Skip to main content
SpringerLink
Log in

Differential Modulatory Effects of Methylmercury (MeHg) on Ahr-regulated Genes in Extrahepatic Tissues of C57BL/6 Mice

  • Research
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Methylmercury (MeHg) and 2,3,7,8-tetrachlorodibenzodioxin (TCDD) are potent environmental pollutants implicated in the modulation of xenobiotic-metabolizing enzymes, particularly the cytochrome P450 1 family (CYP1) which is regulated by the aryl hydrocarbon receptor (AHR). However, the co-exposure to MeHg and TCDD raises concerns about their potential combined effects, necessitating thorough investigation. The primary objective of this study was to investigate the individual and combined effects of MeHg and TCDD on AHR-regulated CYP1 enzymes in mouse extrahepatic tissues. Therefore, C57BL/6 mice were administrated with MeHg (2.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) for 6 and 24 h. The AHR-regulated CYP1 mRNA and protein expression levels were measured in the heart, lung, and kidney, using RT real-time PCR and western blot, respectively. Interestingly, treatment with MeHg exhibited mainly inhibitory effect, particularly, it decreased the basal level of Cyp1a1 and Cyp1a2 mRNA and protein, and that was more evident at the 24 h time point in kidney followed by heart. Similarly, when mice were co-exposed, MeHg was able to reduce the TCDD-induced Cyp1a1 and Cyp1a2 expression, however, MeHg potentiated kidney Cyp1b1 mRNA expression, opposing the observed change on its protein level. Also, MeHg induced antioxidant NAD(P)H:quinone oxidoreductase (NQO1) mRNA and protein in kidney, while heme-oxygenase (HO-1) mRNA was up-regulated in heart and kidney. In conclusion, this study reveals intricate interplay between MeHg and TCDD on AHR-regulated CYP1 enzymes, with interesting inhibitory effects observed that might be significant for procarcinogen metabolism. Varied responses across tissues highlight the potential implications for environmental health.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

The data supporting the findings of this study will be made available upon reasonable request from the corresponding author.

Abbreviations

AHR:

Aryl hydrocarbon receptor

Hg:

Mercury

MeHg:

Methylmercury

Nrf2:

Nuclear factor-erythroid factor 2-related factor 2

NQO1:

NADP(H):quinone oxidoreductase

TCDD:

2,3,7,8-Tetrachlorodibenzo-p-dioxin

XRE:

Xenobiotic-response element

References

  1. Ullrich SM, Tanton TW, Abdrashitova SA (2001) Mercury in the aquatic environment: a review of factors affecting methylation. Crit Rev Environ Sci Technol 31(3):241–293

    Article  CAS  Google Scholar 

  2. Razavi NR, Qu M, Jin B, Ren W, Wang Y, Campbell LM (2014) Mercury biomagnification in subtropical reservoir fishes of eastern China. Ecotoxicology 23:133–146

    Article  CAS  PubMed  Google Scholar 

  3. Ackerman JT, Eagles-Smith CA, Herzog MP (2011) Bird mercury concentrations change rapidly as chicks age: toxicological risk is highest at hatching and fledging. Environ Sci Technol 45(12):5418–5425

    Article  CAS  PubMed  Google Scholar 

  4. Stern AH, Smith AE (2003) An assessment of the cord blood: maternal blood methylmercury ratio: implications for risk assessment. Environ Health Perspect 111(12):1465–1470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Harada M (1995) Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol 25(1):1–24

    Article  CAS  PubMed  Google Scholar 

  6. Fiedler H, Hutzinger O, Timms CW (1990) Dioxins: sources of environmental load and human exposure. Toxicol Environ Chem 29(3):157–234

    Article  CAS  Google Scholar 

  7. Boverhof DR et al (2006) Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice. Toxicol Sci 94(2):398–416

    Article  CAS  PubMed  Google Scholar 

  8. Boverhof DR et al (2005) Temporal and dose-dependent hepatic gene expression patterns in mice provide new insights into TCDD-mediated hepatotoxicity. Toxicol Sci 85(2):1048–1063

    Article  CAS  PubMed  Google Scholar 

  9. Amara IEA, Anwar-Mohamed A, El-Kadi AOS (2013) Posttranslational mechanisms modulating the expression of the cytochrome P450 1A1 gene by methylmercury in HepG2 cells: a role of heme oxygenase-1. Toxicol Lett 219(3):239–247

    Article  CAS  PubMed  Google Scholar 

  10. Alqahtani MA, El-Ghiaty MA, El-Mahrouk SR, El-Kadi AOS (2023) Methylmercury (MeHg) transcriptionally regulates NAD(P)H:quinone oxidoreductase 1 (NQO1) in Hepa-1c1c7 cells. Current research in toxicology 5:100126. https://doi.org/10.1016/j.crtox.2023.100126

  11. Alqahtani MA, El-Ghiaty MA, El-Kadi AOS (2023) Mercury and methylmercury differentially modulate hepatic cytochrome P450 1A1 and 1A2 in vivo and in vitro. J Biochem Mol Toxicol 37(2):e23243

    Article  CAS  PubMed  Google Scholar 

  12. Nebert DW, Karp CL (2008) Endogenous functions of the aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)-metabolized eicosanoids and AHR biology. J Biol Chem 283(52):36061–36065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Walker NJ et al (1999) Characterization of the dose–response of CYP1B1, CYP1A1, and CYP1A2 in the liver of female Sprague-Dawley rats following chronic exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 154(3):279–286

    Article  CAS  PubMed  Google Scholar 

  14. Go R-E, Hwang K-A, Choi K-C (2015) Cytochrome P450 1 family and cancers. J Steroid Biochem Mol Biol 147:24–30

    Article  CAS  PubMed  Google Scholar 

  15. Nebert DW, Dalton TP (2006) The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 6(12):947–960

    Article  CAS  PubMed  Google Scholar 

  16. Rifkind AB (2006) CYP1A in TCDD toxicity and in physiology–with particular reference to CYP dependent arachidonic acid metabolism and other endogenous substrates. Drug Metab Rev 38(1–2):291–335

    Article  CAS  PubMed  Google Scholar 

  17. Wang H, Chen B, He M, Yu X, Hu B (2017) Selenocystine against methyl mercury cytotoxicity in HepG2 cells. Sci Rep 7(1):147

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang W, Clarkson TW, Ballatori N (2000) γ-Glutamyl transpeptidase and L-cysteine regulate methylmercury uptake by HepG2 cells, a human hepatoma cell line. Toxicol Appl Pharmacol 168(1):72–78

    Article  CAS  PubMed  Google Scholar 

  19. Robinson JF, Griffith WC, Yu X, Hong S, Kim E, Faustman EM (2010) Methylmercury induced toxicogenomic response in C57 and SWV mouse embryos undergoing neural tube closure. Reprod Toxicol 30(2):284–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. El-Ghiaty MA, Alqahtani MA, El-Kadi AOS (2022) Down-regulation of hepatic cytochromes P450 1A1 and 1A2 by arsenic trioxide (ATO) in vivo and in vitro: a role of heme oxygenase 1. Chem Biol Interact 364:110049

    Article  CAS  PubMed  Google Scholar 

  21. El-Ghiaty MA, Alqahtani MA, El-Kadi AOS (2023) Modulation of cytochrome P450 1A (CYP1A) enzymes by monomethylmonothioarsonic acid (MMMTAV) in vivo and in vitro. Chem Biol Interact 376:110447. https://doi.org/10.1016/j.cbi.2023.110447

  22. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    Article  CAS  PubMed  Google Scholar 

  23. Wong PS, Vogel CF, Kokosinski K, Matsumura F (2010) Arylhydrocarbon receptor activation in NCI-H441 cells and C57BL/6 mice: possible mechanisms for lung dysfunction. Am J Respir Cell Mol Biol 42(2):210–217

    Article  CAS  PubMed  Google Scholar 

  24. Hu H, Möller G, Abedi-Valugerdi M (1999) Mechanism of mercury-induced autoimmunity: both T helper 1-and T helper 2-type responses are involved. Immunology 96(3):348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Maqbool F et al (2019) Biochemical evidence on the potential role of methyl mercury in hepatic glucose metabolism through inflammatory signaling and free radical pathways. J Cell Biochem 120(9):16195–16205

    Article  PubMed  Google Scholar 

  26. Díaz D, Krejsa CM, White CC, Keener CL, Farin FM, Kavanagh TJ (2001) Tissue specific changes in the expression of glutamate–cysteine ligase mRNAs in mice exposed to methylmercury. Toxicol Lett 122(2):119–129

    Article  PubMed  Google Scholar 

  27. Chang LW, Magos L, Suzuki T (1996) Toxicology of metals. CRC, Boca Raton

    Google Scholar 

  28. Mehra M, Kanwar KC (1980) Biochemical changes resulting from the intraperitoneal administration of mercuric chloride and methylmercuric chloride to mice. Toxicol Lett 6(4–5):319–326

    Article  CAS  PubMed  Google Scholar 

  29. Omata S, Sato M, Sakimura K, Sugano H (1980) Time-dependent accumulation of inorganic mercury in subcellular fractions of kidney, liver, and brain of rats exposed to methylmercury. Arch Toxicol 44:231–241

    Article  CAS  PubMed  Google Scholar 

  30. Norseth T, Clarkson TW (1970) Biotransformation of methylmercury salts in the rat studied by specific determination of inorganic mercury. Biochem Pharmacol 19(10):2775–2783

    Article  CAS  PubMed  Google Scholar 

  31. Safe S (1990) Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Crit Rev Toxicol 21(1):51–88

    Article  CAS  PubMed  Google Scholar 

  32. Denison MS, Pandini A, Nagy SR, Baldwin EP, Bonati L (2002) Ligand binding and activation of the Ah receptor. Chem Biol Interact 141(1–2):3–24

    Article  CAS  PubMed  Google Scholar 

  33. Poland A, Knutson JC (1982) 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 22(1):517–554

    Article  CAS  PubMed  Google Scholar 

  34. Rowland IR, Davies MJ, Grasso P (1977) The effect of elimination of the gastrointestinal flora on the accumulation of methylmercuric chloride by the rat. Biochem Soc Trans 5(2):423–425. https://doi.org/10.1042/bst0050423

    Article  CAS  PubMed  Google Scholar 

  35. Ishihara N (2000) Excretion of methyl mercury in human feces. Arch Environ Heal An Int J 55(1):44–47

    Article  CAS  Google Scholar 

  36. Amara IEA, Anwar-Mohamed A, El-Kadi AOS (2010) Mercury modulates the CYP1A1 at transcriptional and posttranslational levels in human hepatoma HepG2 cells. Toxicol Lett 199(3):225–233

    Article  CAS  PubMed  Google Scholar 

  37. Fujimura M, Usuki F (2022) Cellular conditions responsible for methylmercury-mediated neurotoxicity. Int J Mol Sci 23(13):7218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Usuki F, Fujimura M (2012) Effects of Methylmercury on Cellular Signal Transduction Systems. In: Ceccatelli S, Aschner M (eds) Methylmercury and Neurotoxicity. Current Topics in Neurotoxicity, vol 2. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-2383-6_12

  39. Hayes JD, Dinkova-Kostova AT, McMahon M (2009) Cross-talk between transcription factors AhR and Nrf2: lessons for cancer chemoprevention from dioxin. Toxicol Sci 111(2):199–201

    Article  CAS  PubMed  Google Scholar 

  40. Köhle C, Bock KW (2007) Coordinate regulation of phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2. Biochem Pharmacol 73(12):1853–1862

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The research was funded by the NSERC Discovery Grant [RGPIN 250139] awarded to A.O.S.E. M.A.A received a scholarship from the Saudi government, M.A.E received the Rachel Mandel Scholarship in Lymphoma and Other Blood Cancers and the Alberta Innovates Graduate Student Scholarship, and S.R.E received a scholarship from the Egyptian government.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, Edmonton, Alberta, T6G 2E1, Canada

    Mohammed A. Alqahtani, Mahmoud A. El-Ghiaty, Sara R. El-Mahrouk & Ayman O. S. El-Kadi

Authors
  1. Mohammed A. Alqahtani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahmoud A. El-Ghiaty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara R. El-Mahrouk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ayman O. S. El-Kadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.A.A., A.O.S.E: designed project and supervised the experiments. M.A.A., M.A.E., S.R.E.: conducted the experiments and performed data analysis M.A.A., M.A.E., S.R.E., A.O.S.E: drafted the paper, interpreted the data, and prepared the manuscript for review. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Ayman O. S. El-Kadi.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alqahtani, M.A., El-Ghiaty, M.A., El-Mahrouk, S.R. et al. Differential Modulatory Effects of Methylmercury (MeHg) on Ahr-regulated Genes in Extrahepatic Tissues of C57BL/6 Mice. Biol Trace Elem Res (2024). https://doi.org/10.1007/s12011-023-04050-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12011-023-04050-y

Keywords

Search

Navigation