Skip to main content

Advertisement

SpringerLink
Log in

The inhibition of CFTR in the descended testis of SD rats with unilateral cryptorchidism induced by di-(2-ethylhexyl) phthalate (DEHP)

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is a kind of environmental endocrine disruptors (EEDs), which has been confirmed to cause serious consequences, such as cryptorchidism. Patients with unilateral cryptorchidism still had oligospermia or infertility even if they received orchidopexy before puberty. Testicular dysgenesis syndrome (TDS) attributes this kind of problems to the abnormal testicular development during the embryonic period, and considers that the environmental exposure factors during pregnancy play a major role. Therefore, for unilateral cryptorchidism, even if one testicle has dropped to scrotum, it may be exposed to these substances and cause damage. Cystic fibrosis transmembrane conduction regulator (CFTR) is very important for the maturation of male reproductive system. Previously, cryptorchidism was thought to cause abnormal expression of heat sensitive protein CFTR in testis, but the expression of CFTR in healthy side (descended side) testis was not clear. In this study, we established SD rats with unilateral cryptorchidism by exposure to DEHP (500 mg/kg/day) during pregnancy, and detected the expression of CFTR and downstream signal NF-κB/COX-2/PGE2 in bilateral testis. Finally, we found that the expression of CFTR and downstream signal NF-κB/COX-2/PGE2 in the undescended testis was significantly abnormal, but the expression of them in the descended testis was also abnormal to some extent. Therefore, we speculate that in addition to high temperature will affect the expression of CFTR, there may be other factors that cause abnormal expression of CFTR induced by DEHP, and lead to abnormal male reproductive function eventually, but the specific mechanism needs to be further studied.

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

Access this article

Log in via an institution

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

Data availability

All data generated or analyzed during this study are included in this published article.

References

  • Alberti S, Böhse K, Arndt V et al (2004) The cochaperone HspBP1 inhibits the CHIP ubiquitin ligase and stimulates the maturation of the cystic fibrosis transmembrane conductance regulator. Mol Biol Cell 15(9):4003–4010

    Article  CAS  Google Scholar 

  • Alves MG, Sá R, Jesus TT, Sousa M, Oliveira PF (2015) CFTR regulation of aquaporin-mediated water transport: a target in male fertility. Curr Drug Targets 16(9):993–1006

    Article  CAS  Google Scholar 

  • Borch J, Metzdorff SB, Vinggaard AM, Brokken L, Dalgaard M (2006) Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis. Toxicology 223(1–2):144–155

    Article  CAS  Google Scholar 

  • Brown CR, Hong-Brown LQ, Welch WJ (1997) Strategies for correcting the delta F508 CFTR protein-folding defect. J Bioenerg Biomembr 29(5):491–502

    Article  CAS  Google Scholar 

  • Cao XN, Shen LJ, Wu SD et al (2017) Urban fine particulate matter exposure causes male reproductive injury through destroying blood-testis barrier (BTB) integrity. Toxicol Lett 266:1–12

    Article  CAS  Google Scholar 

  • Chen H, Ruan YC, Xu WM, Chen J, Chan HC (2012a) Regulation of male fertility by CFTR and implications in male infertility. Hum Reprod Update 18(6):703–713

    Article  CAS  Google Scholar 

  • Chen J, Fok KL, Chen H, Zhang XH, Xu WM, Chan HC (2012b) Cryptorchidism-induced CFTR down-regulation results in disruption of testicular tight junctions through up-regulation of NF-κB/COX-2/PGE2. Hum Reprod 27(9):2585–2597

    Article  CAS  Google Scholar 

  • Dadfar MR (2007) Orchidopexy for retractile testes in infertile men: a prospective clinical study. Urol J 4(3):164–168

    Google Scholar 

  • Elborn JS (2016) Cystic fibrosis. Lancet 388(10059):2519–2531

    Article  CAS  Google Scholar 

  • Erythropel HC, Maric M, Nicell JA, Leask RL, Yargeau V (2014) Leaching of the plasticizer di(2-ethylhexyl) phthalate (DEHP) from plastic containers and the question of human exposure. Appl Microbiol Biotechnol 98(24):9967–9981

    Article  CAS  Google Scholar 

  • Fawzy F, Hussein A, Eid MM, El Kashash AM, Salem HK (2015) Cryptorchidism and fertility. Clin Med Insights Reprod Health 9:39–43

    Article  Google Scholar 

  • Fernández MF, Olmos B, Olea N (2007) Exposure to endocrine disruptors and male urogenital tract malformations [cryptorchidism and hypospadias]. Gac Sanit 21(6):500–514

    Article  Google Scholar 

  • Fu G, Dai J, Li Z et al (2020) The role of STAT3/p53 and PI3K-Akt-mTOR signaling pathway on DEHP-induced reproductive toxicity in pubertal male rat. Toxicol Appl Pharmacol 404:115151

    Article  CAS  Google Scholar 

  • Ginsberg G, Ginsberg J, Foos B (2016) Approaches to children’s exposure assessment: case study with diethylhexylphthalate (DEHP). Int J Environ Res Public Health 13(7)

  • Gurney JK, McGlynn KA, Stanley J et al (2017) Risk factors for cryptorchidism. Nat Rev Urol 14(9):534–548

    Article  Google Scholar 

  • Huang L, Gao H, Wang Z et al (2021) Combination nanotherapeutics for dry eye disease treatment in a rabbit model. Int J Nanomed 16:3613–3631

    Article  CAS  Google Scholar 

  • Jensen TK, Andersson AM, Main KM et al (2021) Prenatal paraben exposure and anogenital distance and reproductive hormones during mini-puberty: a study from the Odense Child Cohort. Sci Total Environ 769:145119

    Article  CAS  Google Scholar 

  • Kai H, Shono T, Tajiri T et al (2005) Long-term effects of intrauterine exposure to mono-n-butyl phthalate on the reproductive function of postnatal rats. J Pediatr Surg 40(2):429–433

    Article  Google Scholar 

  • Lee PA, Houk CP (2013) Cryptorchidism. Curr Opin Endocrinol Diabetes Obes 20(3):210–216

    Article  CAS  Google Scholar 

  • Lu Y, Fan S, Song Y et al (2021) The association between anogenital distance and benign prostatic hyperplasia related lower urinary tract symptoms in Chinese aging men. World J Urol 39(7):2645–2653

    Article  CAS  Google Scholar 

  • Main KM, Skakkebaek NE, Toppari J (2009) Cryptorchidism as part of the testicular dysgenesis syndrome: the environmental connection. Endocr Dev 14:167–173

    Article  CAS  Google Scholar 

  • Marozkina NV, Yemen S, Borowitz M et al (2010) Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy. Proc Natl Acad Sci U S A 107(25):11393–11398

    Article  CAS  Google Scholar 

  • Moreno-Mendoza D, Casamonti E, Riera-Escamilla A et al (2020) Short anogenital distance is associated with testicular germ cell tumour development. Andrology 8(6):1770–1778

    Article  CAS  Google Scholar 

  • Pocar P, Fiandanese N, Secchi C et al (2012) Exposure to di(2-ethyl-hexyl) phthalate (DEHP) in utero and during lactation causes long-term pituitary-gonadal axis disruption in male and female mouse offspring. Endocrinology 153(2):937–948

    Article  CAS  Google Scholar 

  • Qu F, Qin XQ, Cui YR et al (2009) Ozone stress down-regulates the expression of cystic fibrosis transmembrane conductance regulator in human bronchial epithelial cells. Chem Biol Interact 179(2–3):219–226

    Article  CAS  Google Scholar 

  • Shen L, Tang X, Wei Y et al (2018) Vitamin E and vitamin C attenuate Di-(2-ethylhexyl) phthalate-induced blood-testis barrier disruption by p38 MAPK in immature SD rats. Reprod Toxicol 81:17–27

    Article  CAS  Google Scholar 

  • Sinisi AA, Pasquali D, Papparella A et al (1998) Antisperm antibodies in cryptorchidism before and after surgery. J Urol 160(5):1834–1837

    Article  CAS  Google Scholar 

  • Skakkebaek NE, Rajpert-De ME, Main KM (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 16(5):972–978

    Article  CAS  Google Scholar 

  • Skakkebaek NE, Rajpert-De ME, Buck LGM et al (2016) Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol Rev 96(1):55–97

    Article  CAS  Google Scholar 

  • Tang X, Wu S, Shen L et al (2018) Di-(2-ethylhexyl) phthalate (DEHP)-induced testicular toxicity through Nrf2-mediated Notch1 signaling pathway in Sprague-Dawley rats. Environ Toxicol 33(7):720–728

    Article  CAS  Google Scholar 

  • Thorup J, Cortes D (2016) Long-term follow-up after treatment of cryptorchidism. Eur J Pediatr Surg 26(5):427–431

    Article  Google Scholar 

  • Toppari J, Virtanen HE, Main KM, Skakkebaek NE (2010) Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): environmental connection. Birth Defects Res A Clin Mol Teratol 88(10):910–919

    Article  CAS  Google Scholar 

  • Trsinar B, Muravec UR (2009) Fertility potential after unilateral and bilateral orchidopexy for cryptorchidism. World J Urol 27(4):513–519

    Article  Google Scholar 

  • Virtanen HE, Toppari J (2008) Epidemiology and pathogenesis of cryptorchidism. Hum Reprod Update 14(1):49–58

    Article  CAS  Google Scholar 

  • Wang W, Wei G, Deng Y, Zhang X (2004) Histopathological changes of the cryptorchid testis and epididymis of mice exposed to DEHP. Zhonghua Nan Ke Xue 10(11):807–814

    Google Scholar 

  • Wei Y, Zhou Y, Tang XL et al (2018) Testicular developmental impairment caused by flutamide-induced and DEHP-induced cryptorchid rat models is mediated by excessive apoptosis and deficient autophagy. Toxicol Mech Methods 28(7):507–519

    Article  CAS  Google Scholar 

  • Wohlfahrt-Veje C, Main KM, Skakkebaek NE (2009) Testicular dysgenesis syndrome: foetal origin of adult reproductive problems. Clin Endocrinol (oxf) 71(4):459–465

    Article  Google Scholar 

  • Wood HM, Elder JS (2009) Cryptorchidism and testicular cancer: separating fact from fiction. J Urol 181(2):452–461

    Article  Google Scholar 

  • Yirong C, Shengchen W, Jiaxin S, Shuting W, Ziwei Z (2020) DEHP induces neutrophil extracellular traps formation and apoptosis in carp isolated from carp blood via promotion of ROS burst and autophagy. Environ Pollut 262:114295

    Article  Google Scholar 

  • Zaman K, Sawczak V, Zaidi A et al (2016) Augmentation of CFTR maturation by S-nitrosoglutathione reductase. Am J Physiol Lung Cell Mol Physiol 310(3):L263-270

    Article  Google Scholar 

  • Zhao TX, Wang JK, Shen LJ et al (2020) Increased m6A RNA modification is related to the inhibition of the Nrf2-mediated antioxidant response in di-(2-ethylhexyl) phthalate-induced prepubertal testicular injury. Environ Pollut 259:113911

    Article  CAS  Google Scholar 

  • Zong T, Lai L, Hu J et al (2015) Maternal exposure to di-(2-ethylhexyl) phthalate disrupts placental growth and development in pregnant mice. J Hazard Mater 297:25–33

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by the fund from Guangzhou Institute of Pediatrics (nos. YIP-2019–036, GWCMC2020-4–011) and the Guangdong Basic and Applied Basic Research Foundation (no. 2020A1515110796).

Author information

Authors and Affiliations

  1. Department of Pediatric Urology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510000, Guangdong, China

    Xiangliang Tang, Dian Li, Tianxin Zhao, Shibo Zhu, Xiaofeng Gao, Rui Zhou, Fuming Deng, Wen Fu, Wei Jia & Guochang Liu

  2. Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510000, Guangdong, China

    Xiangliang Tang, Dian Li, Tianxin Zhao, Shibo Zhu, Xiaofeng Gao, Rui Zhou, Fuming Deng, Wen Fu, Wei Jia & Guochang Liu

Authors
  1. Xiangliang Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tianxin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shibo Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaofeng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rui Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fuming Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wen Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wei Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Guochang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Substantial contributions to conception and design: Xiangliang Tang, Guochang Liu, Wei Jia, Tianxin Zhao, and Dian Li. Animal model construction: Xiangliang Tang, Dian Li, and Tianxin Zhao. Completion of the experiment: Rui Zhou, Shibo Zhu, Fuming Deng, and Xiangliang Tang. Data acquisition: Xiangliang Tang and Xiaofeng Gao. Data analysis: Xiangliang Tang and Tianxin Zhao. Data interpretation: All authors. Drafting the manuscript and critical discussion: Xiangliang Tang and Wen Fu. Revising manuscript critically for important intellectual content: All authors. Final approval of the manuscript: All authors.

Corresponding author

Correspondence to Guochang Liu.

Ethics declarations

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

All authors agree to publish.

Competing interests

The authors declare no competing interests.

Additional information

Responsible Editor: Mohamed M. Abdel-Daim

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

Tang, X., Li, D., Zhao, T. et al. The inhibition of CFTR in the descended testis of SD rats with unilateral cryptorchidism induced by di-(2-ethylhexyl) phthalate (DEHP). Environ Sci Pollut Res 29, 77047–77056 (2022). https://doi.org/10.1007/s11356-022-21134-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-022-21134-9

Keywords

Search

Navigation