Keywords
asthma
mitochondrial metabolizing enzymes
oxidative stress
apoptotic markers
How to Cite
Abstract
Primary plasticizer used in polyvinyl chloride is diisononyl phthalate (DiNP) and exposure to DiNP has been associated with the development of asthma and allergies. In the current study, how DiNP alters pulmonary antioxidant status, inflammation, energy metabolizing enzymes, oncogenic and apoptotic markers in DiNP-induced asthmatic mice was examined. Male BALB/c mice (n=20, 20-30 g) were divided into 2 groups of 10 mice each: group 1 (control) received saline (0.2ml/kg) orally for 23 days, and group 2 (DiNP) received 50 mg/kg DiNP (Intraperitoneal and intranasal) once per day. After the last administration, mice were sacrificed, lungs were removed and used for biochemical and histopathological analysis. DiNP treated mice experienced alterations in their lung histoarchitecture, levels of oncogenic and apoptotic factors, glycolytic, tricarboxylic acid cycle (TCA), and electron transport chain enzymes (ETC), antioxidant status, and inflammatory biomarkers. DiNP decreased the lungs levels of reduced glutathione and ascorbic acid, and the activities of superoxide dismutase, catalase, and glutathione-s-transferase. In the lungs of DiNP-treated mice compared to the control group, malondialdehyde and inflammatory biomarkers (nitric oxide and myeloperoxidase) were significantly greater (p<0.05). Furthermore, the activities of glycolytic enzymes hexokinase, aldolase, lactate dehydrogenase were downregulated with a concomitant increase in NADase (77%). TCA enzymes and ETC enzymes were significantly reduced as well. CAS-3, p53, Bax, c-MYC, K-Ras increased by 65%, 51%, 70%, 59% and 82% respectively while BCL-2 decreased by 74%. Histopathological analysis revealed distortion of the airway structure characterized by inflammatory cell infiltration, oedema, hemorrhage, and constricted alveoli space. Exposure to DiNP caused oxidative stress which promotes lung inflammation via depletion of antioxidants, pulmonary energy transduction enzymes, levels of oncogenic and apoptotic factors were impaired as well, suggesting that the lungs may not be able to perform its morphological and physiological functions effectively.
References
Abu-Soud, H. M., & Hazen, S. L. (2000). Nitric oxide modulates the catalytic activity of myeloperoxidase. Journal of Biological Chemistry, 275(8), 5425-5430.
https://doi.org/10.1074/jbc.275.8.5425
Annis, M. G., Soucie, E. L., Dlugosz, P. J., Cruz‐Aguado, J. A., Penn, L. Z., Leber, B., & Andrews, D. W. (2005). Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. The EMBO Journal, 24(12), 2096-2103.
https://doi.org/10.1038/sj.emboj.7600675
Aubrey, B. J., Kelly, G. L., Janic, A., Herold, M. J., & Strasser, A. (2018). How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?. Cell Death & Differentiation, 25(1), 104-113.
https://doi.org/10.1038/cdd.2017.169
Bai, L., Zhou, L., Han, W., Chen, J., Gu, X., Hu, Z., ... & Cui, J. (2023). BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists. Journal of Translational Medicine, 21(1), 1-18.
https://doi.org/10.1186/s12967-023-03969-z
Boland, K., Flanagan, L., & Prehn, J. H. (2013). Paracrine control of tissue regeneration and cell proliferation by Caspase-3. Cell Death & Disease, 4(7), e725-e725.
https://doi.org/10.1038/cddis.2013.250
Buege, J. A., & Aust, S. D. (1978). [30] Microsomal lipid peroxidation. In Methods in Enzymology (Vol. 52, pp. 302-310). Academic Press.
https://doi.org/10.1016/S0076-6879(78)52032-6
Chen, J. (2016). The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harbor Perspectives in Medicine, 6(3), a026104.
https://doi.org/10.1101/cshperspect.a026104
Colowick, S.P. (1973). The Hexokinases, in: The Enzymes, 9, Academic Press, 1973, pp. 1– 48.
https://doi.org/10.1016/S1874-6047(08)60113-4
Czabotar, P. E., Lessene, G., Strasser, A., & Adams, J. M. (2014). Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nature Reviews Molecular Cell Biology, 15(1), 49-63.
https://doi.org/10.1038/nrm3722
Da Cunha, M. J., Da Cunha, A. A., Scherer, E. B., Machado, F. R., Loureiro, S. O., Jaenisch, R. B., ... & Wyse, A. T. (2014). Experimental lung injury promotes alterations in energy metabolism and respiratory mechanics in the lungs of rats: prevention by exercise. Molecular and Cellular Biochemistry, 389, 229-238.
https://doi.org/10.1007/s11010-013-1944-8
Dozor, A. J. (2010). The role of oxidative stress in the pathogenesis and treatment of asthma. Ann N Y Acad Sci, 1203:133-137.
https://doi.org/10.1111/j.1749-6632.2010.05562.x
Erb, P., Ji, J., Wernli, M., Kump, E., Glaser, A., & Büchner, S. A. (2005). Role of apoptosis in basal cell and squamous cell carcinoma formation. Immunology Letters, 100(1), 68-72.
https://doi.org/10.1016/j.imlet.2005.06.008
Fischer, A. H., Jacobson, K.A., Rose, J., & Zeller, R. (2008). Cold Spring Harbor Protocols 5 4986 pdb.prot.
https://doi.org/10.1101/pdb.prot073411
Green, L. C., Wagner, D. A., Glogowski, J., Skipper, P. L., Wishnok, J. S., & Tannenbaum, S. R. (1982). Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Analytical Biochemistry, 126(1), 131-138.
https://doi.org/10.1016/0003-2697(82)90118-X
Habig, W. H., Pabst, M. J., & Jakoby, W. B. (1974). Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. Journal of Biological Chemistry, 249(22), 7130-7139.
https://doi.org/10.1016/S0021-9258(19)42083-8
Hafezi, S., & Rahmani, M. (2021). Targeting BCL-2 in cancer: advances, challenges, and perspectives. Cancers, 13(6), 1292.
https://doi.org/10.3390/cancers13061292
Hsieh, T. H., Tsai, C. F., Hsu, C. Y., Kuo, P. L., Lee, J. N., Chai, C. Y., ... & Tsai, E. M. (2012). Phthalates induce proliferation and invasiveness of estrogen receptor‐negative breast cancer through the AhR/HDAC6/c‐Myc signaling pathway. The FASEB Journal, 26(2), 778-787.
https://doi.org/10.1096/fj.11-191742
Huang, K. H., Fang, W. L., Li, A. F. Y., Liang, P. H., Wu, C. W., Shyr, Y. M., & Yang, M. H. (2018). Caspase-3, a key apoptotic protein, as a prognostic marker in gastric cancer after curative surgery. International Journal of Surgery, 52, 258-263.
https://doi.org/10.1016/j.ijsu.2018.02.055
Hwang, Y. H., Paik, M. J., & Yee, S. T. (2017). Diisononyl phthalate induces asthma via modulation of Th1/Th2 equilibrium. Toxicology Letters, 272, 49-59.
https://doi.org/10.1016/j.toxlet.2017.03.014
Jagannathan, V., Singh, K., & Damodaran, M. (1956). Carbohydrate metabolism in citric acid fermentation. 4. Purification and properties of aldolase from Aspergillus niger. Biochemical Journal, 63(1), 94.
https://doi.org/10.1042/bj0630094
Jagota, S. K., & Dani, H. M. (1982). A new colorimetric technique for the estimation of vitamin C using Folin phenol reagent. Analytical Biochemistry, 127(1), 178-182.
https://doi.org/10.1016/0003-2697(82)90162-2
Kehinde, S. A., Olajide A. T., Ore, A., & Ogunsanya, S. T. (2023). Dis¬ruption of Renal Energy Metabolism Dynamics and Histoarchitecture in Di¬isononyl Phthalate-Exposed Wistar Rats. Biomed J Sci & Tech Res 48(4)-2023. BJSTR. MS.ID.007679.
https://doi.org/10.26717/BJSTR.2023.48.007679
Kehinde, S. A., Ore, A., Olajide, A. T., Ajagunna, I. E., Oloyede, F. A., Faniyi, T. O., & Fatoki, J. O. (2022a). Diisononyl phthalate inhibits cardiac glycolysis and oxidative phosphorylation by down-regulating cytosolic and mitochondrial energy metabolizing enzymes in murine model. Advances in Redox Research, 6, 100041.
https://doi.org/10.1016/j.arres.2022.100041
Kehinde, S., Ore, A., Olayinka, E., & Olajide, A. (2022b). Inhibition of hepatic energy metabolizing enzymes in murine model exposed to diisononyl phthalate. Baghdad Journal of Biochemistry and Applied Biological Sciences, 3(04).
https://doi.org/10.47419/bjbabs.v3i04.166
Kim, J. J., Shajib, M. S., Manocha, M. M., & Khan, W. I. (2012). Investigating intestinal inflammation in DSS-induced model of IBD. Journal of Visualized Experiments: JoVE, (60).
Kim, U. H., Han, M. K., Park, B. H., Kim, H. R., & An, N. H. (1993). Function of NAD glycohydrolase in ADP-ribose uptake from NAD by human erythrocytes. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1178(2), 121-126.
https://doi.org/10.1016/0167-4889(93)90001-6
Liao, P. C., Bergamini, C., Fato, R., Pon, L. A., and Pallotti, F. (2020). Isolation of mitochondria from cells and tissues. Methods Cell Biol., 155:3-31.
https://doi.org/10.1016/bs.mcb.2019.10.002
Li, C. H. E. N., Jiao, C. H. E. N., Xie, C. M., Yan, Z. H. A. O., Xiu, W. A. N. G., & Zhang, Y. H. (2015). Maternal disononyl phthalate exposure activates allergic airway inflammation via stimulating the phosphoinositide 3-kinase/Akt pathway in rat pups. Biomedical and Environmental Sciences, 28(3), 190-198.
Liu, G., & Summer, R. (2019). Cellular metabolism in lung health and disease. Annual review of physiology, 81, 403-428.
https://doi.org/10.1146/annurev-physiol-020518-114640
Medja, F., Allouche, S., Frachon, P., Jardel, C., Malgat, M., De Camaret, B. M., ... & Lombès, A. (2009). Development and implementation of standardized respiratory chain spectrophotometric assays for clinical diagnosis. Mitochondrion, 9(5), 331-339.
https://doi.org/10.1016/j.mito.2009.05.001
Misra, H. P., & Fridovich, I. (1972). The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. Journal of Biological Chemistry, 247(10), 3170-3175.
https://doi.org/10.1016/S0021-9258(19)45228-9
Momand, J., Wu, H. H., & Dasgupta, G. (2000). MDM2—master regulator of the p53 tumor suppressor protein. Gene, 242(1-2), 15-29.
https://doi.org/10.1016/S0378-1119(99)00487-4
Moron, M. S., Depierre, J. W., & Mannervik, B. (1979). Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochimica et Biophysica Acta (BBA)-General Subjects, 582(1), 67-78.
https://doi.org/10.1016/0304-4165(79)90289-7
Oishi, H., Takano, K., Tomita, K., Takebe, M., Yokoo, H., Yamazaki, M., & Hattori, Y. (2012). Olprinone and colforsin daropate alleviate septic lung inflammation and apoptosis through CREB‐independent activation of the Akt pathway. American Journal of Physiology Lung Cellular and Molecular Physiology, 303(2), L130–L140.
https://doi.org/10.1152/ajplung.00363.2011
Olajide, A.T., Olayinka, E.T., Ore, A., Kehinde, S.A., & Okoye, C.C. (2023). Ellagic acid alleviates pulmonary inflammation and oxidative stress in mouse model of diisononyl phthalate-induced asthma. Life Sciences, Medicine and Biomedicine, 7(1). https://doi.org/10.28916/lsmb.7.1.2023.110
Papke, B., & Der, C. J. (2017). Drugging RAS: Know the enemy. Science, 355(6330), 1158-1163.
https://doi.org/10.1126/science.aam7622
Pawankar, R. (2014). Allergic diseases and asthma: a global public health concern and a call to action. World Allergy Organization Journal, 7(1), 1-3.
https://doi.org/10.1186/1939-4551-7-12
Romkina, A. Y., & Kiriukhin, M. Y. (2017). Biochemical and molecular characterization of the isocitrate dehydrogenase with dual coenzyme specificity from the obligate methylotroph Methylobacillus Flagellatus. Plos one, 12(4), e0176056.
https://doi.org/10.1371/journal.pone.0176056
Sahiner, U. M., Birben, E., Erzurum, S., Sackesen, C., & Kalayci, Ö. (2018). Oxidative stress in asthma: Part of the puzzle. Pediatric Allergy and Immunology, 29(8), 789-800.
https://doi.org/10.1111/pai.12965
Schmidt, J. J., & Colowick, S. P. (1973). Chemistry and subunit structure of yeast hexokinase isoenzymes. Archives of Biochemistry and Biophysics, 158(2), 458-470.
https://doi.org/10.1016/0003-9861(73)90537-7
Shastri, M. D., Chong, W. C., Dua, K., Peterson, G. M., Patel, R. P., Mahmood, M. Q., Tambuwala, M., Chellappan, D. K., Hansbro, N. G., Shukla, S. D., & Hansbro, P. M. (2021). Emerging concepts and directed therapeutics for the management of asthma: regulating the regulators. Inflammopharmacology, 29(1):15-33.
https://doi.org/10.1007/s10787-020-00770-y
Sinha, A. K. (1972). Colorimetric assay of catalase. Analytical biochemistry, 47(2), 389-394.
https://doi.org/10.1016/0003-2697(72)90132-7
Tang, J., Yuan, Y., Wei, C., Liao, X., Yuan, J., Nanberg, E., ... & Yang, X. (2015). Neurobehavioral changes induced by di (2-ethylhexyl) phthalate and the protective effects of vitamin E in Kunming mice. Toxicology Research, 4(4), 1006-1015.
https://doi.org/10.1039/C4TX00250D
Tang, W., Dong, M., Teng, F., Cui, J., Zhu, X., Wang, W., ... & Wei, Y. (2021). Environmental allergens house dust mite induced asthma is associated with ferroptosis in the lungs. Experimental and Therapeutic Medicine, 22(6), 1-10.
https://doi.org/10.3892/etm.2021.10918
Thompson, C. B. (1995). Apoptosis in the pathogenesis and treatment of disease. Science, 267(5203), 1456-1462.
https://doi.org/10.1126/science.7878464
Thorne, C. J. R. (1962). Properties of mitochondrial malate dehydrogenases. Biochimica et Biophysica Acta, 59(3), 624-633.
https://doi.org/10.1016/0006-3002(62)90642-X
Veeger, C., DerVartanian, D. V., & Zeylemaker, W. P. (1969). [16] Succinate dehydrogenase: [EC 1.3. 99.1 Succinate:(acceptor) oxidoreductase]. In Methods in Enzymology (Vol. 13, pp. 81-90). Academic press.
https://doi.org/10.1016/0076-6879(69)13020-7
Xu, M., Xia, L. P., Fan, L. J., Xue, J. L., Shao, W. W., & Xu, D. (2013). Livin and caspase-3 expression are negatively correlated in cervical squamous cell cancer. European Journal of Gynaecological Oncology, 34(2), 152-155.
Yu, X., Tesiram, Y. A., Towner, R. A., Abbott, A., Patterson, E., Huang, S., ... & Kem, D. C. (2007). Early myocardial dysfunction in streptozotocin-induced diabetic mice: a study using in vivo magnetic resonance imaging (MRI). Cardiovascular Diabetology, 6(1), 1-8.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright (c) 2023 Array