Cell growth of BG-1 ovarian cancer cells is promoted by di-n-butyl phthalate and hexabromocyclododecane via upregulation of the cyclin D and cyclin-dependent kinase-4 genes

Abstract

Abstract. Endocrine-disrupting chemicals (EDCs) are environmentally persistent exogenous compounds released from various industrial products such as plastics, pesticides, drugs, detergents and cosmetics. They can cause a variety of adverse effects to the reproductive, developmental, immune and nervous systems in humans and wildlife. Di-n-butyl phthalate (DBP) is the main compound of phthalates and is reported to inhibit estrogen receptor (ER)-mediated gene expression and to interfere with normal fetal development of the male reproductive system. Hexabromocyclododecane (HBCD or HBCDD) is one of the brominated flame retardants (BFRs) which have been widely used in plastic, electronic and textile applications and are known to cause endocrine disruption with toxicity of the nervous system. In the present study, the estrogenic effects of DBP and HBCD were examined in an ovarian cancer cell line, BG-1, expressing high levels of ER via MTT assay and semi-quantitative reverse-transcription PCR. Treatment with DBP (10 -8 -10 -5 M) or HBCD (2x10 -8 -2x10 -6 M) resulted in increased cell proliferation of BG-1 cells as observed with 17-β estradiol (E2). In addition, both DBP and HBCD upregulated the expression levels of cell cycle-regulatory genes, such as cyclin D and cyclin-dependent kinase-4 (cdk-4), which are downstream target genes of ER, at 6 h after treatment. However, the expression of the p21 gene was not altered by DBP or HBCD at any time as with E2. Taken together, these results suggest that DBP and HBCD are EDCs which have apparent estrogenic activities by stimulating the cell proliferation of BG-1 cells and by inducing the expression of cyclin D and cdk-4. Our results suggest that DBP and HBCD have sufficient potency to disrupt the endocrine system and to stimulate cell growth in ER-positive cancer cells.

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

“…In addition to immune evasion mechanisms ( 36 , 142 , 145 ), they interfere with wide spectrum of cancer-related mechanisms ( 36 , 173 , 429 , 462–464 ). DEHP ( 472 ) is also an endocrine disruptor ( 466 , 467 ) that can impact multiple hallmarks such as immune evasion, resistance to cell death, evasion of antiproliferative signaling, sustained proliferative signaling and tumor-promoting inflammation ( 36 , 288 , 468 , 469 ).…”

Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A

“…Zhao et al (2006) demonstrated increased gene expression for Cyclin B in cancerous cervical tissue from human subjects. Gene expression for Cyclin D and Cdk-4 has been shown to be up-regulated in BG-1 ovarian cancer cells following exposure to di-n-butyl phthalate and hexabromocyclododecane (another BFR) through putative estrogenic activity (Park et al 2012). In the present study, expression of Igf1 , the gene encoding growth factor IGF-1, increased in both sections of the uterus.…”

Douching, Talc Use, and Risk of Ovarian Cancer

“…In an animal study, exposure to di-(2-ethylhexyl) phthalate at 500 and 2,000 mg/kg demonstrated ovarian toxicity through decreased progesterone and increased apoptosis in granulosa cells (23). Further, ovarian cancer cell lines have been found to increase cell proliferation and to up-regulate cell-cycle regulatory genes following treatment with di-n-butyl phthalate (24). We did not collect detailed information about specific products used in douching, so we are unable to estimate exposure to individual phthalates.…”