Expression of iron metabolism genes as markers of organ toxicity

  • I. P. Kindrat Ivano-Frankivsk National Medical University, Ukraine, 76018, Ivano-Frankivsk, Galytska str., 2; National Center for Toxicological Research, U.S.A., 72079, Jefferson, NCTR str., 3900
  • H. M. Erstenyuk Ivano-Frankivsk National Medical University, Ukraine, 76018, Ivano-Frankivsk, Galytska str., 2

Abstract

Aim. An increasing number of toxicants in the environment causes harmful effects on organism, resulting in broad range of metabolic disturbances, including iron metabolism. Perturbations in iron homeostasis may lead to the development of various pathological states, including organ injury and carcinogenesis. In this study, we investigated the effect of liver toxicant, bis-(2-ethylhexyl) phtalete (DEHP), and kidney toxicant, aristolochic acid (AA), on tissue-specific iron metabolism in rats. Methods. Gene expression in the livers and kidneys of Fischer 344 rats was determined by quantitative reverse transcription-PCR. Results. DEHP treatment increased the expression of liver toxicity and DNA damage marker genes, and iron-related genes, Ftl1, Fth1, Slc40a1, and decrease the expression of miR-122 and Hamp in the livers, but not in the kidneys. In contrast, AA increased the expression of kidney toxicity and DNA damage markers, and iron homeostasis genes, Ftl1, Fth1, Slc40a1 in the kidneys. Conclusions. Our results indicate an existence of organ-specific changes in the expression of iron metabolism genes in rats treated with DEHP and AA, respectively. These changes were accompanied by increasing of DNA damage and toxicity markers in the liver of DEHP-treated rats and in the kidneys of rats treated with AA.

Keywords: toxicity, iron metabolism, liver, kidney.

References

Gianfreda L., Rao M.A. Interactions between xenobiotics and microbial and enzymatic soil activity. Crit Rev Environ Sci Technol. 2008. V. 38. P. 269–310. doi: 10.1080/10643380701413526.

Sorrentino P., D’Angelo S., Ferbo U., Micheli P., Bracigliano A., Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol. 2009. V. 50. P. 351–357. doi: 10.1016/j.jhep.2008.09.011.

Kew M.C. Hepatic iron overload and hepatocellular carcinoma. Cancer Lett. 2009. V. 286. P. 38–43. doi: 10.1159/000343856.

Nakajima T., Hopf B.N., Schulte A.P. Di(2-ethylhexyl) phthalate (DEHP). IARC Monogr Eval Carcinog Risks Hum. 2000. V. 77. P. 41–148.

Stiborová M., Sopko B., Hodek P., Frei E., Schmeiser H.H., Hudecek J. The binding of aristolochic acid I to the active site of human cytochromes P450 1A1 and 1A2 explains their potential to reductively activate this human carcinogen. Cancer Lett. 2005. V. 229 (2). P. 193–204. doi: 10.1016/j.canlet.2005.06.038.

Sidorenko V.S., Attaluri S., Zaitseva I., Iden C.R., Dickman K.G., Johnson F., Grollman A.P. Bioactivation of the human carcinogen aristolochic acid. Carcinogenesis. 2014. V. 35 (8). P. 1814–1822. doi: 10.1093/carcin/bgu095.

Schmittgen T.D., Livak K.J. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008. V. 3. P. 1101–1108. doi: 10.1038/nprot.2008.73.

Rusyn I., Corton J.C. Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl) phthalate. Mutat Res. 2012. V. 750 (2). P. 141–158. doi: 10.1016/j.mrrev.2011.12.004.

Merrick B.A., Witzmann F.A. The role of toxicoproteomics in assessing organ specific toxicity. EXS. 2009. V. 99. P. 367–400. doi: 10.1007/978-3-7643-8336-7_13.

Thakral S., Ghoshal K. miR-122 is a unique molecule with great potential in diagnosis, prognosis of liver disease, and therapy both as miRNA mimic and antimir. Curr Gene Ther. 2015. V. 15 (2). P. 142–150. doi: 10.2174/1566523214666141224095610.

Oyadomari S., Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004. V. 11 (4). P. 381–389. doi: 10.1038/sj.cdd.4401373.

Lu Y., Cederbaum A.I. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med. 2008. V. 44 (5). P. 723–738. doi: 10.1016/j.freeradbiomed.2007.11.004.

Parmar D., Srivastava S.P., Seth P.K. Effect of di(2-ethylhexyl)phthalate (DEHP) on hepatic mixed function oxidases in different animal species. Toxicol Lett. 1988. V. 40 (3). P. 209–217. doi: 10.1016/0378-4274(88)90043-4.

Lane B.R. Molecular markers of kidney injury. Urol Oncol. 2013. V. 31 (5). P. 682–685. doi: 10.1016/j.urolonc.2011.05.007.

Fuchs T.C., Mally A., Wool A., Beiman M., Hewitt P. An exploratory evaluation of the utility of transcriptional and urinary kidney injury biomarkers for the prediction of aristolochic acid-induced renal injury in male rats. Vet Pathol. 2014. V. 51 (3). P. 680–694. doi: 10.1177/0300985813498779.

Waldvogel-Abramowski S., Waeber G., Gassner C., Buser A., Frey B.M., Favrat B., Tissot J.D. Physiology of iron metabolism. Transfus Med Hemother. 2014. V. 41 (3). P. 213–221. doi: 10.1159/000362888.

Bogdan A.R., Miyazawa M., Hashimoto K., Tsuji Y. Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease. Trends Biochem Sci. 2016. V. 41 (3). P. 274–286. doi: 10.1016/j.tibs.2015.11.012.

Ahmad S., Moriconi F., Naz N., Sultan S., Sheikh N., Ramadori G., Malik I.A. Ferritin L and ferritin H are differentially located within hepatic and extra hepatic organs under physiological and acute phase conditions. Int J Clin Exp Pathol. 2013. V. 6 (4). P. 622–629. Retrieved from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606851.

Kim D.S., Choi Y.P., Kang S., Gao M.Q., Kim B., Park H.R., Choi Y.D., Lim J.B., Na H.J., Kim H.K., Nam Y.P., Moon M.H., Yun H.R., Lee D.H., Park W.M., Cho N.H. Panel of candidate biomarkers for renal cell carcinoma. J Proteome Res. 2010. V. 9 (7). P. 3710–3719. doi: 10.1021/pr100236r.

De Domenico I., Ward D.M., Kaplan J. Hepcidin and ferroportin: the new players in iron metabolism. Semin Liver Dis. 2011. V. 31 (3). P. 272–279. doi: 10.1055/s-0031-1286058.

Veuthey T., D'Anna M.C., Roque M.E. Role of the kidney in iron homeostasis: renal expression of Prohepcidin, Ferroportin, and DMT1 in anemic mice. Am J Physiol Renal Physiol. 2008. V. 295 (4). P. F1213–1221. doi: 10.1152/ajprenal.90216.2008.

Anderson E.R., Shah Y.M. Iron homeostasis in the liver. Compr Physiol. 2013. V. 3 (1). P. 315–330. doi: 10.1002/cphy.c120016.

Ganz T., Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012. V. 1823 (9). P. 1434–1443. doi: 10.1016/j.bbamcr.2012.01.014.

Kulaksiz H., Theilig F., Bachmann S., Gehrke S.G., Rost D., Janetzko A., Cetin Y., Stremmel W. The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J Endocrinol. 2005. V. 184 (2). P. 361–370. doi: 10.1677/joe.1.05729.

Prá D., Franke S.I., Henriques J.A., Fenech M. Iron and genome stability: an update. Mutat Res. 2012. V. 733 (1–2). P. 92–99. doi: 10.1016/j.mrfmmm.2012.02.001.

Walter P.B., Knutson M.D., Paler-Martinez A., Lee S., Xu Y., Viteri F.E., Ames B.N. Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats. Proc Natl Acad Sci USA. 2002. V. 99 (4). P. 2264–2269. doi: 10.1073/pnas.261708798.

Powell C.L., Swenberg J.A., Rusyn I. Expression of base excision DNA repair genes as a biomarker of oxidative DNA damage. Cancer Lett. 2005. V. 229 (1). P. 1–11. doi: 10.1016/j.canlet.2004.12.002.

Saito Y., Nakaoka T., Saito H. microRNA-34a as a Therapeutic Agent against Human Cancer. J Clin Med. 2015. V. 4 (11). P. 1951–1559. doi: 10.3390/jcm4111951.

Dutta K.K., Zhong Y., Liu Y.T., Yamada T., Akatsuka S., Hu Q., Yoshihara M., Ohara H., Takehashi M., Shinohara T., Masutani H., Onuki J., Toyokuni S. Association of microRNA-34a overexpression with proliferation is cell type-dependent. Cancer Sci. 2007. V. 98 (12). P. 1845–1852. doi: 10.1111/j.1349-7006.2007.00619.x.