Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

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

  • Received : 2021.07.21
  • Accepted : 2021.09.29
  • Published : 2022.01.15
⟨ Previous Next ⟩

Abstract

Before being recalled and banned from the Korean market, humidifer disinfectants (HDs) were added to the humidifer 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 frst litter, longer pregnancy intervals, fewer pups per litter, and fewer pregnancies. In this study, endocrine-disrupting efects 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 efects. However, it is difcult to conclude that HDs has no endocrine disruption efects, and further research on the efects of HDs mixtures, and in vivo tests including Uterotrophic bioassay and Hershberger bioassay would be necessary.

Keywords

Acknowledgement

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

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 humidifer 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
  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 humidifer 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
  3. Park K (2016) An analysis of a humidifer disinfectant case from a toxicological perspective. Environ Health Toxicol 31:e2016013. https://doi.org/10.5620/eht.e2016013
  4. Lee JH, Lee JH (2017) Humidifer disinfectant-associated specifc diseases should be called together as "humidifer disinfectant syndrome." Environ Health Toxicol 32:e2017017. https://doi.org/10.5620/eht.e2017017
  5. Kim HR, Hwang GW, Naganuma A, Chung KH (2016) Adverse health efects of humidifer disinfectants in Korea: lung toxicity of polyhexamethylene guanidine phosphate. J Toxicol Sci 41:711-717. https://doi.org/10.2131/jts.41.711
  6. Lee SJ, Park JH, Lee JY, Jeong YJ, Song JA, Lee KH, Kim DJ (2016) Establishment of a mouse model for pulmonary infammation and fbrosis by intratracheal instillation of polyhexamethyleneguanidine phosphate. J Toxicol Pathol 29:95-102. https://doi.org/10.1293/tox.2015-0067
  7. Song JA, Kim WJ, Kim YB, Kim BS, Lee KH (2018) Time course of polyhexamethyleneguanidine phosphate-induced lung infammation and fbrosis in mice. Toxicol Appl Pharmacol 345:94-102. https://doi.org/10.1016/j.taap.2018.02.013
  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
  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
  10. Kim MS, Kim SH, Jeon D, Kim HY, Lee K (2018) Changes in expression of cytokines in polyhexamethylene guanidine-induced lung fbrosis in mice: comparison of bleomycin-induced lung fbrosis. Toxicology 393:185-192. https://doi.org/10.1016/j.tox.2017.11.017
  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 fbrosis. Chem Biol Interact 292:76-83. https://doi.org/10.1016/j.cbi.2018.07.008
  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 fbrosis in subchronic inhalation exposure. Inhal Toxicol 32:419-430. https://doi.org/10.1080/08958378.2020.1836091
  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
  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
  15. Kim H, Ji K (2019) Exposure to humidifer disinfectants induces developmental efects and disrupts thyroid endocrine systems in zebrafsh larvae. Ecotoxicol Environ Saf 184:109663. https://doi.org/10.1016/j.ecoenv.2019.109663
  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
  18. Park C, Song H, Choi J, Sim S, Kojima H, Park J, Iida M, Lee Y (2020) The mixture efects of bisphenol derivatives on estrogen receptor and androgen receptor. Environ Pollut 260:114036. https://doi.org/10.1016/j.envpol.2020.114036
  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
  21. Michalikova K, Linhartova L, Ezechias 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
  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
  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 humidifer 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
  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
  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