert their effects by binding to nicotinic acetylcholine receptors. They are used as a seed coating in a variety of crops, fruits and vegetables. Due to their relative persistence in the environment, and because neonicotinoids are used as seed treatments and repeatedly applied, concerns regarding human exposure have been raised. The impacts of neonicotinoid insecticides on human health have not been studied in great detail, but an increasing body of evidence suggests they have the potential to disrupt endocrine functions.
During my PhD, I investigated the effects of environmentally-relevant concentrations of widely used neonicotinoids on the promoter specific expression and activity of aromatase in cellular models mimicking the development of breast cancer and the interactions between a fetus and the placenta. Aromatase is a key enzyme in estrogen biosynthesis, as it is responsible of the final conversion of androstenedione to estrone, and testosterone to estradiol. The CYP19 gene is expressed in a tissue-specific manner by the activation of various promoters located in the noncoding region of the gene.
We found that exposure to neonicotinoids in breast cancer cellular models led to an increased CYP19 expression and, ultimately, to an increase in aromatase activity. In the H295R cellular model, we found that neonicotinoids increase CYP19 expression by activating two promoters (PII and I.3). In the Hs578T cellular model, we found that neonitocinoid exposure resulted in a switch in CYP19 promoter usage, involving the inhibition of I.4 promoter activity and an increase of PII. I.3 and I.7 promoter-mediated CYP19 expression and aromatase catalytic activity. PII and I.3 promoters are normally inactive in the breast. Breast cancer is characterized by an over-expression of CYP19 through an inhibition of the normal I.4 promoter and an increase in the activity of PII, I.3 and I.7 promoters. These studies allowed us to demonstrate in vitro that neonitocinoids may stimulate a change in CYP19 promoter usage similar to that observed in patients with hormone-dependent breast cancer.
We also found that exposure to neonicotinoids in a feto-placental co-culture model led to an increase in aromatase activity, and subsequently an increase in estrone and estradiol production. Interestingly, we also found that neonicotinoids inhibited the production of estriol (an estrogen uniquely produced during pregnancy and critical for placental development) by 70-80% because of the metabolism of neonicotinoids by CYP3A7 enzyme, which blocked the normal estriol production.
Caron-Beaudoin, É., Denison, M. S., & Sanderson, J. T. (2016). Effects of neonicotinoids on promoter-specific expression and activity of aromatase (CYP19) in human adrenocortical carcinoma (H295R) and primary umbilical vein endothelial (HUVEC) cells. Toxicological Sciences, 149(1), 134-144.
Caron-Beaudoin, E., Viau, R., Hudon-Thibeault, A. A., Vaillancourt, C., & Sanderson, J. T. (2017). The use of a unique co-culture model of fetoplacental steroidogenesis as a screening tool for endocrine disruptors: The effects of neonicotinoids on aromatase activity and hormone production. Toxicology and applied pharmacology, 332, 15-24.
Caron-Beaudoin, É., Viau, R., & Sanderson, J. T. (2018). Effects of neonicotinoid pesticides on promoter-specific aromatase (CYP19) expression in Hs578t breast cancer cells and the role of the VEGF pathway. Environmental health perspectives, 126(4), 047014.
Fonds de recherche du Québec - Nature et technologies (FRQNT)