Abstract
Backgrounds
High molecular weight (HMW) hyaluronic acid (HA) is a major component of the extracellular matrix and functions as an anti-inflammatory and anti-permeability agent. Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer in polymers and it is a common endocrine-disrupting compound that is found in the environment. In this study, we aimed to evaluate the effect of HMW-HA on skin disorders caused by DEHP.
Objectives
We determined the effect of HMW-HA on various cellular processes and pathways in HaCaT keratinocytes treated with DEHP.
Results
The results demonstrated that DEHP-induced cell proliferation significantly increased after HMW-HA treatment in HaCaT keratinocytes. Levels of matrix metalloproteinase (MMP)-2, MMP-9, phospho-nuclear factor-kappa B, cyclooxygenase-2, cleaved-caspase-3, and poly-adenosine diphosphate-ribose polymerase were significantly lower in cells exposed to HMW-HA than in DEHP-treated cells. In addition, DEHP-associated phosphorylation of protein kinase B, extracellular signal-regulated kinase 1/2, and p38 was lower in HMW-HA-treated cells than in DEHP-treated cells.
Conclusion
Therefore, our findings provide evidence that HMW-HA treatment involves the anti-inflammatory cell pathways that prevent or mitigate skin disorders caused by exposure to DEHP.
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References
Caldwell JC (2012) DEHP: genotoxicity and potential carcinogenic mechanisms-a review. Mutation Res 751:82–157
Campo GM, Avenoso A, Campo S, D’Ascola A et al (2010a) Molecular size hyaluronan differently modulates toll-like receptor-4 in LPS induced inflammation in mouse chondrocytes. Biochimie 92:204–215
Campo GM, Avenoso A, Campo S, D’Ascola A et al (2010b) Differential effect of molecular mass hyaluronan on lipopolysaccharide-induced damage in chondrocytes. Innate Immun 16:48–63
Chen YWJ, Abatangelo G (1999) Functions of hyaluronan in wound repair. Wound Rep Reg 7:79–89
Cyphert JM, Trempus CS, Garantziotis S (2015) Size matters: molecular weight specificity of hyaluronan effects in cell biology. Int J Cell Biol. https://doi.org/10.1155/2015/563818
Delmage JM, Powars DR, Jaynes PK, Allerton SE (1986) The selective suppression of immunogenicity by hyaluronic acid. Ann Clin Lab Sci 16:303–310
Ewins BA et al (2006) Techniques for quantifying effects of dietary antioxidants on transcription factor translocation and nitric oxide production in cultured cells. Genes Nutr 1:125–131
Gavrilescu M et al (2015) Emerging pollutants in the environment: present and future challenges in biomonitoring, ecological risks and bioremediation. Nature Biotechnol 32:147–156
Ha M et al (2016) Di-(2-ethylhexyl) phthalate inhibits testosterone level through disturbed hypotha-lamic-pituitary-testis axis and ERK-mediated 5α-Reductase 2. Sci Total Environ 563–564:566–575
Halden RU (2010) Plastics and health risks. Annu Rev Publ Health 31(179–194):2010
He YY, Huang JL, Gentry JB, Chignell CF (2003) Epidermal growth factor receptor down-regulation induced by UVA in human keratinocytes does not require the receptor kinase activity. J Biol Chem 278:42457–42465
Jiang D, Liang J, Noble PW (2011) Hyaluronan as an immune regulator in human diseases. Phys Rev 91:221–264
Khokha R, Murthy A, Weiss A (2013) Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 13:649–665
Koniecki D, Wang R, Moody RP, Zhu J (2011) Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure. Environ Res 111:329–336
Laurent TC, Fraser RE (1992) Hyaluronan. FASEB J 6:2397–2404
Li L et al (2007) Growth factor regulation of hyaluronan synthesis and degradation in human dermal fibroblasts: importance of hyaluronan for the mitogenic response of PDGF-BB. Biochem J 404:327–336
McKee CM et al (1996) Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest 98:2403–2413
McKee RH, Butala JH, David RM, Gans G (2004) NTP center for the evaluation of risks to human reproduction reports on phthalates: addressing the data gaps. Reprod Toxicol 18:1–22
Mlynarcikova A, Nagyova E, Fickova M, Scsukova S (2009) Effects of selected endocrine disruptors on meiotic maturation, cumulus expansion, synthesis of hyaluronan and progesterone by porcine oocyte-cumulus complexes. Toxicol in Vitro 23:371–377
Net S et al (2015) Reliable quantification of phthalates in environmental matrices (air, water, sludge, sediment and soil): a review. Sci Total Environ 515–516:162–180
Neumann A et al (1999) High molecular weight hyaluronic acid inhibits advanced glycation endproductinduced NF-κB activation and cytokine expression. FEBS Lett 453:283–287
Liu L, Liu Y, Li J, Du G et al (2011) Microbial production of hyaluronic acid: current state, challenges and perspectives. Microb Cell Fact 10:99
Ockenga W et al (2014) Epidermal growth factor receptor transactivation is required for mitogen-activated protein kinase activation by muscarinic acetylcholine receptors in HaCaT keratinocytes. Int J Mol Sci 15:21433–21454
Oksala O et al (1995) Expression of proteoglycans and hyaluronan during wound healing. J Histochem Cytochem 43:125–135
Pan TL et al (2014) Dermal toxicity elicited by phthalates: evaluation of skin absorption, immunohistology, and functional proteomics. Food ChemToxicol 65:105–114
Price RD, Berry MG, Navsaria HA (2007) Hyaluronic acid: the scientific and clinical evidence. J Plastic, Reconstr Aesthet Surg 60:1110–1119
Qin L et al (2014) Inhibition of smooth muscle cell proliferation by ezetimibe via the cyclin D1-MAPK pathway. J Pharmacol Sci 125:283–291
Qiang J, Christos CZ (2016) Endocrine-disrupting chemicals and skin manifestations. Rev Endocr Metab Dis 17:449–457
Rayahin JE et al (2015) High and low molecular weight hyaluronic acid differentially influences macrophage activation. ACS Biomaterials Sci Eng 1:481–493
Rundhaug JE, Fischer SM (2008) Cyclo-oxygenase-2 Plays a Critical Role in UV-induced Skin Carcinogenesis. Photochem Photobiol 84:322–329
Sathyanarayana S et al (2008) Baby care products: possible sources of infant phthalate exposure. Pediatr 121:e260–e268
Strozyk E, Kulms D (2013) The role of AKT/mTOR pathway in stress response to UV-irradiation: implication in skin carcinogenesis by regulation of apoptosis, autophagy and senescence. Int J Mol Sci 14:15260–15285
Sugahara K, Schwartz NB, Dorfman A (1979) Biosynthesis of hyaluronic acid by Streptococcus. J Biol Chem 254:6252–6261
Takahashi K et al (2000) Effect of hyaluronan on chondrocyte apoptosis and nitric oxide production in experimentally induced osteoarthritis. J Rheumatol 27:1713–1720
Tomaszewski KE, Heindel SW, Jenkins WL, Melnick RL (1990) Induction of peroxisomal acyl CoA oxidase activity and lipid peroxidation in primary rat hepatocyte cultures. Toxicol 65:49–60
Tseng IL et al (2013) Phthalates induce neurotoxicity affecting locomotor and thermotactic behaviors and AFD neurons through oxidative stress in caenorhabditis elegans. PLoS ONE 8:82657
Tzellos TG, Sinopidis X, Kyrgidis A, Vahtsevanos K et al (2011) Differential hyaluronan homeostasis and expression of proteoglycans in juvenile and adult human skin. J Dermatol Sci 61:69–72
Wang IJ, Karmaus WJ (2015) The effect of phthalate exposure and filaggrin gene variants on atopic dermatitis. Environ Res 136:213–218
Young CN et al (2008) Reactive oxygen species in tumor necrosis factor-α-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease. J Invest Dermatol 128:2606–2614
Yu HM, Stephanopoulos G (2008) Metabolic engineering of Escherichia coli for biosynthesis of hyaluronic acid. Metab Eng 10:24–32
Yuan L et al (2013) MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells. Food Chem Toxicol 53:62–68
Zhang R et al (2017) Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway. Oncol Lett 14:4305–4310
Acknowledgements
This study was supported by a National Research Foundation of Korea grant (no. 2017R1D1A1B03034223) founded by the Korean government.
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JHK conceived and designed the experiments, performed the experiments, analyzed the data, and wrote the paper.
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Kim, J.H. Hyaluronic acid suppresses the effect of di-(2-ethylhexyl) phthalate in HaCaT keratinocytes. Mol. Cell. Toxicol. 18, 549–556 (2022). https://doi.org/10.1007/s13273-022-00227-z
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DOI: https://doi.org/10.1007/s13273-022-00227-z