Expression of calmodulin-related genes in lead-exposed mice

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The toxic metal lead is a widespread environmental polutant that can adversely affect human health. However, the underlying mechanisms of lead-induced toxicity are still largely unknown. The mechanism of lead toxicity was presumed to involve cross reaction between Pb2+ and Ca2+ with calmodulin dependent systems. The aim of the present study was thus to identify differential expression of calmodulin-related genes in the spleen of lead-exposed mice. We performed microarray analysis to identify differentially expressed genes. RNAs from spleen tissue of lead exposed animals (n=6) and controls (n=6) were converted to labeled cRNA and hybridized to Illumina mouse WG-6_v2_Bead Chip. Expression profiles were analyzed using Illumina BeadStudio Application. Real-time RT-PCR was conducted to validate the microarray data. By microarray analysis 5 calmodulin-related genes (MAP2K6, CAMKK2, CXCR4, PHKA2, MYLK) were found to be differently expressed in lead exposed compared with control mice (p<0.05). The results of Real-time RT-PCR showed that MAP2K6 and CAMKK2 were up-regulated and CXCR4 was down-regulated in lead exposure, but there were no significant differences in PHKA2 and MYLK expression between the lead exposed and control group. These results show that lead exposure produced significant changes in expression of a variety of genes in the spleen and can affect calmodulin-related gene expression.

Bussolaro D, Filipak NF, Gargioni R, Fernandes LC, Randi MA, Pelletier E. (2008). The immune response of peritoneal macrophages due to exposure to inorganic lead in the house mouse Mus musculus. Toxicol In Vitro 22: 254–260.

Chen YY, Lee MH, Hs u CC, Wei CL, Tsai YC. (2012). Methyl cinnamate inhibits adipocyte differentiation via activation of the CaMKK2-AMPK pathway in 3T3 -L1 preadipocytes. J Agric Food Chem 60: 955–963.

Cui Y, Zhu YG, Zhai R, Huang Y, Qiu Y, Liang J. (2005). Exposure to metal mixtures and human health impacts in a contaminated area in Nanning, China. Environ Int 31: 784–790.

DeLuca J, Hardy CA, Burright RG, Donovick PJ, Tuggy RL. (1982). The effects of dietary fat and lead ingestion on blood lead levels in mice. J Toxicol Environ Health 3: 441–447.

Fernandis AZ, Cherla RP, Ganju RK. (2003). Differential regulation of CXCR4-mediated T-cell chemotaxis and mitogen-activated protein kinase activation by the membrane tyrosine phosphatase, CD45. J Bio Chem 278: 9536–9543.

García-Lestón J, Roma-Torres J, Mayan O, Schroecksnadel S, Fuchs D, Moreira AO. (2012). Assessment of immunotoxicity parameters in individuals occupationally exposed to lead. J Toxico l Environ Health A 75: 807–818.

Gardner OS, Shiau CW, Chen CS, Graves LM. (2005). Peroxisome proliferator-activated receptor gamma-independent activation of p38 MAPK by thiazolidinediones involves calcium/calmodulin-dependent protein kinase II and protein kinase R: correlation with endoplasmic reticulum stress. J Bio Chem 280: 10109–1011.

Hossain MA, Bouton CM, Pevsner J, Laterra J. (2000). Induction of vascular endothelial growth factor in human astrocytes by lead. Involvement of a protein kinase C/activator protein-1 complex-dependent and hypoxiainducible factor 1-independent signaling pathway. J Biolog Chem 275: 27874–27882.

Katsumoto K, Kume S. (2011). Endoderm and mesoderm reciprocal signaling mediated by CXCL12 and CXCR4 regulates the migration of angioblasts and establishes the pancreatic fate. Development 138: 1947–1955.

Kern M, Wisniewski M, Cabell L, Audesirk G. (2000). Inorganic lead and calcium interact positively in activation of calmodulin. Neurotoxicology 21: 353–363.

Kirberger M, Wong HC, Jiang J, Yang JJ. (2013). Metal toxicity and opportunistic binding of Pb(2+) in proteins. J Inorg Biochem 125: 40–49.

Mainiero F, Colombara M, Antonini V, Strippoli R, Merola M, Poffe O. (2003). p38 MAPK is a critical regulator of the constitutive and the beta 4 integrin-regulated expression of IL-6 in human normal thymic epithelial cells. Eur J Immunol 33: 3038–3048.

Mishra KP, Singh VK, Rani R, Yadav VS, Chandran V, Srivastava SP. (2003). Effect of lead exposure on the immune response of some occupationally exposed individuals. Toxicology 188: 251–259.

Racioppi L, Means AR. (2012). Calcium/calmodulin-dependent protein kinase 2: roles in signaling and pathophysiology. J Bio Chem 287: 31658–31665.

Simons T. (1986). Cellular interactions between lead and calcium. Br Med Bulletin 42: 431–434.

Sun L, Zhao ZY, Hu J, Zhou XL. (2005). Potential association of lead exposure during early development of mice with alteration of hippocampus nitric oxide levels and learning memory. Biomed Environ Sci 6: 375–378.

Sun L, Zhao ZY, Liang GQ, Jian SJ, Yuan H. (2012). Effects of lead on calmodulin content, proliferation and interleukin-2 in lymphocytes of mice. Toxicol Environ Chem 94: 958–964.

Taylor MP, Winder C, Lanphear BP. (2014). Australia’s leading public health body delays action on the revision of the public health goal for blood lead exposures. Environ Int 70C: 113–117.

Toscano CD, O’Callaghan JP, Guilarte TR. (2005). Calcium/calmodulin-dependent protein kinase II activity and expression are altered in the hippocampus of Pb-exposed rats. Brain Res 1044: 51–58.

Wang W, Duan B, Xu H, Xu L, Xu TL. (2006). Calcium-permeable acid-sensing ion channel is a molecular target of the neurotoxic metal ion lead. J Bio Chem 281: 2497–2505.

Zhu ZW, Yang RL, Dong GJ, Zhao ZY. (2005). Study on the neurotoxic effects of low-level lead exposure in rats. J Zhejiang Univ Sci B 7: 686–692.

Interdisciplinary Toxicology

The Journal of Institute of Experimental Pharmacology of Slovak Academy of Sciences

Journal Information

CiteScore 2017: 2.36

SCImago Journal Rank (SJR) 2017: 0.580
Source Normalized Impact per Paper (SNIP) 2017: 1.134


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