Skip to main content
Log in

Assessment of agonistic and antagonistic properties of humidifier disinfectants to the estrogenic and androgenic receptors by transactivation assay

  • Original Article
  • Published:
Toxicological Research Aims and scope Submit manuscript

Abstract

Before being recalled and banned from the Korean market, humidifier disinfectants (HDs) were added to the humidifier water tank to prevent microbial growth. The known HDs active ingredients included the are oligo(2-(2-ethoxy)ethoxyethyl guanidine (PGH), polyhexamethylene guanidine (PHMG), a mixture of methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT), didecyldimethyl ammonium chloride (DDAC), Sodium dichloroisocyanurate (NaDCC), and alkyldimethylbenzyl ammonium chloride (BAC). Previous epidemiological studies have suggested that PHMG induces fatal lung disease in pregnant, post-partum women, and young children. In an animal study, a mixture of DDAC and BAC exhibited decreased fertility and fecundity; increased time to first litter, longer pregnancy intervals, fewer pups per litter, and fewer pregnancies. In this study, endocrine-disrupting effects of HDs were investigated using estrogen receptor (ER) and androgen receptor (AR) transactivation assay based on OECD Test guidelines. Unexpectedly, unlike the previously reported reproductive toxicity data, in the present study, HDs did not show ER and AR transcriptional activation agonist and/or antagonist effects. However, it is difficult to conclude that HDs has no endocrine disruption effects, and further research on the effects of HDs mixtures, and in vivo tests including Uterotrophic bioassay and Hershberger bioassay would be necessary.

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.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Paek D, Koh Y, Park DU, Cheong HK, Do KH, Lim CM, Hong SJ, Kim YH, Leem JH, Chung KH, Choi YY, Lee JH, Lim SY, Chung EH, Cho YA, Chae EJ, Joh JS, Yoon Y, Lee KH, Choi BY, Gwack J (2015) Nationwide study of humidifier disinfectant lung injury in South Korea 1994–2011. incidence and dose-response relationships. Annals Am Thorac Soc 12:1813–1821. https://doi.org/10.1513/AnnalsATS.201504-221OC

    Article  Google Scholar 

  2. Park DU, Ryu SH, Lim HK, Kim SK, Choi YY, Ahn JJ, Lee E, Hong SB, Do KH, Cho JL, Bae MJ, Shin DC, Paek DM, Hong SJ (2017) Types of household humidifier disinfectant and associated risk of lung injury (HDLI) in South Korea. Sci Total Environ 596–597:53–60. https://doi.org/10.1016/j.scitotenv.2017.04.040

    Article  CAS  PubMed  Google Scholar 

  3. Park K (2016) An analysis of a humidifier disinfectant case from a toxicological perspective. Environ Health Toxicol 31:e2016013. https://doi.org/10.5620/eht.e2016013

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lee JH, Lee JH (2017) Humidifier disinfectant-associated specific diseases should be called together as “humidifier disinfectant syndrome.” Environ Health Toxicol 32:e2017017. https://doi.org/10.5620/eht.e2017017

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kim HR, Hwang GW, Naganuma A, Chung KH (2016) Adverse health effects of humidifier disinfectants in Korea: lung toxicity of polyhexamethylene guanidine phosphate. J Toxicol Sci 41:711–717. https://doi.org/10.2131/jts.41.711

    Article  CAS  PubMed  Google Scholar 

  6. Lee SJ, Park JH, Lee JY, Jeong YJ, Song JA, Lee KH, Kim DJ (2016) Establishment of a mouse model for pulmonary inflammation and fibrosis by intratracheal instillation of polyhexamethyleneguanidine phosphate. J Toxicol Pathol 29:95–102. https://doi.org/10.1293/tox.2015-0067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Song JA, Kim WJ, Kim YB, Kim BS, Lee KH (2018) Time course of polyhexamethyleneguanidine phosphate-induced lung inflammation and fibrosis in mice. Toxicol Appl Pharmacol 345:94–102. https://doi.org/10.1016/j.taap.2018.02.013

    Article  CAS  PubMed  Google Scholar 

  8. Park DU, Park JH, Yang KW, Park JH, Kwon JH, Oh HB (2020) Properties of polyhexamethylene guanidine (PHMG) associated with fatal lung injury in Korea. Molecules 25:3301–3313. https://doi.org/10.3390/molecules25143301

    Article  CAS  PubMed Central  Google Scholar 

  9. Cho HJ, Lee SY, Park DU, Ryu SH, Yoon JS, Jung SS, Lee E, Yang SI, Hong SJ (2019) Early-life exposure to humidifier disinfectant determines the prognosis of lung function in children. BMC Pulm Med 19:261–271. https://doi.org/10.1186/s12890-019-1028-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim MS, Kim SH, Jeon D, Kim HY, Lee K (2018) Changes in expression of cytokines in polyhexamethylene guanidine-induced lung fibrosis in mice: comparison of bleomycin-induced lung fibrosis. Toxicology 393:185–192. https://doi.org/10.1016/j.tox.2017.11.017

    Article  CAS  PubMed  Google Scholar 

  11. Hu HH, Chen DQ, Wang TN, Feng YL, Cao G, Vaziri ND, Zhao YY (2018) New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact 292:76–83. https://doi.org/10.1016/j.cbi.2018.07.008

    Article  CAS  PubMed  Google Scholar 

  12. Zhu X, Kong X, Ma S, Liu R, Li X, Gao S, Ren D, Zheng Y, Tang J (2020) TGFβ/Smad mediated the polyhexamethyleneguanide areosol-induced irreversible pulmonary fibrosis in subchronic inhalation exposure. Inhal Toxicol 32:419–430. https://doi.org/10.1080/08958378.2020.1836091

    Article  CAS  PubMed  Google Scholar 

  13. Park J, Lee H, Park K (2019) Eye irritation tests of polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) using a tissue model of reconstructed human cornea-like epithelium. Environ Health Toxicol 34:e2019004. https://doi.org/10.5620/eht.e2019004

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lee H, Park J, Park K (2021) Fibrosis as a result of polyhexamethylene guanide exposure in cultured Statens Seruminstitut Rabbit Cornea (SIRC) cells. Environ Anal Health Toxicol 36:e2021009. https://doi.org/10.5620/eaht.2021009

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kim H, Ji K (2019) Exposure to humidifier disinfectants induces developmental effects and disrupts thyroid endocrine systems in zebrafish larvae. Ecotoxicol Environ Saf 184:109663. https://doi.org/10.1016/j.ecoenv.2019.109663

    Article  CAS  PubMed  Google Scholar 

  16. OECD (2021) Test guideline no 455, performance-based test guideline for stably transfected transactivation in vitro assays to detect estrogen receptor agonists and antagonists. https://www.oecd.org/chemicalsafety/testing/oecdguidelinesforthetestingofchemicals.htm

  17. Yamasaki K, Takeyoshi M, Yakabe Y, Sawaki M, Imatanaka N, Takatsuki M (2002) Comparison of reporter gene assay and immature rat uterotrophic assay of twenty-three chemicals. Toxicology 170:21–30. https://doi.org/10.1016/s0300-483x(01)00505-4

    Article  CAS  PubMed  Google Scholar 

  18. Park C, Song H, Choi J, Sim S, Kojima H, Park J, Iida M, Lee Y (2020) The mixture effects of bisphenol derivatives on estrogen receptor and androgen receptor. Environ Pollut 260:114036. https://doi.org/10.1016/j.envpol.2020.114036

    Article  CAS  PubMed  Google Scholar 

  19. OECD (2020) Test guideline 458. Androgen receptor transactivation assays for detection of androgenic agonist and antagonist activity of chemicals using stably transfected cell lines. https://www.oecd.org/chemicalsafety/testing/oecdguidelinesforthetestingofchemicals.htm

  20. Sun S, Park E, Choi Y, Lee H, Ahn BY, Dong M (2016) Development and pre-validation of an in vitro transactivation assay for detection of (anti)androgenic potential compounds using 22Rv1/MMTV cells. Reprod Toxicol 60:156–166. https://doi.org/10.1016/j.reprotox.2016.02.006

    Article  CAS  PubMed  Google Scholar 

  21. Michalíková K, Linhartová L, Ezechiáš M, Cajthaml T (2018) Assessment of agonistic and antagonistic properties of widely used oral care antimicrobial substances toward steroid estrogenic and androgenic receptors. Chemosphere 217:534–541. https://doi.org/10.1016/j.chemosphere.2018.11.006

    Article  CAS  PubMed  Google Scholar 

  22. Lee J, Jeong JS, Kim SY, Im WJ, Shin YJ, Lee K, Choi SJ, Heo Y, Jeong EJ, Nam SY, Yu WJ (2019) Reproductive and developmental toxicity screening of polyhexamethylene guanidine phosphate by oral gavage in rats. Regul Toxicol Pharmacol 108:104440. https://doi.org/10.1016/j.yrtph.2019.104440

    Article  CAS  PubMed  Google Scholar 

  23. Lee J, Choi SJ, Jeong JS, Kim SY, Lee SH, Yang MJ, Lee SJ, Shin YJ, Lee K, Jeong EJ, Nam SY, Yu WJ (2021) A humidifier disinfectant biocide, polyhexamethylene guanidine phosphate, inhalation exposure during pregnancy induced toxicities in rats. J Hazard Mater 404:124007. https://doi.org/10.1016/j.jhazmat.2020.124007

    Article  CAS  PubMed  Google Scholar 

  24. Melin VE, Potineni H, Hunt P, Griswold J, Siems B, Werre SR, Hrubec TC (2014) Exposure to common quaternary ammonium disinfectants decreases fertility in mice. Reprod Toxicol 50:163–170. https://doi.org/10.1016/j.reprotox.2014.07.071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Melin VE, Melin TE, Dessify BJ, Nguyen CT, Shea CS, Hrubec TC (2016) Quaternary ammonium disinfectants cause subfertility in mice by targeting both male and female reproductive processes. Reprod Toxicol 59:159–166. https://doi.org/10.1016/j.reprotox.2015.10.006

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a Grant from the Dongduk Women’s University

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kwangsik Park.

Ethics declarations

Conflict of interest

The authors have no conflict of interests to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, H., Park, J. & Park, K. Assessment of agonistic and antagonistic properties of humidifier disinfectants to the estrogenic and androgenic receptors by transactivation assay. Toxicol Res. 38, 99–109 (2022). https://doi.org/10.1007/s43188-021-00111-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43188-021-00111-3

Keywords

Navigation