Treatment of BG-1 Ovarian Cancer Cells Expressing Estrogen Receptors with Lambda-cyhalothrin and Cypermethrin Caused a Partial Estrogenicity Via an Estrogen Receptor-dependent Pathway Kim, Cho-Won; Go, Ryeo-Eun; Choi, Kyung-Chul;
Synthetic pyrethroids (SPs) are the most common pesticides which are recently used for indoor pest control. The widespread use of SPs has resulted in the increased exposure to wild animals and humans. Recently, some SPs are suspected as endocrine disrupting chemicals (EDCs) and have been assessed for their potential estrogenicity by adopting various analyzing assays. In this study, we examined the estrogenic effects of lambda-cyhalothrin (LC) and cypermethrin (CP), the most commonly used pesticides in Korea, using BG-1 ovarian cancer cells expressing estrogen receptors (ERs). To evaluate the estrogenic activities of two SPs, LC and CP, we employed MTT assay and reverse-transcription polymerase chain reaction (RT-PCR) in LC or CP treated BG-1 ovarian cancer cells. In MTT assay, LC () and CP () significantly induced the growth of BG-1 cancer cells. LC or CP-induced cell growth was antagonized by addition of ICI 182,720 (), an ER antagonist, suggesting that this effect appears to be mediated by an ER-dependent manner. Moreover, RT-PCR results showed that transcriptional level of cyclin D1, a cell cycle-regulating gene, was significantly up-regulated by LC and CP, while these effects were reversed by co-treatment of ICI 182,780. However, p21, a cyclin D-ckd-4 inhibitor gene, was not altered by LC or CP. Moreover, expression was not significantly changed by LC and CP, while down-regulated by E2. Finally, in xenografted mouse model transplanted with human BG-1 ovarian cancer cells, E2 significantly increased the tumor volume compare to a negative control, but LC did not. Taken together, these results suggest that LC and CP may possess estrogenic potentials by stimulating the growth of BG-1 ovarian cancer cells via partially ER signaling pathway associated with cell cycle as did E2, but this estrogenic effect was not found in in vivo mouse model.
Choi, K.C. and Jeung, E.B. (2003) The biomarker and endocrine disruptors in mammals. J. Reprod. Dev., 49, 337-345.
Diamanti-Kandarakis, E., Bourguignon, J.P., Giudice, L.C., Hauser, R., Prins, G.S., Soto, A.M., Zoeller, R.T. and Gore, A.C. (2009) Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr. Rev., 30, 293-342.
Hwang, K.A., Park, S.H., Yi, B.R. and Choi, K.C. (2011) Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab. Anim. Res., 27, 99-107.
Korach, K.S., Chae, K., Gibson, M. and Curtis, S. (1991) Estrogen receptor stereochemistry: ligand binding and hormonal responsiveness. Steroids, 56, 263-270.
Sun, H., Xu, X.L., Xu, L.C., Song, L., Hong, X., Chen, J.F., Cui, L.B. and Wang, X.R. (2007) Antiandrogenic activity of pyrethroid pesticides and their metabolite in reporter gene assay. Chemosphere, 66, 474-479.
Garey, J. and Wolff, M.S. (1998) Estrogenic and antiprogestagenic activities of pyrethroid insecticides. Biochem. Biophys. Res. Commun., 251, 855-859.
Kunimatsu, T., Yamada, T., Ose, K., Sunami, O., Kamita, Y., Okuno, Y., Seki, T. and Nakatsuka, I. (2002) Lack of (anti-) androgenic or estrogenic effects of three pyrethroids (esfenvalerate, fenvalerate, and permethrin) in the Hershberger and uterotrophic assays. Regul. Toxicol. Pharmacol., 35, 227-237.
Casida, J.E. (1980) Pyrethrum flowers and pyrethroid insecticides. Environ. Health Perspect., 34, 189-202.
Liu, H., Zhao, M., Zhang, C., Ma, Y. and Liu, W. (2008) Enantioselective cytotoxicity of the insecticide bifenthrin on a human amnion epithelial (FL) cell line. Toxicology, 253, 89-96.
Liu, H., Xu, L., Zhao, M., Liu, W., Zhang, C. and Zhou, S. (2009) Enantiomer-specific, bifenthrin-induced apoptosis mediated by MAPK signalling pathway in Hep G2 cells. Toxicology, 261, 119-125.
Zhao, M., Zhang, Y., Liu, W., Xu, C., Wang, L. and Gan, J. (2008) Estrogenic activity of lambda-cyhalothrin in the MCF-7 human breast carcinoma cell line. Environ. Toxicol. Chem., 27, 1194-1200.
Bloomquist, J.R. (1996) Ion channels as targets for insecticides. Annu. Rev. Entomol., 41, 163-190.
McCarthy, A.R., Thomson, B.M., Shaw, I.C. and Abell, A.D. (2006) Estrogenicity of pyrethroid insecticide metabolites. J. Environ. Monit., 8, 197-202.
Glickman, A.H. and Lech, J.J. (1982) Differential toxicity of trans-permethrin in rainbow trout and mice. II. Role of target organ sensitivity. Toxicol. Appl. Pharmacol., 66, 162-171.
Jin, M., Li, L., Xu, C., Wen, Y. and Zhao, M. (2010) Estrogenic activities of two synthetic pyrethroids and their metabolites. J. Environ. Sci. (China), 22, 290-296.
Colborn, T., vom Saal, F.S. and Soto, A.M. (1993) Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ. Health Perspect., 101, 378-384.
Kim, I.Y., Shin, J.H., Kim, H.S., Lee, S.J., Kang, I.H., Kim, T.S., Moon, H.J., Choi, K.S., Moon, A. and Han, S.Y. (2004) Assessing estrogenic activity of pyrethroid insecticides using in vitro combination assays. J. Reprod. Dev., 50, 245-255.
Du, G., Shen, O., Sun, H., Fei, J., Lu, C., Song, L., Xia, Y., Wang, S. and Wang, X. (2010) Assessing hormone receptor activities of pyrethroid insecticides and their metabolites in reporter gene assays. Toxicol. Sci., 116, 58-66.
Sun, H., Chen, W., Xu, X., Ding, Z., Chen, X. and Wang, X. (2014) Pyrethroid and their metabolite, 3-phenoxybenzoic acid showed similar (anti)estrogenic activity in human and rat estrogen receptor alpha-mediated reporter gene assays. Environ. Toxicol. Pharmacol., 37, 371-377.
Li, Y.F., Pan, C., Hu, J.X., Li, J. and Xu, L.C. (2013) Effects of cypermethrin on male reproductive system in adult rats. Biomed. Environ. Sci., 26, 201-208.
Liu, L., Hu, J.X., Wang, H., Chen, B.J., He, Z. and Xu, L.C. (2010) Effects of beta-cypermethrin on male rat reproductive system. Environ. Toxicol. Pharmacol., 30, 251-256.
Kang, N.H., Hwang, K.A., Kim, T.H., Hyun, S.H., Jeung, E.B. and Choi, K.C. (2012) Induced growth of BG-1 ovarian cancer cells by 17beta-estradiol or various endocrine disrupting chemicals was reversed by resveratrol via downregulation of cell cycle progression. Mol. Med. Rep., 6, 151-156.
Park, M.A., Hwang, K.A., Lee, H.R., Yi, B.R., Jeung, E.B. and Choi, K.C. (2012) Cell growth of BG-1 ovarian cancer cells is promoted by di-n-butyl phthalate and hexabromocyclododecane via upregulation of the cyclin D and cyclindependent kinase-4 genes. Mol. Med. Rep., 5, 761-766.
Park, M.A., Hwang, K.A., Lee, H.R., Yi, B.R., Jeung, E.B. and Choi, K.C. (2013) Benzophenone-1 stimulated the growth of BG-1 ovarian cancer cells by cell cycle regulation via an estrogen receptor alpha-mediated signaling pathway in cellular and xenograft mouse models. Toxicology, 305, 41-48.
Neubert, D. (1997) Vulnerability of the endocrine system to xenobiotic influence. Regul. Toxicol. Pharmacol., 26, 9-29.
Hwang, K.A., Kang, N.H., Yi, B.R., Lee, H.R., Park, M.A. and Choi, K.C. (2013) Genistein, a soy phytoestrogen, prevents the growth of BG-1 ovarian cancer cells induced by 17beta-estradiol or bisphenol A via the inhibition of cell cycle progression. Int. J. Oncol., 42, 733-740.