Proteasome and p62/SQSTM1 are involved in methylmercury toxicity mitigation in mouse embryonic fibroblast cells
Methylmercury (MeHg), an environmental pollutant, disrupts and impairs cellular function. MeHg binds to various cellular proteins, causing dysfunction and misfolding, which are considered underlying causes of MeHg toxicity. The p62 protein, also termed SQSTM1, is a ubiquitin-binding protein that tar...
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| Published in | Journal of toxicological sciences Vol. 48; no. 6; pp. 355 - 361 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Japan
The Japanese Society of Toxicology
01.01.2023
Japan Science and Technology Agency |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0388-1350 1880-3989 1880-3989 |
| DOI | 10.2131/jts.48.355 |
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| Abstract | Methylmercury (MeHg), an environmental pollutant, disrupts and impairs cellular function. MeHg binds to various cellular proteins, causing dysfunction and misfolding, which are considered underlying causes of MeHg toxicity. The p62 protein, also termed SQSTM1, is a ubiquitin-binding protein that targets ubiquitinated substrates to undergo autophagy and plays a key role in ameliorating MeHg toxicity. p62 also delivers ubiquitinated substrates to proteasomes. However, the role of these degradation systems in mitigating MeHg toxicity remains unknown. Herein, we explored the impact of the proteasome inhibitor MG132 on MeHg toxicity and examined the toxicity of co-treatment with MG132 and MeHg in p62KO mouse embryonic fibroblasts (MEFs) by analyzing cell viability, immunoblotting, mRNA levels, immunofluorescence, and the mercury content. The proteasome inhibitor MG132 enhanced MeHg-induced cytotoxicity while reducing intracellular mercury levels in MEFs. Co-treatment with MG132 and MeHg markedly increased levels of p62 and ubiquitinated proteins. Furthermore, co-treatment with MG132 and MeHg reduced p62KO MEF viability compared to that of wild-type MEFs. Our findings suggest that the proteasome participates in mitigating MeHg cytotoxicity, while p62 may play an important role in transporting MeHg-induced ubiquitinated proteins to the proteasome, as well as in autophagy. Collectively, these results imply that p62, and proteasome, and autophagy are vital for cytoprotection against MeHg toxicity. |
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| AbstractList | Methylmercury (MeHg), an environmental pollutant, disrupts and impairs cellular function. MeHg binds to various cellular proteins, causing dysfunction and misfolding, which are considered underlying causes of MeHg toxicity. The p62 protein, also termed SQSTM1, is a ubiquitin-binding protein that targets ubiquitinated substrates to undergo autophagy and plays a key role in ameliorating MeHg toxicity. p62 also delivers ubiquitinated substrates to proteasomes. However, the role of these degradation systems in mitigating MeHg toxicity remains unknown. Herein, we explored the impact of the proteasome inhibitor MG132 on MeHg toxicity and examined the toxicity of co-treatment with MG132 and MeHg in p62KO mouse embryonic fibroblasts (MEFs) by analyzing cell viability, immunoblotting, mRNA levels, immunofluorescence, and the mercury content. The proteasome inhibitor MG132 enhanced MeHg-induced cytotoxicity while reducing intracellular mercury levels in MEFs. Co-treatment with MG132 and MeHg markedly increased levels of p62 and ubiquitinated proteins. Furthermore, co-treatment with MG132 and MeHg reduced p62KO MEF viability compared to that of wild-type MEFs. Our findings suggest that the proteasome participates in mitigating MeHg cytotoxicity, while p62 may play an important role in transporting MeHg-induced ubiquitinated proteins to the proteasome, as well as in autophagy. Collectively, these results imply that p62, and proteasome, and autophagy are vital for cytoprotection against MeHg toxicity. Methylmercury (MeHg), an environmental pollutant, disrupts and impairs cellular function. MeHg binds to various cellular proteins, causing dysfunction and misfolding, which are considered underlying causes of MeHg toxicity. The p62 protein, also termed SQSTM1, is a ubiquitin-binding protein that targets ubiquitinated substrates to undergo autophagy and plays a key role in ameliorating MeHg toxicity. p62 also delivers ubiquitinated substrates to proteasomes. However, the role of these degradation systems in mitigating MeHg toxicity remains unknown. Herein, we explored the impact of the proteasome inhibitor MG132 on MeHg toxicity and examined the toxicity of co-treatment with MG132 and MeHg in p62KO mouse embryonic fibroblasts (MEFs) by analyzing cell viability, immunoblotting, mRNA levels, immunofluorescence, and the mercury content. The proteasome inhibitor MG132 enhanced MeHg-induced cytotoxicity while reducing intracellular mercury levels in MEFs. Co-treatment with MG132 and MeHg markedly increased levels of p62 and ubiquitinated proteins. Furthermore, co-treatment with MG132 and MeHg reduced p62KO MEF viability compared to that of wild-type MEFs. Our findings suggest that the proteasome participates in mitigating MeHg cytotoxicity, while p62 may play an important role in transporting MeHg-induced ubiquitinated proteins to the proteasome, as well as in autophagy. Collectively, these results imply that p62, and proteasome, and autophagy are vital for cytoprotection against MeHg toxicity.Methylmercury (MeHg), an environmental pollutant, disrupts and impairs cellular function. MeHg binds to various cellular proteins, causing dysfunction and misfolding, which are considered underlying causes of MeHg toxicity. The p62 protein, also termed SQSTM1, is a ubiquitin-binding protein that targets ubiquitinated substrates to undergo autophagy and plays a key role in ameliorating MeHg toxicity. p62 also delivers ubiquitinated substrates to proteasomes. However, the role of these degradation systems in mitigating MeHg toxicity remains unknown. Herein, we explored the impact of the proteasome inhibitor MG132 on MeHg toxicity and examined the toxicity of co-treatment with MG132 and MeHg in p62KO mouse embryonic fibroblasts (MEFs) by analyzing cell viability, immunoblotting, mRNA levels, immunofluorescence, and the mercury content. The proteasome inhibitor MG132 enhanced MeHg-induced cytotoxicity while reducing intracellular mercury levels in MEFs. Co-treatment with MG132 and MeHg markedly increased levels of p62 and ubiquitinated proteins. Furthermore, co-treatment with MG132 and MeHg reduced p62KO MEF viability compared to that of wild-type MEFs. Our findings suggest that the proteasome participates in mitigating MeHg cytotoxicity, while p62 may play an important role in transporting MeHg-induced ubiquitinated proteins to the proteasome, as well as in autophagy. Collectively, these results imply that p62, and proteasome, and autophagy are vital for cytoprotection against MeHg toxicity. |
| Author | Takanezawa, Yasukazu Ohshiro, Yuka Uraguchi, Shimpei Nakamura, Ryosuke Kiyono, Masako |
| Author_xml | – sequence: 1 fullname: Nakamura, Ryosuke organization: Department of Public Health, School of Pharmacy, Kitasato University – sequence: 1 fullname: Kiyono, Masako organization: Department of Public Health, School of Pharmacy, Kitasato University – sequence: 1 fullname: Ohshiro, Yuka organization: Department of Public Health, School of Pharmacy, Kitasato University – sequence: 1 fullname: Takanezawa, Yasukazu organization: Department of Public Health, School of Pharmacy, Kitasato University – sequence: 1 fullname: Uraguchi, Shimpei organization: Department of Public Health, School of Pharmacy, Kitasato University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/37258240$$D View this record in MEDLINE/PubMed |
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| References | Takanezawa, Y., Nakamura, R., Sone, Y., Uraguchi, S. and Kiyono, M. (2019b): An autophagy deficiency promotes methylmercury-induced multinuclear cell formation. Biochem. Biophys. Res. Commun., 511, 460-467. Korolchuk, V.I., Mansilla, A., Menzies, F.M. and Rubinsztein, D.C. (2009): Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol. Cell, 33, 517-527. Tominaga, T., Goto, M., Onoue, T., Mizoguchi, A., Sugiyama, M., Tsunekawa, T., Hagiwara, D., Morishita, Y., Ito, Y., Iwama, S., Suga, H., Banno, R. and Arima, H. (2017): Sequestosome 1 (SQSTM1/p62) maintains protein folding capacity under endoplasmic reticulum stress in mouse hypothalamic organotypic culture. Neurosci. Lett., 656, 103-107. Usuki, F., Fujimura, M. and Yamashita, A. (2017): Endoplasmic reticulum stress preconditioning modifies intracellular mercury content by upregulating membrane transporters. Sci. Rep., 7, 12390. Karagas, M.R., Choi, A.L., Oken, E., Horvat, M., Schoeny, R., Kamai, E., Cowell, W., Grandjean, P. and Korrick, S. (2012): Evidence on the human health effects of low-level methylmercury exposure. Environ. Health Perspect., 120, 799-806. Shin, W.H., Park, J.H. and Chung, K.C. (2020): The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson’s disease. BMB Rep., 53, 56-63. Seibenhener, M.L., Babu, J.R., Geetha, T., Wong, H.C., Krishna, N.R. and Wooten, M.W. (2004): Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol. Cell. Biol., 24, 8055-8068. Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Øvervatn, A., Stenmark, H. and Johansen, T. (2005): p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol., 171, 603-614. Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y.S., Ueno, I., Sakamoto, A., Tong, K.I., Kim, M., Nishito, Y., Iemura, S., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka, K. and Yamamoto, M. (2010): The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol., 12, 213-223. Yokoo, E.M., Valente, J.G., Grattan, L., Schmidt, S.L., Platt, I. and Silbergeld, E.K. (2003): Low level methylmercury exposure affects neuropsychological function in adults. Environ. Health, 2, 8. Takanezawa, Y., Nakamura, R., Sugimoto, T., Ohshiro, Y., Uraguchi, S. and Kiyono, M. (2021): p62/sequestosome 1 attenuates methylmercury-induced endoplasmic reticulum stress in mouse embryonic fibroblasts. Toxicol. Lett., 353, 93-99. Ke, T., Gonçalves, F.M., Gonçalves, C.L., Dos Santos, A.A., Rocha, J.B., Farina, M., Skalny, A., Tsatsakis, A., Bowman, A.B. and Aschner, M. (2019): Post-translational modifications in MeHg-induced neurotoxicity. Biochim. Biophys. Acta Mol. Basis Dis., 1865, 2068-2081. Liu, W.J., Ye, L., Huang, W.F., Guo, L.J., Xu, Z.G., Wu, H.L., Yang, C. and Liu, H.F. (2016): p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cell. Mol. Biol. Lett., 21, 29. Hiraoka, H., Nakahara, K., Kaneko, Y., Akiyama, S., Okuda, K., Iwawaki, T., Fujimura, M., Kumagai, Y., Takasugi, N. and Uehara, T. (2017): Modulation of unfolded protein response by methylmercury. Biol. Pharm. Bull., 40, 1595-1598. Wang, L., Jiang, H., Yin, Z., Aschner, M. and Cai, J. (2009): Methylmercury toxicity and Nrf2-dependent detoxification in astrocytes. Toxicol. Sci., 107, 135-143. Salminen, A., Kaarniranta, K., Haapasalo, A., Hiltunen, M., Soininen, H. and Alafuzoff, I. (2012): Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease. Prog. Neurobiol., 96, 87-95. Auger, N., Kofman, O., Kosatsky, T. and Armstrong, B. (2005): Low-level methylmercury exposure as a risk factor for neurologic abnormalities in adults. Neurotoxicology, 26, 149-157. Amm, I., Sommer, T. and Wolf, D.H. (2014): Protein quality control and elimination of protein waste: the role of the ubiquitin-proteasome system. Biochim. Biophys. Acta, 1843, 182-196. Takanezawa, Y., Nakamura, R., Sone, Y., Uraguchi, S. and Kiyono, M. (2016): Atg5-dependent autophagy plays a protective role against methylmercury-induced cytotoxicity. Toxicol. Lett., 262, 135-141. Hwang, G.-W., Sasaki, D. and Naganuma, A. (2005): Overexpression of Rad23 confers resistance to methylmercury in saccharomyces cerevisiae via inhibition of the degradation of ubiquitinated proteins. Mol. Pharmacol., 68, 1074-1078. Cohen-Kaplan, V., Livneh, I., Avni, N., Fabre, B., Ziv, T., Kwon, Y.T. and Ciechanover, A. (2016): p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome. Proc. Natl. Acad. Sci. USA, 113, E7490-E7499. Unoki, T., Akiyama, M., Kumagai, Y., Gonçalves, F.M., Farina, M., da Rocha, J.B. and Aschner, M. (2018): Molecular pathways associated with methylmercury-induced Nrf2 modulation. Front. Genet., 9, 373. Hwang, G.-W., Furuchi, T. and Naganuma, A. (2002): A ubiquitin-proteasome system is responsible for the protection of yeast and human cells against methylmercury. FASEB J., 16, 709-711. Takanezawa, Y., Nakamura, R., Harada, R., Sone, Y., Uraguchi, S. and Kiyono, M. (2017): Sequestosome1/p62 protects mouse embryonic fibroblasts against low-dose methylercury-induced cytotoxicity and is involved in clearance of ubiquitinated proteins. Sci. Rep., 7, 16735. Clarkson, T.W. and Magos, L. (2006): The toxicology of mercury and its chemical compounds. Crit. Rev. Toxicol., 36, 609-662. Adams, J. (2003): The proteasome: structure, function, and role in the cell. Cancer Treat. Rev., 29 (Suppl 1), 3-9. Takanezawa, Y., Nakamura, R., Matsuda, H., Yagi, T., Egawa, Z., Sone, Y., Uraguchi, S., Adachi, T. and Kiyono, M. (2019a): Intracellular demethylation of methylmercury to inorganic mercury by organomercurial lyase (MerB) strengthens cytotoxicity. Toxicol. Sci., 170, 438-451. Kumagai, Y., Kanda, H., Shinkai, Y. and Toyama, T. (2013): The role of the Keap1/Nrf2 pathway in the cellular response to methylmercury. Oxid. Med. Cell. Longev., 2013, 848279. 22 23 24 25 26 27 28 10 11 12 13 14 15 16 17 18 19 1 2 3 4 5 6 7 8 9 20 21 |
| References_xml | – reference: Clarkson, T.W. and Magos, L. (2006): The toxicology of mercury and its chemical compounds. Crit. Rev. Toxicol., 36, 609-662. – reference: Kumagai, Y., Kanda, H., Shinkai, Y. and Toyama, T. (2013): The role of the Keap1/Nrf2 pathway in the cellular response to methylmercury. Oxid. Med. Cell. Longev., 2013, 848279. – reference: Takanezawa, Y., Nakamura, R., Sone, Y., Uraguchi, S. and Kiyono, M. (2016): Atg5-dependent autophagy plays a protective role against methylmercury-induced cytotoxicity. Toxicol. Lett., 262, 135-141. – reference: Korolchuk, V.I., Mansilla, A., Menzies, F.M. and Rubinsztein, D.C. (2009): Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol. Cell, 33, 517-527. – reference: Hiraoka, H., Nakahara, K., Kaneko, Y., Akiyama, S., Okuda, K., Iwawaki, T., Fujimura, M., Kumagai, Y., Takasugi, N. and Uehara, T. (2017): Modulation of unfolded protein response by methylmercury. Biol. Pharm. Bull., 40, 1595-1598. – reference: Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y.S., Ueno, I., Sakamoto, A., Tong, K.I., Kim, M., Nishito, Y., Iemura, S., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka, K. and Yamamoto, M. (2010): The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol., 12, 213-223. – reference: Takanezawa, Y., Nakamura, R., Harada, R., Sone, Y., Uraguchi, S. and Kiyono, M. (2017): Sequestosome1/p62 protects mouse embryonic fibroblasts against low-dose methylercury-induced cytotoxicity and is involved in clearance of ubiquitinated proteins. Sci. Rep., 7, 16735. – reference: Shin, W.H., Park, J.H. and Chung, K.C. (2020): The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson’s disease. BMB Rep., 53, 56-63. – reference: Amm, I., Sommer, T. and Wolf, D.H. (2014): Protein quality control and elimination of protein waste: the role of the ubiquitin-proteasome system. Biochim. Biophys. Acta, 1843, 182-196. – reference: Usuki, F., Fujimura, M. and Yamashita, A. (2017): Endoplasmic reticulum stress preconditioning modifies intracellular mercury content by upregulating membrane transporters. Sci. Rep., 7, 12390. – reference: Karagas, M.R., Choi, A.L., Oken, E., Horvat, M., Schoeny, R., Kamai, E., Cowell, W., Grandjean, P. and Korrick, S. (2012): Evidence on the human health effects of low-level methylmercury exposure. Environ. Health Perspect., 120, 799-806. – reference: Tominaga, T., Goto, M., Onoue, T., Mizoguchi, A., Sugiyama, M., Tsunekawa, T., Hagiwara, D., Morishita, Y., Ito, Y., Iwama, S., Suga, H., Banno, R. and Arima, H. (2017): Sequestosome 1 (SQSTM1/p62) maintains protein folding capacity under endoplasmic reticulum stress in mouse hypothalamic organotypic culture. Neurosci. Lett., 656, 103-107. – reference: Takanezawa, Y., Nakamura, R., Matsuda, H., Yagi, T., Egawa, Z., Sone, Y., Uraguchi, S., Adachi, T. and Kiyono, M. (2019a): Intracellular demethylation of methylmercury to inorganic mercury by organomercurial lyase (MerB) strengthens cytotoxicity. Toxicol. Sci., 170, 438-451. – reference: Adams, J. (2003): The proteasome: structure, function, and role in the cell. Cancer Treat. Rev., 29 (Suppl 1), 3-9. – reference: Takanezawa, Y., Nakamura, R., Sone, Y., Uraguchi, S. and Kiyono, M. (2019b): An autophagy deficiency promotes methylmercury-induced multinuclear cell formation. Biochem. Biophys. Res. Commun., 511, 460-467. – reference: Wang, L., Jiang, H., Yin, Z., Aschner, M. and Cai, J. (2009): Methylmercury toxicity and Nrf2-dependent detoxification in astrocytes. Toxicol. Sci., 107, 135-143. – reference: Hwang, G.-W., Sasaki, D. and Naganuma, A. (2005): Overexpression of Rad23 confers resistance to methylmercury in saccharomyces cerevisiae via inhibition of the degradation of ubiquitinated proteins. Mol. Pharmacol., 68, 1074-1078. – reference: Auger, N., Kofman, O., Kosatsky, T. and Armstrong, B. (2005): Low-level methylmercury exposure as a risk factor for neurologic abnormalities in adults. Neurotoxicology, 26, 149-157. – reference: Cohen-Kaplan, V., Livneh, I., Avni, N., Fabre, B., Ziv, T., Kwon, Y.T. and Ciechanover, A. (2016): p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome. Proc. Natl. Acad. Sci. USA, 113, E7490-E7499. – reference: Salminen, A., Kaarniranta, K., Haapasalo, A., Hiltunen, M., Soininen, H. and Alafuzoff, I. (2012): Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease. Prog. Neurobiol., 96, 87-95. – reference: Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Øvervatn, A., Stenmark, H. and Johansen, T. (2005): p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol., 171, 603-614. – reference: Ke, T., Gonçalves, F.M., Gonçalves, C.L., Dos Santos, A.A., Rocha, J.B., Farina, M., Skalny, A., Tsatsakis, A., Bowman, A.B. and Aschner, M. (2019): Post-translational modifications in MeHg-induced neurotoxicity. Biochim. Biophys. Acta Mol. Basis Dis., 1865, 2068-2081. – reference: Liu, W.J., Ye, L., Huang, W.F., Guo, L.J., Xu, Z.G., Wu, H.L., Yang, C. and Liu, H.F. (2016): p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cell. Mol. Biol. Lett., 21, 29. – reference: Seibenhener, M.L., Babu, J.R., Geetha, T., Wong, H.C., Krishna, N.R. and Wooten, M.W. (2004): Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol. Cell. Biol., 24, 8055-8068. – reference: Yokoo, E.M., Valente, J.G., Grattan, L., Schmidt, S.L., Platt, I. and Silbergeld, E.K. (2003): Low level methylmercury exposure affects neuropsychological function in adults. Environ. Health, 2, 8. – reference: Takanezawa, Y., Nakamura, R., Sugimoto, T., Ohshiro, Y., Uraguchi, S. and Kiyono, M. (2021): p62/sequestosome 1 attenuates methylmercury-induced endoplasmic reticulum stress in mouse embryonic fibroblasts. Toxicol. Lett., 353, 93-99. – reference: Unoki, T., Akiyama, M., Kumagai, Y., Gonçalves, F.M., Farina, M., da Rocha, J.B. and Aschner, M. (2018): Molecular pathways associated with methylmercury-induced Nrf2 modulation. Front. Genet., 9, 373. – reference: Hwang, G.-W., Furuchi, T. and Naganuma, A. (2002): A ubiquitin-proteasome system is responsible for the protection of yeast and human cells against methylmercury. 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| Snippet | Methylmercury (MeHg), an environmental pollutant, disrupts and impairs cellular function. MeHg binds to various cellular proteins, causing dysfunction and... |
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| SubjectTerms | Animals Autophagy Cell death Cell viability Cytotoxicity Dimethylmercury Embryo fibroblasts Fibroblasts Immunoblotting Immunofluorescence Mercury Mercury (metal) Mercury - metabolism Mercury Poisoning - drug therapy Mercury Poisoning - prevention & control Methylmercury Methylmercury Compounds - metabolism Methylmercury Compounds - toxicity MG132 Mice Mitigation mRNA p62 Protein p62/SQSTM1 Proteasome Proteasome Endopeptidase Complex - metabolism Proteasome inhibitors Proteasome Inhibitors - metabolism Proteasome Inhibitors - pharmacology Proteasomes Protein transport Proteins Sequestosome-1 Protein - genetics Sequestosome-1 Protein - metabolism Substrates Toxicity Ubiquitin Ubiquitinated Proteins - metabolism |
| Title | Proteasome and p62/SQSTM1 are involved in methylmercury toxicity mitigation in mouse embryonic fibroblast cells |
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