Molecular Biology Reports

, Volume 45, Issue 6, pp 1937–1945 | Cite as

Expression of the miR-190 family is increased under DDT exposure in vivo and in vitro

  • Tatiana S. KalininaEmail author
  • Vladislav V. Kononchuk
  • Vladimir Y. Ovchinnikov
  • Mikhail D. Chanyshev
  • Lyudmila F. Gulyaeva
Original Article


A non-genotoxic insecticide dichlorodiphenyltrichloroethane (DDT), can affect mRNA and microRNA levels, however, its precise mechanism of action remains poorly understood. Using in silico methods we found that the rat miR-190 family is potentially regulated by CAR and ER receptors activated by DDT. We showed that exposure to DDT results in a dose- and organ-dependent increase in the expression of miR-190a, -190b in the liver, uterus, ovaries and mammary gland of female Wistar rats. Additionally, we demonstrate a decrease in protein product level of Tp53inp1, the target gene of these microRNAs, in the rat uterus. It is known that miR-190 is probably regulated by ER in humans, thus we measured the level of miR-190a, -190b in primary cultures of malignant and normal human endometrial cells treated with different doses of DDT. We detected an increase in miR-190b level in normal endometrial cells under DDT exposure. Thus, our results indicate that DDT exposure lead to change in the expression of oncogenic miR-190 family and its target gene Tp53inp1 which may be due to activation of CAR and ER.


MicroRNA Dichlorodiphenyltrichloroethane Xenobiotics Constitutive androstane receptor Estrogen receptor 





Chlororganic pesticide


Endocrine disrupting chemical




Estrogen receptor


Constitutive androstane receptor


Phenobarbital-responsive enhancer module


Estrogen response element





This work is supported by the Russian Science Foundation, Project # 15-15-30012.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All experimental procedures were approved by the Bioethics Committee of the Institute of Molecular Biology and Biophysics and carried out in accordance with Directive 2010/63/EU.

Supplementary material

11033_2018_4343_MOESM1_ESM.pdf (217 kb)
Supplementary material 1 (PDF 216 KB)


  1. 1.
    Tilghman SL, Bratton MR, Segar HC et al (2012) Endocrine disruptor regulation of microRNA expression in breast carcinoma cells. PLoS ONE 7(3):e32754CrossRefGoogle Scholar
  2. 2.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854CrossRefGoogle Scholar
  3. 3.
    Farazi TA, Hoell JI, Morozov P et al (2013) MicroRNAs in human cancer. Adv Exp Med Biol 774:1–20CrossRefGoogle Scholar
  4. 4.
    Yanokura M, Banno K, Kobayashi Y et al (2010) MicroRNA and endometrial cancer: roles of small RNAs in human tumors and clinical applications (review). Oncol Lett 1(6):935–940CrossRefGoogle Scholar
  5. 5.
    Su Z, Yang Z, Xu Y et al (2015) MicroRNAs in apoptosis, autophagy and necroptosis. Oncotarget 6(11):8474–8490CrossRefGoogle Scholar
  6. 6.
    Zhang J, Ma L (2012) MicroRNA control of epithelial–mesenchymal transition and metastasis. Cancer Metastasis Rev 31(3–4):653–662CrossRefGoogle Scholar
  7. 7.
    Valastyan S, Weinberg RA (2011) Roles for microRNAs in the regulation of cell adhesion molecules. J Cell Sci 124(Pt 7):999–1006CrossRefGoogle Scholar
  8. 8.
    Chen T (2010) The role of microRNA in chemical carcinogenesis. J Environ Sci Health C 28(2):89–124CrossRefGoogle Scholar
  9. 9.
    Vrijens K, Bollati V, Nawrot TS (2015) MicroRNAs as potential signatures of environmental exposure or effect: a systematic review. Environ Health Perspect 123(5):399–411CrossRefGoogle Scholar
  10. 10.
    Pogribny IP, Beland FA, Rusyn I (2016) The role of microRNAs in the development and progression of chemical-associated cancers. Toxicol Appl Pharmacol 312:3–10CrossRefGoogle Scholar
  11. 11.
    Shen YL, Jiang YG, Greenlee AR et al (2009) MicroRNA expression profiles and miR-10a target in anti-benzo[a]pyrene-7,8-diol-9,10-epoxide-transformed human 16HBE cells. Biomed Environ Sci 22(1):14–21CrossRefGoogle Scholar
  12. 12.
    Pogribny IP, Muskhelishvili L, Tryndyak VP et al (2009) The tumor-promoting activity of 2-acetylaminofluorene is associated with disruption of the p53 signaling pathway and the balance between apoptosis and cell proliferation. Toxicol Appl Pharmacol 235(3):305–311CrossRefGoogle Scholar
  13. 13.
    Hernández LG, van Steeg H, Luijten M et al (2009) Mechanisms of non-genotoxic carcinogens and importance of a weight of evidence approach. Mutat Res 682(2–3):94–109CrossRefGoogle Scholar
  14. 14.
    Longnecker MP, Rogan WJ, Lucier G (1997) The human health effects of DDT (dichlorodiphenyltrichloroethane) and PCBs (polychlorinated biphenyls) and an overview of organochlorines in public health. Ann Rev Public Health 18:211–244CrossRefGoogle Scholar
  15. 15.
    Jayaraj R, Megha P, Sreedev P (2016) Organochlorine pesticides, their toxic effects on living organisms and their fate in the environment. Interdiscip Toxicol 9(3–4):90–100CrossRefGoogle Scholar
  16. 16.
    Ejaz S, Akram W, Lim CW et al (2004) Endocrine disrupting pesticides: a leading cause of cancer among rural people in Pakistan. Exp Oncol 26(2):98–105PubMedGoogle Scholar
  17. 17.
    Xu X, Dailey AB, Talbott EO et al (2010) Associations of serum concentrations of organochlorine pesticides with breast cancer and prostate cancer in U.S. adults. Environ Health Perspect 118(1):60–66CrossRefGoogle Scholar
  18. 18.
    Turusov VS, Day NE, Tomatis L et al (1973) Tumors in CF-1 mice exposed for six consecutive generations to DDT. J Natl Cancer Inst 51(3):983–997CrossRefGoogle Scholar
  19. 19.
    Turusov V, Rakitsky V, Tomatis L (2002) Dichlorodiphenyltrichloroethane (DDT): ubiquity, persistence, and risks. Environ Health Perspect 110(2):125–138CrossRefGoogle Scholar
  20. 20.
    Jaga K (2000) What are the implications of the interaction between DDT and estrogen receptors in the body? Med Hypotheses 54(1):18–25CrossRefGoogle Scholar
  21. 21.
    Kiyosawa N, Kwekel JC, Burgoon LD et al (2008) Species-specific regulation of PXR/CAR/ER-target genes in the mouse and rat liver elicited by o, p’-DDT. BMC Genom 9:487CrossRefGoogle Scholar
  22. 22.
    Robison AK, Schmidt WA, Stancel GM (1985) Estrogenic activity of DDT: estrogen-receptor profiles and the responses of individual uterine cell types following o,p’-DDT administration. J Toxicol Environ Health 16(3–4):493–508CrossRefGoogle Scholar
  23. 23.
    Konno Y, Negishi M, Kodama S (2008) The roles of nuclear receptors CAR and PXR in hepatic energy metabolism. Drug Metab Pharmacokinet 23(1):8–13CrossRefGoogle Scholar
  24. 24.
    Klinčić D, Herceg RS, Matek SM, Grzunov J, Dukić B (2014) Polychlorinated biphenyls and organochlorine pesticides in human milk samples from two regions in Croatia. Environ Toxicol Pharmacol 37(2):543–552CrossRefGoogle Scholar
  25. 25.
    Cohn BA, Wolff MS, Cirillo PM, Sholtz RI (2007) DDT and breast cancer in young women: new data on the significance of age at exposure. Environ Health Perspect 115(10):1406–1414PubMedPubMedCentralGoogle Scholar
  26. 26.
    Kalinina TS, Kononchuk VV, Gulyaeva LF (2017) Expression of hormonal carcinogenesis genes and related regulatory microRNAs in uterus and ovaries of DDT-treated female rats. Biochemistry 82(10):1118–1128PubMedGoogle Scholar
  27. 27.
    Chu HW, Cheng CW, Chou WC et al (2014) A novel estrogen receptor-microRNA 190a-PAR-1-pathway regulates breast cancer progression, a finding initially suggested by genome-wide analysis of loci associated with lymph-node metastasis. Hum Mol Genet 23(2):355–367CrossRefGoogle Scholar
  28. 28.
    Koval OA, Sakaeva GR, Fomin AS et al (2015) Sensitivity of endometrial cancer cells from primary human tumor samples to new potential anticancer peptide lactaptin. J Cancer Res Ther 11(2):345–351CrossRefGoogle Scholar
  29. 29.
    Uphoff CC, Drexler HG (2002) Comparative PCR analysis for detection of mycoplasma infections in continuous cell lines. In Vitro Cell Dev Biol Anim 38(2):79–85CrossRefGoogle Scholar
  30. 30.
    Chen C, Ridzon DA, Broomer AJ et al (2005) Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33(20):e179CrossRefGoogle Scholar
  31. 31.
    Cramer EM, Shao Y, Wang Y et al (2014) miR-190 is upregulated in Epstein-Barr Virus type I latency and modulates cellular mRNAs involved in cell survival and viral reactivation. Virology 464–465:184–195CrossRefGoogle Scholar
  32. 32.
    Słomczyńska M (2008) Xenoestrogens: mechanisms of action and some detection studies. Pol J Vet Sci 11(3):263–269PubMedGoogle Scholar
  33. 33.
    Wallace BD, Redinbo MR (2013) Xenobiotic-sensing nuclear receptors involved in drug metabolism: a structural perspective. Drug Metab Rev 45(1):79–100CrossRefGoogle Scholar
  34. 34.
    Almog N, Briggs C, Beheshti A et al (2013) Transcriptional changes induced by the tumor dormancy-associated miR-190. Transcription 4(4):177–191CrossRefGoogle Scholar
  35. 35.
    Beezhold K, Liu J, Kan H et al (2011) miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis. Toxicol Sci 123(2):411–420CrossRefGoogle Scholar
  36. 36.
    Thomson DW, Bracken CP, Goodall GJ (2011) Experimental strategies for microRNA target identification. Nucl Acids Res 39(16):6845–6853CrossRefGoogle Scholar
  37. 37.
    Belletti B, Baldassarre G (2012) New light on p27kip1 in breast cancer. Cell Cycle 11(19):3701–3702CrossRefGoogle Scholar
  38. 38.
    Jiang PH, Motoo Y, Garcia S et al (2006) Down-expression of tumor protein p53-induced nuclear protein 1 in human gastric cancer. World J Gastroenterol 12(5):691–696CrossRefGoogle Scholar
  39. 39.
    Jiang F, Liu T, He Y et al (2011) MiR-125b promotes proliferation and migration of type II endometrial carcinoma cells through targeting TP53INP1 tumor suppressor in vitro and in vivo. BMC Cancer 11:425CrossRefGoogle Scholar
  40. 40.
    McCampbell AS, Mittelstadt ML, Dere R et al (2016) Loss of p27 associated with risk for endometrial carcinoma arising in the setting of obesity. Curr Mol Med 16(3):252–265CrossRefGoogle Scholar
  41. 41.
    Cizeron-Clairac G, Lallemand F, Vacher S et al (2015) MiR-190b, the highest up-regulated miR in ERα-positive compared to ERα-negative breast tumors, a new biomarker in breast cancers? BMC Cancer 15:499CrossRefGoogle Scholar
  42. 42.
    Ziel HK (1982) Estrogen’s role in endometrial cancer. Obstet Gynecol 60(4):509–515PubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Institute of Molecular Biology and BiophysicsNovosibirskRussia
  2. 2.Novosibirsk State UniversityNovosibirskRussia
  3. 3.Institute of Cytology and GeneticsNovosibirskRussia

Personalised recommendations