Genome-wide evidences of bisphenol a toxicity using Schizosaccharomyces pombe
To clarify reliable toxic mechanisms of bisphenol A (BPA), an endocrine disrupting chemical, we approached an alternative animal and whole genome analyses with the yeast knockout library (YKO) of Schizosaccharomyces pombe. As results, the 50% growth inhibition concentrations (GI50) of BPA was approximately 600 μM and the YKO—three step screening revealed the top 10 target candidate genes including dbp2, utp18, srs1, tif224, use1, qcr1, etc. The screening results were confirmed in human embryonic stem cell (hES)-derived hepatic cells and HepG2 human liver cancer cells. We found BPA down-regulated UQCRC, the human orthlog of S. pombe- qcr1, as a part of the mitochondrial respiratory chain, in HepG2 cells and hESs during cell differentiation into hepatic cells. Therefore, BPA may induce mitochondrial dysfunction and disruption of differentiation by suppressing UQCRC1.
KeywordsBisphenol A Differentiation UQCRC1 Genome Mitochondria Yeast
This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea Government (MSIP) (No. 2011-0030074).
Compliance with ethical standards
Conflict of interest
No potential conflict of interest was reported by the authors.
- Agarwal S, Yadav A, Tiwari SK, Seth B, Chauhan LK, Khare P, Ray RS, Chaturvedi RK (2016) Dynamin-related protein 1 inhibition mitigates bisphenol a-mediated alterations in mitochondrial dynamics and neural stem cell proliferation and differentiation. J Biol Chem 291:15923–15939CrossRefPubMedPubMedCentralGoogle Scholar
- Baek ST, Kim DU, Han S, Woo IS, Nam M, Kim L, Heo KS, Lee H, Hwang HR, Choi SJ, Won M, Lee M, Park SK, Lee S, Kwon HJ, Maeng PJ, Park HM, Park Y, Kim D, Hoe KL (2008) Genome-wide drug-induced haploinsufficient screening of fission yeast for identification of hydrazinocurcumin targets. J Microbiol Biotechnol 18:263–269PubMedGoogle Scholar
- Godoy P, Hengstler JG, Ilkavets I, Meyer C, Bachmann A, Müller A, Tuschl G, Mueller SO, Dooley S (2009) Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor β–induced apoptosis. Hepatology 49:2031–2043CrossRefPubMedGoogle Scholar
- Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, Bode JG, Bolleyn J, Borner C, Böttger J (2013) Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol 87:1315–1530CrossRefPubMedPubMedCentralGoogle Scholar
- Grand View Research (2014) Global bisphenol A (BPA) market demand is expected to grow At CAGR of 4.7% from 2014 To 2020: New Report By Grand View Research, Inc., https://globenewswire.com, 2017Google Scholar
- Hoffman GG, Lee S, Christiano AM, Chung-Honet LC, Cheng W, Katchman S, Uitto J, Greenspan DS (1993) Complete coding sequence, intron/exon organization, and chromosomal location of the gene for the core I protein of human ubiquinol-cytochrome c reductase. J Biol Chem 268:21113–21119PubMedGoogle Scholar
- Lee AY, St Onge RP, Proctor MJ, Wallace IM, Nile AH, Spagnuolo PA, Jitkova Y, Gronda M, Wu Y, Kim MK, Cheung-Ong K, Torres NP, Spear ED, Han MK, Schlecht U, Suresh S, Duby G, Heisler LE, Surendra A, Fung E, Urbanus ML, Gebbia M, Lissina E, Miranda M, Chiang JH, Aparicio AM, Zeghouf M, Davis RW, Cherfils J, Boutry M, Kaiser CA, Cummins CL, Trimble WS, Brown GW, Schimmer AD, Bankaitis VA, Nislow C, Bader GD, Giaever G (2014b) Mapping the cellular response to small molecules using chemogenomic fitness signatures. Science 344:208–211CrossRefPubMedPubMedCentralGoogle Scholar
- NIEHS (2016) Bisphenol A. https://www.niehs.nih.gov/health/topics/agents/sya-bpa/. Accessed Jan 28, 2018
- Rajesh RV, Heo G, Park M, Nam J, Kim N, Yoon D, Kim T, Lee H (2010) Proteomic analysis of bovine omental, subcutaneous and intramuscular preadipocytes during in vitro adipogenic differentiation. Comp Biochem Physiol Part D Genom Proteom 5:234–244Google Scholar
- Şenyıldız M, Karaman EF, Baş SS, Pirinççi PA, Özden S (2016) Alteration on global and gene-spesific DNA methylation and global histone modifications in HepG2 cells in response to BPA. J Fac Pharm Istanbul/İstanbul Ecz Fak Derg 46:97–114Google Scholar