Skip to main content
Log in

Hyaluronic acid suppresses the effect of di-(2-ethylhexyl) phthalate in HaCaT keratinocytes

  • Original Article
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Caldwell JC (2012) DEHP: genotoxicity and potential carcinogenic mechanisms-a review. Mutation Res 751:82–157

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Chen YWJ, Abatangelo G (1999) Functions of hyaluronan in wound repair. Wound Rep Reg 7:79–89

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Delmage JM, Powars DR, Jaynes PK, Allerton SE (1986) The selective suppression of immunogenicity by hyaluronic acid. Ann Clin Lab Sci 16:303–310

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Halden RU (2010) Plastics and health risks. Annu Rev Publ Health 31(179–194):2010

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Jiang D, Liang J, Noble PW (2011) Hyaluronan as an immune regulator in human diseases. Phys Rev 91:221–264

    CAS  Google Scholar 

  • Khokha R, Murthy A, Weiss A (2013) Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 13:649–665

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Laurent TC, Fraser RE (1992) Hyaluronan. FASEB J 6:2397–2404

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Oksala O et al (1995) Expression of proteoglycans and hyaluronan during wound healing. J Histochem Cytochem 43:125–135

    Article  CAS  PubMed  Google Scholar 

  • Pan TL et al (2014) Dermal toxicity elicited by phthalates: evaluation of skin absorption, immunohistology, and functional proteomics. Food ChemToxicol 65:105–114

    Article  CAS  Google Scholar 

  • Price RD, Berry MG, Navsaria HA (2007) Hyaluronic acid: the scientific and clinical evidence. J Plastic, Reconstr Aesthet Surg 60:1110–1119

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Qiang J, Christos CZ (2016) Endocrine-disrupting chemicals and skin manifestations. Rev Endocr Metab Dis 17:449–457

    Article  CAS  Google Scholar 

  • Rayahin JE et al (2015) High and low molecular weight hyaluronic acid differentially influences macrophage activation. ACS Biomaterials Sci Eng 1:481–493

    Article  CAS  Google Scholar 

  • Rundhaug JE, Fischer SM (2008) Cyclo-oxygenase-2 Plays a Critical Role in UV-induced Skin Carcinogenesis. Photochem Photobiol 84:322–329

    Article  CAS  PubMed  Google Scholar 

  • Sathyanarayana S et al (2008) Baby care products: possible sources of infant phthalate exposure. Pediatr 121:e260–e268

    Article  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sugahara K, Schwartz NB, Dorfman A (1979) Biosynthesis of hyaluronic acid by Streptococcus. J Biol Chem 254:6252–6261

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K et al (2000) Effect of hyaluronan on chondrocyte apoptosis and nitric oxide production in experimentally induced osteoarthritis. J Rheumatol 27:1713–1720

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Wang IJ, Karmaus WJ (2015) The effect of phthalate exposure and filaggrin gene variants on atopic dermatitis. Environ Res 136:213–218

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu HM, Stephanopoulos G (2008) Metabolic engineering of Escherichia coli for biosynthesis of hyaluronic acid. Metab Eng 10:24–32

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a National Research Foundation of Korea grant (no. 2017R1D1A1B03034223) founded by the Korean government.

Author information

Authors and Affiliations

Authors

Contributions

JHK conceived and designed the experiments, performed the experiments, analyzed the data, and wrote the paper.

Corresponding author

Correspondence to Jin Hee Kim.

Ethics declarations

Conflict of interest

JHK states that there are no conflicts of interest to disclose.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-022-00227-z

Keywords

Navigation