Polystyrene microplastic-induced endoplasmic reticulum stress contributes to growth plate endochondral ossification disorder in young rat.

Publisher: John Wiley & Sons Country of Publication: United States NLM ID: 100885357 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-7278 (Electronic) Linking ISSN: 15204081 NLM ISO Abbreviation: Environ Toxicol Subsets: MEDLINE

Original Publication: New York, NY : John Wiley & Sons, c1999-

Endoplasmic Reticulum Stress*/drug effects ; Growth Plate*/drug effects ; Growth Plate*/pathology ; Microplastics*/toxicity ; Polystyrenes*/toxicity; Animals ; Female ; Rats ; Rats, Sprague-Dawley ; Osteogenesis/drug effects ; Chondrocytes/drug effects ; Tibia/drug effects ; Tibia/pathology

Background: Previous studies on the effects of microplastics (MPs) on bone in early development are limited. This study aimed to investigate the adverse effects of MPs on bone in young rats and the potential mechanism.
Methods: Three-week-old female rats were orally administered MPs for 28 days, and endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL) and ER stress agonist tunicamycin (TM) were added to evaluate the effect of ER stress on toxicity of MPs. The indicators of growth and plasma markers of bone turnover were evaluated. Tibias were analyzed using micro-computed tomography (micro-CT). Histomorphological staining of growth plates was performed, and related gene expression of growth plate chondrocytes was tested.
Results: After exposure of MPs, the rats had decreased growth, shortened tibial length, and altered blood calcium and phosphorus metabolism. Trabecular bone was sparse according to micro-CT inspection. In the growth plate, the thickness of proliferative zone substantial reduced while the thickness of hypertrophic zone increased significantly, and the chondrocytes were scarce and irregularly arranged according to tibial histological staining. The transcription of the ER stress-related genes BIP, PERK, ATF4, and CHOP dramatically increased, and the transcription factors involved in chondrocyte proliferation, differentiation, apoptosis, and matrix secretion were aberrant according to RT-qPCR and western blotting. Moreover, the addition of TM showed higher percentage of chondrocyte death. Administration of SAL alleviated all of the MPs-induced symptoms.
Conclusion: These results indicated that MPs could induce growth retardation and longitudinal bone damage in early development. The toxicity of MPs may attribute to induced ER stress and impaired essential processes of the endochondral ossification after MPs exposure.
(© 2024 Wiley Periodicals LLC.)

Geyer R. Production, use, and fate of synthetic polymers. In: Letcher TM, ed. Plastic Waste and Recycling. Elsevier; 2020:13‐32.
Wallace HM, Alexander J, Barregård L. Presence of microplastics and nanoplastics in food, with particular focus on seafood. EFSA J. 2016;14(6):e04501.
Muncke J, Andersson A‐M, Backhaus T, et al. Impacts of food contact chemicals on human health: a consensus statement. Environ Health. 2020;19(1):25.
Li D, Shi Y, Yang L, et al. Microplastic release from the degradation of polypropylene feeding bottles during infant formula preparation. Nat Food. 2020;1(11):746‐754.
Cox KD, Covernton GA, Davies HL, Dower JF, Juanes F, Dudas SE. Human consumption of microplastics. Environ Sci Technol. 2019;53(12):7068‐7074.
Ramsperger A, Narayana VKB, Gross W, et al. Environmental exposure enhances the internalization of microplastic particles into cells. Sci Adv. 2020;6(50):eabd1211.
Shi X, Wang X, Huang R, et al. Cytotoxicity and genotoxicity of polystyrene micro‐ and nanoplastics with different size and surface modification in A549 cells. Int J Nanomedicine. 2022;17:4509‐4523.
Leslie HA, Van Velzen MJ, Brandsma SH, Vethaak AD, Garcia‐Vallejo JJ, Lamoree MH. Discovery and quantification of plastic particle pollution in human blood. Environ Int. 2022;163:107199.
Amato‐Lourenço LF, Carvalho‐Oliveira R, Júnior GR, dos Santos GL, Ando RA, Mauad T. Presence of airborne microplastics in human lung tissue. J Hazard Mater. 2021;416:126124.
Ragusa A, Svelato A, Santacroce C, et al. Plasticenta: first evidence of microplastics in human placenta. Environ Int. 2021;146:106274.
Pan C, Wu Y, Hu S, et al. Polystyrene microplastics arrest skeletal growth in puberty through accelerating osteoblast senescence. Environ Pollut. 2023;322:121217.
Wang Z, Liang H, Tu X, et al. Bisphenol A and pubertal height growth in school‐aged children. J Expo Sci Environ Epidemiol. 2019;29(1):109‐117.
Xu X, Tang Y, Lang Y, et al. Oral exposure to ZnO nanoparticles disrupt the structure of bone in young rats via the OPG/RANK/RANKL/IGF‐1 pathway. Int J Nanomedicine. 2020;15:9657‐9668.
Lind T, Lejonklou MH, Dunder L, et al. Low‐dose developmental exposure to bisphenol A induces sex‐specific effects in bone of Fischer 344 rat offspring. Environ Res. 2017;159:61‐68.
Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423(6937):332‐336.
Lui JC, Nilsson O, Baron J. Recent research on the growth plate: recent insights into the regulation of the growth plate. J Mol Endocrinol. 2014;53(1):T1‐T9.
Geister KA, Camper SA. Advances in skeletal dysplasia genetics. Annu Rev Genomics Hum Genet. 2015;16:199‐227.
Deng Y, Zhang Y, Lemos B, Ren H. Tissue accumulation of microplastics in mice and biomarker responses suggest widespread health risks of exposure. Sci Rep. 2017;7(1):46687.
Schirinzi GF, Pérez‐Pomeda I, Sanchís J, Rossini C, Farré M, Barceló DJER. Cytotoxic effects of commonly used nanomaterials and microplastics on cerebral and epithelial human cells. Environ Res. 2017;159:579‐587.
Lavers JL, Hutton I, Bond AL. Clinical pathology of plastic ingestion in marine birds and relationships with blood chemistry. Environ Sci Technol. 2019;53(15):9224‐9231.
Jiang S, Guo W, Tian G, et al. Clinical application status of articular cartilage regeneration techniques: tissue‐engineered cartilage brings new hope. Stem Cells Int. 2020;2020:5690252.
Li M, Yin H, Yan Z, et al. The immune microenvironment in cartilage injury and repair. Acta Biomater. 2022;140:23‐42.
Peng Z, Sun H, Bunpetch V, et al. The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials. 2021;268:120555.
Xue X, Piao J‐H, Nakajima A, et al. Tumor necrosis factor α (TNFα) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)‐dependent fashion, and the UPR counteracts ROS accumulation by TNFα. J Biol Chem. 2005;280(40):33917‐33925.
Görlach A, Klappa P, Kietzmann T. The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal. 2006;8(9–10):1391‐1418.
Tsang KY, Chan D, Cheslett D, et al. Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function. PLoS Biol. 2007;5(3):e44.
Quinn R. Comparing rat's to human's age: how old is my rat in people years? Nutrition. 2005;21(6):775‐777.
Su L, Xue Y, Li L, et al. Microplastics in taihu lake, China. Environ Pollut. 2016;216:711‐719.
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27.
Qiao J, Chen R, Wang M, et al. Perturbation of gut microbiota plays an important role in micro/nanoplastics‐induced gut barrier dysfunction. Nanoscale. 2021;13(19):8806‐8816.
Liu D, Zhang Y, Li X, et al. eIF2α si\gnaling regulates ischemic osteonecrosis through endoplasmic reticulum stress. Sci Rep. 2017;7(1):1‐14.
Xing Y, Ge Y, Liu C, Zhang X, Jiang J, Wei YJO. ER stress inducer tunicamycin suppresses the self‐renewal of glioma‐initiating cell partly through inhibiting Sox2 translation. Oncotarget. 2016;7(24):36395.
Chen B, Hong W, Tang Y, Zhao Y, Aguilar ZP, Xu H. Protective effect of the NAC and Sal on zinc oxide nanoparticles‐induced reproductive and development toxicity in pregnant mice. Food Chem Toxicol. 2020;143:111552.
Wang W, Guan J, Feng Y, et al. Polystyrene microplastics induced nephrotoxicity associated with oxidative stress, inflammation, and endoplasmic reticulum stress in juvenile rats. Front Nutr. 2022;9:1059660.
Mashmoul M, Azlan A, Yusof BNM, Khaza'ai H, Mohtarrudin N, Boroushaki MT. Effects of saffron extract and crocin on anthropometrical, nutritional and lipid profile parameters of rats fed a high fat diet. J Funct Foods. 2014;8:180‐187.
Organization WH. WHO Calls for More Research into Microplastics and a Crackdown on Plastic Pollution. World Health Organization (WHO); 2019.
Zhang H, Ricciardi BF, Yang X, Shi Y, Camacho NP, Bostrom MG. Polymethylmethacrylate particles stimulate bone resorption of mature osteoclasts in vitro. Acta Orthop. 2008;79(2):281‐288.
Ormsby RT, Cantley M, Kogawa M, et al. Evidence that osteocyte perilacunar remodelling contributes to polyethylene wear particle induced osteolysis. Acta Biomater. 2016;33:242‐251.
Liu A, Richards L, Bladen CL, Ingham E, Fisher J, Tipper JL. The biological response to nanometre‐sized polymer particles. Acta Biomater. 2015;23:38‐51.
Feng Y, Yuan H, Wang W, et al. Co‐exposure to polystyrene microplastics and lead aggravated ovarian toxicity in female mice via the PERK/eIF2alpha signaling pathway. Ecotoxicol Environ Saf. 2022;243:113966.
Ciosek Z, Kot K, Kosik‐Bogacka D, Lanocha‐Arendarczyk N, Rotter I. The effects of calcium, magnesium, phosphorus, fluoride, and Lead on bone tissue. Biomolecules. 2021;11(4):506.
Anderson JJ, Adatorwovor R, Roggenkamp K, Suchindran CM. Lack of influence of calcium/phosphorus ratio on hip and lumbar bone mineral density in older Americans: NHANES 2005‐2006 cross‐sectional data. J Endocr Soc. 2017;1(5):407‐414.
Cheng W, Xu X, Lang Y, et al. Anatase and rutile TiO2 nanoparticles lead effective bone damage in young rat model via the igf‐1 signaling pathway. Int J Nanomedicine. 2021;16:7233‐7247.
Ning B, Londono I, Laporte C, Villemure I. Validation of an in vivo micro‐CT‐based method to quantify longitudinal bone growth of pubertal rats. Bone. 2022;154:116207.
Zhang ZM, Li ZC, Jiang LS, Jiang SD, Dai LY. Micro‐CT and mechanical evaluation of subchondral trabecular bone structure between postmenopausal women with osteoarthritis and osteoporosis. Osteoporos Int. 2009;21(8):1383‐1390.
Mackie E, Ahmed Y, Tatarczuch L, Chen K‐S, Mirams M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol. 2008;40(1):46‐62.
Álvarez‐García Ó, García‐López E, Loredo V, et al. Rapamycin induces growth retardation by disrupting angiogenesis in the growth plate. Kidney Int. 2010;78(6):561‐568.
Kang X, Yang W, Feng D, et al. Cartilage‐specific autophagy deficiency promotes ER stress and impairs chondrogenesis in PERK‐ATF4‐CHOP–dependent manner. J Bone Miner Res. 2017;32(10):2128‐2141.
Hecht JT, Nelson LD, Crowder E, et al. Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet. 1995;10(3):325‐329.
Spiess M, Rutishauser J. Endoplasmic reticulum storage diseases. Swiss Med Wkly. 2002;132(1718):211‐222.
Pan L, Yu D, Zhang Y, et al. Polystyrene microplastics‐triggered mitophagy and oxidative burst via activation of PERK pathway. Sci Total Environ. 2021;781:146753.
Chen Y, Yang Y, Miller ML, et al. Hepatocyte‐specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Hepatology. 2007;45(5):1118‐1128.
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519‐529.
Cameron TL, Bell KM, Gresshoff IL, et al. XBP1‐independent UPR pathways suppress C/EBP‐β mediated chondrocyte differentiation in ER‐stress related skeletal disease. PLoS Genet. 2015;11(9):e1005505.
Wang C, Tan Z, Niu B, et al. Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia. Elife. 2018;7:e37673.
Tan L, Register TC, Yammani RRJA. Age‐related decline in expression of molecular chaperones induces endoplasmic reticulum stress and chondrocyte apoptosis in articular cartilage. Aging Dis. 2020;11(5):1091.
Kwan Tat S, Amiable N, Pelletier JP, et al. Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis. Rheumatology. 2009;48(12):1482‐1490.
Xiong J, Piemontese M, Onal M, et al. Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. PLoS One. 2015;10(9):e0138189.
Meijome TE, Hooker RA, Cheng YH, et al. GATA‐1 deficiency rescues trabecular but not cortical bone in OPG deficient mice. J Cell Physiol. 2015;230(4):783‐790.

20224ACB206013 Jiangxi Province Natural Science Foundation of China-Key Program; Z-2019-41-2201 Special Academic Exchange Fund for China Children's Growth and Development and Scientific Research Fund for Young Pediatric Endocrinologists

Keywords: endochondral ossification disorder; growth plates; microplastics; young period

Date Created: 20240305 Date Completed: 20240515 Latest Revision: 20240515

20240515

10.1002/tox.24182

38440912