Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription

Abstract

Background: There is increasing concern about endocrine-disrupting chemicals (EDCs) which may produce adverse health effects in humans and other species. One such chemical, bisphenol-A (BPA), a monomer of polycarbonate plastics, is widely used in consumer products; it has been reported to contain estrogenic activity through binding to estrogen receptors. Cytochrome P450 monooxygenase 3A4 (CYP3A4) is one of the key enzymes for the metabolism of endogenous steroids and foreign chemicals in liver. The orphan nuclear receptor, steroid and xenobiotic receptor (SXR/PXR), has recently been isolated. A variety of known inducers of CYP3A4 bind to SXR/PXR, and stimulate transcription on xenobiotic-response elements (XREs) located in the promoter region of the CYP3A4 gene. Recent study has shown that EDCs, diethylhexylphthalate (DEHP) and nonylphenol, but not BPA, induce mouse SXR/PXR-mediated transcription. However, it is known that species differences in SXR alter CYP3A inducibility. Objective: To test whether BPA stimulates human SXR/PXR-mediated transcription using reporter gene assays. Methods: Transfection assays were performed with human SXR/PXR expression plasmid and a reporter plasmid containing the XREs in the CYP3A4 gene promoter in HepG2 cells. BPA-induced interaction of human SXR/PXR with steroid receptor coactivator-1 (SRC-1) was analyzed by mammalian two-hybrid assays. Results: BPA, as well as DEHP, activated human SXR-mediated transcription on the XREs. In mammalian two-hybrid assays, BPA recruited SRC-1 to the ligand-binding domain of human SXR/PXR. Conclusions: Our observations have indicated that BPA may be a human-speci®c inducer of the CYP3A4 gene, and may in¯uence the metabolism of endogenous steroids, drugs, and other xenobiotics.

Putative Role of the Orphan Nuclear Receptor SXR (Steroid and Xenobiotic Receptor) in the Mechanism of CYP3A4 Inhibition by Xenobiotics

“…1. GAL4 SXR-LBD and GAL4 SRC-1-RID were constructed by ligating the LBD of human SXR (amino acids 107-434) (10) and nuclear receptor-interacting domain (RID) containing three LXXLL motifs in human SRC-1 (amino acids 595-780) (14) into the pM expression vector (CLONTECH, Palo Alto, CA), respectively. VP16 SXR-LBD and VP16 SRC-1-RID were constructed by ligating the same amino acid * The costs of publication of this article were defrayed in part by the payment of page charges.…”

“…Cells were grown for 24 h in the absence or presence of ligands and then harvested. Cell extracts were analyzed for both luciferase and ␤-galactosidase activity to correct for transfection efficiency as described previously (10). The corrected luciferase activities of untreated samples were normalized to the luciferase activities of samples as described in the figure legends.…”

“…Recent studies revealed that the various inducers of the CYP3A4 recruit the nuclear receptor coactivators such as steroid receptor coactivator-1 (SRC-1) to the ligand-binding domain (LBD) of SXR (2,3,9,10). However, it is not known whether SXR represses basal transcription.…”

The Growth Behavior of Chlorella vulgaris in Bisphenol a under different Cultural Conditions

“…Bisphenol A (BPA), which is made by Phenol and acetone [2], is an industrially important chemical that is used as a raw material in the manufacture of many products such as engineering plastics (e.g., epoxy resins/ polycarbonate plastics), food cans (i.e., lacquer coatings), and dental composites/sealants [3]. Extensive evidence indicates that BPA induces feminization during gonadal ontogeny of fishes [4], reptiles [5], birds [6], and human [7,8], and it is identified as an endocrine disruptor and leads to carcinogenesis [9]. Biology is exposed to ubiquitous BPA Though its hazardous effects, more than 5 million metric tons of BPA was produced in 2011 and was mainly used in East Asia (Korea, China and Japan), and kept increasing year by year [10,11].…”

Endocrine Disruptors and Breast Cancer Risk - Time to Consider the Environment

“…However, the Interaction of BPA with ERα was entirely unique and different from that of weak estrogens (estrone and estriol), partial ERα agonists (raloxifene or 4-OH-tamoxifen), or a pure ERα antagonists (Gould et al, 1998). Furthermore, BPA rapidly initiates complex set of signaling which could not be explained by its binding to estrogen receptors and it exerts many of these effects at low doses even lower than the current "safe" exposure limit for humans (Krishnan et al, 1993;Takeshita et al, 2001;Quesada et al, 2002). Current research is focused on understanding the full spectrum and the mechanisms of BPA endocrine disrupting actions (Watson et al, 2007a;2007b).…”