title: Bisphenol A, an environmental endocrine-disrupting chemical, inhibits hypoxic response via degradation of hypoxia-inducible factor 1alpha (HIF-1alpha): structural requirement of bisphenol A for degradation of HIF-1alpha.
abstract: Bisphenol A (BpA), an endocrine-disrupting chemical, is known to be a xenoestrogen and to affect the reproductive functions of animals. Recent reports have documented BpA-induced developmental abnormalities in the neuronal systems of humans and animals, and these effects appear to be non-estrogenic. In this study, we found that BpA inhibited the hypoxic response of human hepatoma cells. The expression of hypoxic response genes such as the erythropoietin (EPO) gene is done via a hypoxia inducible factor 1 (HIF-1)-dependent signaling pathway. To investigate possible structural requirements for this inhibitory effect, several BpA analogs were synthesized and added to this system. The blocking of two phenol groups in BpA did not change the effect, but the inhibition completely disappeared by the removal of two central methyl groups in BpA (the resulting compound is designated BpF). BpA, but not BpF, promoted degradation of the HIF-1alpha protein, which is a component of HIF-1, followed by inhibition of EPO induction. An immunoprecipitation assay indicated that BpA dissociated heat shock protein 90 (Hsp90) from HIF-1alpha and destabilized HIF-1alpha protein. HIF-1alpha is usually degraded first by ubiquitination and then by the proteasome pathway. Cobalt ion inhibits ubiquitination of HIF-1alpha and stabilizes it. In the present study, BpA promoted HIF-1alpha degradation in the presence of cobalt and in the presence of proteasome inhibitor. These results suggest that BpA degraded HIF-1alpha via a currently unknown pathway, and that this phenomenon required two methyl groups in BpA.
authors.affiliation: Department of Bioscience and Nanobiotechnology Research Center, School of Science and Technology, Kwansei Gakuin University, Gakuen, Sanda 669-1337, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kubo
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Maezawa
authors.forename: Mayuko
authors.initials: M
authors.lastname: Osada
authors.forename: Shigeo
authors.initials: S
authors.lastname: Katsumura
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Funae
authors.forename: Susumu
authors.initials: S
authors.lastname: Imaoka
mesh_terms: D000395:Air Pollutants, Occupational / Q000737:chemistry / Q000494:pharmacology; D001559:Benzhydryl Compounds; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D003035:Cobalt / Q000737:chemistry / Q000494:pharmacology; D004921:Erythropoietin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004968:Estrogens, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D011233:Precipitin Tests; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism*; D000098826:Bisphenol A Compounds
chemical_list: D000395:Air Pollutants, Occupational; D001559:Benzhydryl Compounds; D003035:Cobalt; D004921:Erythropoietin; D004968:Estrogens, Non-Steroidal; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010636:Phenols; D014157:Transcription Factors; C497442:HIF1A protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds