Sublethal Doses of Inorganic Mercury Induce Dose-Depended Upregulation of RPA1 Content and Inhibit p53 Expression in the Brain of Rainbow Trout (Oncorhynchus mykiss)

Year 2019, Volume: 6 Issue: 3, 462 - 476, 23.07.2019

Mehmet Reşit Taysı , Bünyamin Söğüt Victor S. Nedzvetsky Muammer Kırıcı Can Ali Ağca

https://doi.org/10.30910/turkjans.595352

Abstract

Mercury (Hg) is one of most
toxic and widespread element of aquatic environment. Almost every kind of the
fish can accumulate Hg. Hg-induced peculiarities of cellular malfunction could
be used as adequate biomarker to estimate the contamination risk in polluted
aquatic ecosystems. The brain cells are high susceptible to the Hg compounds cytotoxicity.
Various Hg species have different harmful effects on both structure and
function of the brain cells. Neurotoxicity of inorganic Hg remains discussable
and studied restrictedly. In this study, we have studied the role of RPA1 and
p53 proteins in brain cell response to sublehtal (25% LD₅₀ and 50%
LD₅₀₎ doses of inorganic Hg in rainbow trout (Oncorhynchus mykiss). LD₅₀ value of Hg chloride in
presented study was determined as 551 µg/L relate to 96 hours exposure. Two
sublethal doses were used in the exposure rainbow trout at 2 and 7 days. The
treatment with Hg chloride induced in fish brain dose-dependent increase in ROS
level as well as time-dependent growth. Moreover, the exposure to both 25% and
50% LD₅₀ Hg doses have caused significant upregulation of RPA1
expression. In the brain tissue of fish exposed to Hg for 2 days, it stimulated
slightly expression of p53. Contrary, 7 days exposure induced significant
decrease in p53 expression. The results of presented study evidence that
sublethal doses of inorganic Hg are extremely neurotoxic and can induce in the
fish brain signaling pathways disturbance through decline of stress sensor
protein p53. Besides, the increase in RPA1 expression let to assume that brain
cells of the fish can repair ROS-induced DNA breaks and prevent genotoxic
effect of inorganic Hg. Overall, current data pointed out that inorganic
mercury is high toxic to fish brain cells and this question requires future
research.

Keywords

Rainbow trout, fish brain

Thanks

This study was produced from the doctoral thesis prepared by the first author consultation with the second author.

İnorganik Civanın Subletal Dozlarının Gökkuşağı Alabalığı (Oncorhynchus mykiss) Beyin Dokusunda Doza Bağlı RPA1 İçeriğini Yükseltmesi ve P53 Ekspresyonunu Engellemesi

Abstract

Civa
(Hg), su ortamının en toksik ve yaygın unsurlarından biridir. Hemen hemen her
balık türü Hg’ ya maruz kaldığı zaman bunu dokularında biriktirebilir. Civa ile
indüklenen hücresel fonksiyon bozukluğu, sucul ortamdaki kirlenme riskini
tahmin etmek için yeterli biyobelirteç olarak kullanılabilir. Beyin hücreleri,
civa bileşiklerinin sitoksisitesine karşı oldukça hassastır. Çeşitli civa
türleri, beyin hücrelerinin hem yapısı hem de işlevi üzerinde farklı zararlı
etkilere sahiptir. Son zamanlarda yapılan çalışmalarda inorganik civanın
nörotoksisitesi tartışılmaya devam etse de tamamıyla incelenmemiştir. Bu
çalışmada organik civanın subletal dozlarına maruz bırakılan gökkuşağı
alabalığının beyin dokusunda rpa1 ve p53 proteinlerinin rolünü araştırdık.
Sunulan çalışmada civa klorürün LD₅₀ değeri, 96 saat maruz kalma ile
551 μg / L olarak belirlenmiştir. Gökkuşağı alabalıkları 2 ve 7 günlük zaman
aralıklarında iki subletal doza maruz bırakıldı. Civa klorüre maruz bırakılan
balıkların beyin dokusunda doz ve zaman bağımlı olarak ROS seviyesinde bir
artış belirlenmiştir. Ayrıca, hem % 25 hem de % 50 LD₅₀ civa
dozlarına maruz kalma süresince RPA1 ekspresyonunun önemli ölçüde
upregülasyonuna neden olmuştur. 2 gün süre ile Hg maruz bırakılan balıkların
beyin dokusunda, p53 ekspresyonunu zayıf bir şekilde uyarmıştır. Bunun tam
tersine olarak, 7 günlük maruz kalma, p53 ekspresyonunda önemli bir azalmaya
neden oldu. Sunulan çalışmanın sonuçları inorganik civanın alt dozlarının son
derece nörotoksik olduğunu ve stres sensörü proteini p53 ün azalması ile balık
beyni sinyal yollarında bozukluğa neden olabileceğini kanıtlamaktadır. Ayrıca,
RPA1 ekspresyonundaki artış, balıkların beyin hücrelerinin ROS kaynaklı DNA
kırılmalarını tamir edebileceğini ve inorganik Hg'nin genotoksik etkisini
önleyebileceğini göstermektedir. Genel olarak, mevcut veriler inorganik
civaların balık beyin hücrelerine toksik olduğunu ve bu sorunun gelecekte de
araştırılmasının gerekliliğine işaret etmektedir.

Keywords

Gökkuşağı alabalığı, balık beyni

References

• Amlund, H., Lundebye, A.K., Berntssen, M.H. 2007. Accumulation and elimination of methylmercury in Atlantic cod (Gadus morhua L.) following dietary exposure. Aquat Toxicol., 1; 83(4): 323-30.
• Antunes Dos Santos, A., Ferrer, B., Marques Gonçalves, F., Tsatsakis, A.M., Renieri, E.A., Skalny, A.V., Farina, M., Rocha, J.B.T., Aschner, M. 2018. Oxidative Stress in Methylmercury-Induced Cell Toxicity. Toxics., 9:6(3). pii: E47. doi: 10.3390/toxics6030047.
• Aschner, M., Aschner, J.L. 1990. Mercury neurotoxicity: mechanisms of blood-brain barrier transport. Neurosci Biobehav Rev., 14(2): 169-76.
• Bagchi, D., Bagchi, M., Stohs, S.J. 2001. Chromium (VI)-induced oxidative stress, apoptotic cell death and modulation of p53 tumor suppressor gene. Mol Cell Biochem., 222(1-2): 149-58.
• Bensaad, K., Vousden, K.H. 2007. p53: new roles in metabolism. Trends Cell Biol., 2007 Jun; 17(6): 286-91.
• Binz, S.K., Sheehan, A.M., Wold, M.S. 2004. Replication protein a phosphorylation and the cellular response to DNA damage. DNA Repair, 3(8-9): 1015-1024. https://doi.org/10.1016/j.dnarep.2004.03.028.
• Brandão, F., Cappello, T., Raimundo, J., Santos, M.A., Maisano, M., Mauceri, A., Pacheco, M,, Pereira, P. 2015. Unravelling the mechanisms of mercury hepatotoxicity in wild fish (Liza aurata) through a triad approach: bioaccumulation, metabolomic profiles and oxidative stress. Metallomics, 7(9):1352-63.
• Brawer, J.R., McCarthy, G.F., Gornitsky, M., Frankel, D., Mehindate, K., Schipper, H.M. 1998. Mercuric chloride induces a stress response in cultured astrocytes characterized by mitochondrial uptake of iron. Neurotoxicology, 19(6): 767-76.
• Cariccio, V.L., Samа, A., Bramanti, P., Mazzon, E. 2019. Mercury Involvement in neuronal damage and in neurodegenerative diseases. Biol Trace Elem Res., 187(2): 341-356.
• Carocci, A., Rovito, N., Sinicropi, M.S., Genchi, G. 2014. Mercury toxicity and neurodegenerative effects. Rev Environ Contam Toxicol., 229: 1-18. doi: 10.1007/978-3-319-03777-6_1.
• Chang, Y., Lee, W.Y., Lin, Y.J., Hsu, T. 2017. Mercury (II) impairs nucleotide excision repair (NER) in zebrafish (Danio rerio) embryos by targeting primarily at the stage of DNA incision. Aquat Toxicol., 192: 97-104.
• Cho, J.G., Park, S., Lim, C.H., Kim, H.S., Song, S.Y., Roh, T.Y., Sung, J.H., Suh, W., Ham, S.J., Lim, K.H., Park, S.G. 2016. ZNF224, Krüppel like zinc finger protein, induces cell growth and apoptosis-resistance by down-regulation of p21 and p53 via miR-663a. Oncotarget, 24; 7(21): 31177-90.
• Choi, J.H., Lindsey-Boltz, L.A., Kemp, M., Mason, A.C., Wold, M.S., Sancar, A. 2010. Reconstitution of RPA-covered single-stranded DNA-activated ATR-Chk1 signaling. Proc. Natl. Acad. Sci. USA., 3: 107(31): 13660-5.
• Ciardullo, S., Aureli, F., Coni, E., Guandalini, E., Iosi, F., Raggi, A., Rufo, G., Cubadda, F. 2008. Bioaccumulation potential of dietary arsenic, cadmium, lead, mercury, and selenium in organs and tissues of rainbow trout (Oncorhyncus mykiss) as a function of fish growth. J. Agric. Food Chem., 9;56(7): 2442-51.doi: 10.1021/jf703572t.
• Crespo-López ME, Macêdo GL, Pereira SI, Arrifano GP, Picanço-Diniz DL, do Nascimento JL, Herculano AM 2009. Mercury and human genotoxicity: critical considerations and possible molecular mechanisms. Pharmacol. Res. 60: 212-220.
• Du, T., Ciccotosto, G.D., Cranston, G.A., Kocak, G., Masters, C.L., Crouch, P.J., Cappai, R., White, A.R. 2008. Eurotoxicity from glutathione depletion is mediated by Cu-dependent p53 activation. Free Radic Biol Med., 1;44(1):44-55.
• Eagles-Smith, C.A., Ackerman, J.T., Willacker, J.J., Tate, M.T., Lutz, M.A., Fleck, J.A., Stewart, A.R., Wiener, J.G., Evers, D.C., Lepak, J.M., Davis, J.A., Pritz, C.F. 2016a. Spatial and temporal patterns of mercury concentrations in freshwater fish across the Western United States and Canada. Sci Total Environ., 15;568:1171-1184. doi: 10.1016/j.scitotenv.
• Eagles-Smith, C.A., Wiener, J.G., Eckley, C.S., Willacker, J.J., Evers, D.C., Marvin-DiPasquale, M., Obrist, D., Fleck, J.A., Aiken, G.R., Lepak, J.M., Jackson, A.K., Webster, J.P., Stewart, A.R., Davis, J.A., Alpers, C.N., Ackerman, J.T. 2016b. Mercury in western North America: A synthesis of environmental contamination, fluxes, bioaccumulation, and risk to fish and wildlife. Sci Total Environ., 15:568:1213-1226. doi: 10.1016/j.scitotenv.
• Eckerich, C., Fackelmayer, F.O., Knippers, R. 2001. Zinc affects the conformation of nucleoprotein filaments formed by replication protein A (RPA) and long natural DNA molecules. Biochim. Biophys. Acta., 1538(1): 67-75.
• Fuschi, P., Carrara, M., Voellenkle, C., Garcia-Manteiga, J.M., Righini, P., Maimone, B., Sangalli, E., Villa, F., Specchia, C., Picozza, M., Nano, G., Gaetano, C., Spinetti, G., Puca, A.A., Magenta, A., Martelli, F. 2017. Central role of the p53 pathway in the noncoding-RNA response to oxidative stress. Aging (Albany NY). 12; 9(12): 2559-2586.
• Giblin, F.J., Massaro, E.J. 1975. The erythrocyte transport and transfer of methylmercury to the tissues of the rainbow trout (Salmo gairdneri). Toxicology, 5: 243-254.
• Gómez-Oliván, L.M., Mendoza-Zenil, Y.P., SanJuan-Reyes, N., Galar-Martínez, M., Ramírez-Durán, N., Rodríguez Martín-Doimeadios, R.D.C., Rodríguez-Fariñas, N., Islas-Flores, H., Elizalde-Velázquez, A., García-Medina, S., Pérez-Pastén Borja, R. 2017. Geno- and cytotoxicity induced on Cyprinus carpio by aluminum, iron, mercury and mixture thereof. Ecotoxicol Environ. Saf., 135: 98-105.
• Harayashiki, C.A.Y., Reichelt-Brushett, A., Benkendorff, K. 2019. Behavioural and brain biomarker responses in yellowfin bream (Acanthopagrus australis) after inorganic mercury ingestion. Mar. Environ. Res., 144: 62-71. doi: 10.1016/j.
• Has-Schön, E., Bogut, I., Vuković, R., Galović, D., Bogut, A., Horvatić, J. 2015. Distribution and age-related bioaccumulation of lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As) in tissues of common carp (Cyprinus carpio) and European catfish (Sylurus glanis) from the Buško Blato reservoir (Bosnia and Herzegovina). Chemosphere, 135: 289-296.
• Horowitz, H.M., Jacob, D.J., Amos, H.M., Streets, D.G., Sunderland, E.M. 2014. Historical Mercury releases from commercial products: global environmental implications. Environ. Sci. Technol., 2: 48(17): 10242-50. doi: 10.1021/es501337j.
• Hu, J., Liu, Z.S., Tang, S.L., He, Y.M. 2007. Effect of hydroxyapatite nanoparticles on the growth and p53/c-Myc protein expression of implanted hepatic VX2 tumor in rabbits by intravenous injection. World J. Gastroenterol., 28; 13(20): 2798-802.
• Hu, Z., Holzschuh, J., Driever, W. 2015. Loss of DDB1 Leads to Transcriptional p53 Pathway Activation in Proliferating Cells, Cell Cycle Deregulation, and Apoptosis in Zebrafish Embryos. PLoSOne,30; 10(7):e0134299.doi:10.1371/journal.pone.0134299.
• Iftode, C., Daniely, Y., Borowiec, J.A. 1999. Replication protein A (RPA): the eukaryotic SSB. Crit. Rev. Biochem. Mol. Biol., 34(3): 141-80.
• Ishibashi, T., Kimura, S., Furukawa, T., Hatanaka, M., Hashimoto, J., Sakaguchi, K. 2001. Two types of replication protein A 70 kDa subunit in rice, Oryza sativa: molecular cloning, characterization, and cellular & tissue distribution. Gene., 11: 272(1-2): 335-43.
• Jancsó A, Gyurcsik B, Mesterházy E, Berkecz R.. 2013. Competition of zinc(II) with cadmium(II) or mercury(II) in binding to a 12-mer peptide. J. Inorg. Biochem., 126: 96-103.
• Jebbett, N.J., Hamilton, J.W., Rand, M.D., Eckenstein, F. 2013. Low level methylmercury enhances CNTF-evoked STAT3 signaling and glial differentiation in cultured cortical progenitor cells. Neurotoxicology, 38: 91-100.
• Jensen, S., Jernelöv, A. 1969. Biological methylation of mercury in aquatic organisms. Nature, 6; 223(5207): 753-4.
• Jensen, H.L.B., Lillenes, M.S., Rabano, A., Gьnther, C.C., Riaz, T., Kalayou, S.T., Ulstein, I.D., Bшhmer, T., Tшnjum, T. 2018. Expression of nucleotide excision repair in Alzheimer's disease is higher in brain tissue than in blood. Neurosci Lett., 672:53-58.
• Jiang, D., Rusling, J.F. 2019. Oxidation Chemistry of DNA and p53 Tumor Suppressor Gene. Chemistry Open, 22; 8(3): 252-265.
• Jomova, K., Valko, M. 2011. Advances in metal-induced oxidative stress and human disease. Toxicology, 283(2-3): 65-87.
• Kanakis, D., Levidou, G., Gakiopoulou, H., Eftichiadis, C., Thymara, I., Fragkou, P., Trigka, E.A., Boviatsis, E., Patsouris, E., Korkolopoulou, P. 2011. Replication protein A: a reliable biologic marker of prognostic and therapeutic value in human astrocytic tumors. Hum. Pathol., 42(10): 1545-53.
• Kenšová, R., Kružíková, K., Havránek, J., Haruštiaková, D., Svobodová, Z. 2012. Distribution of mercury in rainbow trout tissues at embryo-larval and juvenile stages. Scientific World Journal, 652496. doi: 10.1100/2012/652496.
• Kim, Y.J., Lee, Y.J., Kim, H.J., Kim, H.S., Kang, M.S., Lee, S.K., Park, M.K., Murata, K., Kim, H.L., Seo, Y.R. 2018. A molecular mechanism of nickel (II): reduction of nucleotide excision repair activity by structural and functional disruption of p53. Carcinogenesis, 21; 39(9): 1157-1164.
• Korbas, M., Macdonald, T.C., Pickering, I.J., George, G.N., Krone, P.H. 2012. Chemical form matters: differential accumulation of mercury following inorganic and organic mercury exposures in zebrafish larvae. ACS Chem. Biol., 7(2): 411-20.
• Laurier, F.J.G., Mason, R.P., Gill, G.A., Whalin, L. 2004. Mercury distributions in the North Pacific Ocean-20 years of observations. Marine Chemistry, 90: 3-19. doi: 10.1016/j.marchem.2004.02.025.
• Leonard, S.S., Harris, G.K., Shi, X. 2004. Metal-induced oxidative stress and signal transduction. Free Radic. Biol. Med., 37(12): 1921-42.
• Lieberman, H.B., Panigrahi, S.K., Hopkins, K.M., Wang, L., Broustas, C.G. 2017. p53 and RAD9, the DNA Damage Response, and Regulation of Transcription Networks. Radiat Res., 187(4): 424-432.
• Liu, Q., Basu, N., Goetz, G., Jiang, N., Hutz, R.J., Tonellato, P.J., Carvan, M.J. 2013. Differential gene expression associated with dietary methylmercury (MeHg) exposure in rainbow trout (Oncorhynchus mykiss) and zebrafish (Danio rerio). Ecotoxicology, 22(4):740-51. doi: 10.1007/s10646-013-1066-9.
• Lohren, H., Blagojevic, L., Fitkau, R., Ebert, F., Schildknecht, S., Leist, M., Schwerdtle, T. 2015. Toxicity of organic and inorganic mercury species in differentiated human neurons and human astrocytes. J. Trace Elem. Med. Biol., 32: 200-8. doi: 10.1016/j.jtemb.2015.06.008.
• Lohren, H., Bornhorst, J., Fitkau, R., Pohl, G., Galla, H.J., Schwerdtle, T. 2016. Effects on and transfer across the blood-brain barrier in vitro-Comparison of organic and inorganic mercury species. BMC Pharmacol Toxicol., 17(1): 63.
• Loikkanen, J., Chvalova, K., Naarala, J., Vдhдkangas, K.H., Savolainen, K.M. 2003. Pb2+-induced toxicity is associated with p53-independent apoptosis and enhanced by glutamate in GT1-7 neurons. Toxicol Lett., 30; 144(2): 235-46.
• Łuczyńska J, Paszczyk B, Łuczyński MJ. 2018. Fish as a bioindicator of heavy metals pollution in aquatic ecosystem of Pluszne Lake, Poland, and risk assessment for consumer's health. Ecotoxicol Environ. Saf., 153: 60-67.
• Malfa, G.A., Tomasello, B., Sinatra, F., Villaggio, G., Amenta, F., Avola, R., Renis, M. 2014. "Reactive" response evaluation of primary human astrocytes after methylmercury exposure. J. Neurosci Res., 92(1): 95-103.
• Marcel, V., Nguyen Van Long, F., Diaz, J.J. 2018. 40 Years of Research Put p53 in Translation. Cancers (Basel), 21: 10(5). pii: E152.
• Mason, A.G., Tomé, S., Simard, J.P., Libby, R.T., Bammler, T.K., Beyer, R.P., Morton, A.J., Pearson, C.E., La Spada, A.R. 2014. Expression levels of DNA replication and repair genes predict regional somatic repeat instability in the brain but are not altered by polyglutamine disease protein expression or age. Hum. Mol. Genet., 23(6): 1606-18.
• Meena, R.A.A., Sathishkumar, P., Ameen, F., Yusoff, A.R.M., Gu, F.L. 2017. Heavy metal pollution in immobile and mobile components of lentic ecosystems-a review. Environ. Sci. Pollut. Res. Int., 25(5): 4134-4148. doi: 10.1007/s11356-017-0966-2.
• Mieiro, C.L., Pacheco, M., Pereira, M.E., Duarte, A.C. 2011. Mercury organotropism in feral European sea bass (Dicentrarchus labrax). Arch. Environ. Contam. Toxicol., 61(1): 135-43. doi: 10.1007/s00244-010-9591-5.
• Miller, S.M., Ballou, D.P., Massey, V., Williams, C.H., Walsh, C.T. 1986. Two-electron reduced mercuric reductase binds Hg(II) to the active site dithiol but does not catalyze Hg(II) reduction. J. Biol. Chem.,261(18): 8081-4.
• Monnet-Tschudi, F., Zurich, M.G., Honegger, P. 1996. Comparison of the developmental effects of two mercury compounds on glial cells and neurons in aggregate cultures of rat telencephalon. Brain Res., 25; 741(1-2): 52-9.
• Naïja A, Kestemont P, Chénais B, Haouas Z, Blust R, Helal AN, Marchand J.2018. Effects of Hg sublethal exposure in the brain of peacock blennies Salaria pavo: Molecular, physiological and histopathological analysis. Chemosphere, 193: 1094-1104. doi: 10.1016/j.chemosphere.2017.11.118
• Obrist, D., Kirk, J.L., Zhang, L. Sunderland EM, Jiskra M, Selin NE. 2018. A review of global environmental mercury processes in response to human and natural perturbations: Changes of emissions, climate, and land use. Ambio., 47(2): 116-140. doi: 10.1007/s13280-017-1004-9.
• Ohgoh, M., Shimizu, H., Ogura, H., Nishizawa, Y. 2000. Astroglial trophic support and neuronal cell death: influence of cellular energy level on type of cell death induced by mitochondrial toxin in cultured rat cortical neurons. Journal of Neurochemistry, 75: 925-933.
• Orihel, D.M., Paterson, M.J., Blanchfield, P.J., Bodaly, R.A. 2007. Hintelmann H. Experimental evidence of a linear relationship between inorganic mercury loading and methylmercury accumulation by aquatic biota. Environ. Sci. Technol., 15; 41(14): 4952-8.
• Patrick, S.M., Turchi, J.J. 1999. Replication protein A (RPA) binding to duplex cisplatin-damaged DNA is mediated through the generation of single-stranded DNA. J. Biol. Chem., 21; 274(21): 14972-8.
• Pereira P, Raimundo J, Araújo O, Canário J, Almeida A, Pacheco M. 2014. Fish eyes and brain as primary targets for mercury accumulation - a new insight on environmental risk assessment. Sci. Total Environ., 8: 494-495.
• Pereira P, Raimundo J, Barata M, Araújo O, Pousão-Ferreira P, Canário J, Almeida A, Pacheco M. 2015. A new page on the road book of inorganic mercury in fish body - tissue distribution and elimination following waterborne exposure and post-exposure periods. Metallomics, 7(3): 525-35.
• Pereira, P., Puga, S., Cardoso, V., Pinto-Ribeiro, F., Raimundo, J., Barata, M., Pousгo-Ferreira, P., Pacheco, M., Almeida, A. 2016. Inorganic mercury accumulation in brain following waterborne exposure elicits a deficit on the number of brain cells and impairs swimming behavior in fish (white seabream-Diplodus sargus). Aquat. Toxicol., 170: 400-412.
• Pereira, P., Korbas, M., Pereira, V., Cappello, T., Maisano, M., Canário, J., Almeida, A., and Pacheco, M. 2019. A multidimensional concept for mercury neuronal and sensory toxicity in fish - From toxicokinetics and biochemistry to morphometry and behavior. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbagen.2019.01.020
• Pirrone, N., Mason, R. 2009. Mercury Fate and Transport in the Global Atmosphere. Emission, Measurements and Models. Elsevier, 637 p
• Pletz, J., Sanchez-Bayo, F., Tennekes, HA. 2016. Dose-response analysis indicating time-dependent neurotoxicity caused by organic and inorganic mercury-Implications for toxic effects in the developing brain. Toxicology, 10; 347-349: 1-5.
• Porter, J.R., Fisher, B.E., Baranello, L., Liu, J.C., Kambach, D.M., Nie, Z., Koh, W.S., Luo, J., Stommel, J.M., Levens, D., Batchelor, E. 2017. Global Inhibition with Specific Activation: How p53 and MYC Redistribute the Transcriptome in the DNA Double-Strand Break Response. Mol. Cell., 21; 67(6): 1013-1025. e9.
• Rensburg, M.J., Rooy, M., Bester, M.J., Serem, J.C., Venter, C., Oberholzer, H.M. 2019. Oxidative and haemostatic effects of copper, manganese and mercury, alone and in combination at physiologically relevant levels: An ex vivo study. Hum. Exp. Toxicol., 38(4): 419-433.
• Rooney, J.P. 2014. The retention time of inorganic mercury in the brain--a systematic review of the evidence. Toxicol. Appl. Pharmacol., 274(3): 425-35.
• Ruff, P., Donnianni, R.A., Glancy, E., Oh, J., Symington, L.S. 2016. RPA Stabilization of Single-Stranded DNA Is Critical for Break-Induced Replication. Cell. Rep., 17(12): 3359-3368.
• Santovito, G., Piccinni, E., Boldrin, F., Irato, P. 2012. Comparative study on metal homeostasis and detoxification in two Antarctic teleosts. Comp. Biochem. Physiol., 155: 580-586.
• Schmid, K., Sassen, A., Staudenmaier, R., Kroemer, S., Reichl, F.X., Harréus, U., Hagen, R., Kleinsasser, N. 2007. Mercuric dichloride induces DNA damage in human salivary gland tissue cells and lymphocytes. Arch. Toxicol., 81: 759-767.
• Sevcikova, M., Modra, H., Blahova, J., Dobsikova, R., Kalina, J., Zitka, O., Kizek, R., Svobodova, Z. 2015. Factors affecting antioxidant response in fish from a long-term mercury-contaminated reservoir. Arch. Environ. Contam. Toxicol., 69(4): 431-9. doi: 10.1007/s00244-015-0213-0.
• Simmons, S.O., Fan, C.Y., Yeoman, K., Wakefield, J., Ramabhadran, R. 2011. NRF2 Oxidative Stress Induced by Heavy Metals is Cell Type Dependent. Curr. Chem. Genomics, 5: 1-12. doi: 10.2174/1875397301105010001.
• Simon, O., Boudou, A. 2001. Direct and trophic contamination of the herbivorous carp Ctenopharyngodon idella by inorganic mercury and methylmercury. Ecotoxicol Environ. Saf., 50(1): 48-59.
• Szunyogh, D., Gyurcsik, B., Larsen, F.H., Stachura, M., Thulstrup, P.W., Hemmingsen, L., Jancsу, A. 2015. Zn(II) and Hg(II) binding to a designed peptide that accommodates different coordination geometries. Dalton Trans., 44(28): 12576-88.
• Takahashi, T., Fujimura, M., Koyama, M., Kanazawa, M., Usuki, F., Nishizawa, M., Shimohata, T. 2017. Methylmercury Causes Blood-Brain Barrier Damage in Rats via Upregulation of Vascular Endothelial Growth Factor Expression. PLoS ONE 12(1): e0170623.
• Taniguchi, J.B., Kondo, K., Fujita, K., Chen, X., Homma, H,. Sudo, T., Mao, Y., Watase, K., Tanaka, T., Tagawa, K., Tamura, T., Muramatsu, S.I., Okazawa, H. 2016. 3RpA1 ameliorates symptoms of mutant ataxin-1 knock-in mice and enhances DNA damage repair. Hum Mol Genet. 20:4432-4447.
• Tolomeo, K. 2016. Joint Commission on hospital accreditation. more on managing hazardous materials and waste. A further examination into EC.02.02.01. Jt. Comm. Perspect., 36(1): 13-4.
• UNEP, Mercury - Time to Act, United Nations Environment Programme, 2013.
• Van der Oost, R., Beyer, J., Vermeulen, N. 2003. Fish bioaccumulation and biomarkers in environmental risk assessment: a review. Environ. Toxicol. Pharmacol., 13: 57-149.
• Vieira, L.R., Gravato, C., Soares, A.M., Morgado, F., Guilhermino, L. 2009. Acute effects of copper and mercury on the estuarine fish Pomatoschistus microps: linking biomarkers to behaviour. Chemosphere, 76(10): 1416-27. doi: 10.1016/j.
• Wang, W-X., Wong, R. S. K. 2003. Bioaccumulation kinetics and exposure pathways of inorganic mercury and methylmercury in a marine fish, the sweetlips Plectorhinchus gibbosus. Marine Ecology Progress Series, 261: 257-268.
• Wang, Y., Wang, D., Lin, L., Wang, M. 2015. Quantitative proteomic analysis reveals proteins involved in the neurotoxicity of marine medaka Oryzias melastigma chronically exposed to inorganic mercury. Chemosphere, 119: 1126-1133.
• Wold, M.S. 1997. Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu Rev Biochem., 66: 61-92.
• Zeng, L., Zheng, J.L., Wang, Y.H., Xu, M.Y., Zhu, A.Y., Wu, C.W. 2016. The role of Nrf2/Keap1 signaling in inorganic mercury induced oxidative stress in the liver of large yellow croaker Pseudosciaena crocea. Ecotoxicol Environ Saf., 132: 345-52. doi: 10.1016/j.ecoenv.2016.05.002.
• Zheng, W., Aschner, M., Ghersi-Egea, J.F. 2003. Brain barrier systems: a new frontier in metal neurotoxicological research. Toxicol Appl Pharmacol., 1; 192(1): 1-11. Zou, L., Elledge, S.J. 2003. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science, 6; 300(5625): 1542-8.