Skip to main content

Advertisement

SpringerLink
Log in

Chronic Fluoride Exposure Induces Ovarian Dysfunction and Potential Association with Premature Ovarian Failure in Female Rats

  • Research
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Chronic fluorosis has been widely investigated for its adverse effects on skeletal and neurological health; however, its impact on reproductive health, especially in females, remains underexplored. In this study, female Sprague-Dawley rats were exposed to different fluoride concentrations (0.75, 50, and 100 mg/L) in their drinking water for six months. Dental fluorosis and increased urinary fluoride content were observed in fluoride-exposed rats, reflecting fluoride accumulation and exposure levels. Chronic fluorosis resulted in reduced ovary organ coefficient, indicating harmful effects on ovarian tissue. Additionally, the number of ovarian primordial and primary/secondary follicles decreased, while the number of atresia follicles increased. Furthermore, chronic fluorosis led to disrupted estrous cycles. Hormonal analysis revealed altered secretion of estrogen, progesterone, anti-Müllerian hormone, luteinizing hormone, follicular stimulating hormone, and inhibin B in response to fluoride exposure. Ultrastructural observation of ovarian granulosa cells showed evidence of apoptosis, which was further confirmed by flow cytometry. Caspase-3 activity was increased, and ATP levels were decreased, suggesting mitochondrial impairment and apoptosis induction. The mRNA and protein expression of BMP15 and GDF9, essential regulators of ovarian function, significantly decreased with increasing fluoride concentration. Furthermore, gene expression analysis identified a panel of premature ovarian failure-related genes that were downregulated in fluoride-exposed rat ovaries. These findings suggest that chronic fluoride exposure may contribute to ovarian dysfunction and possibly the pathogenesis of premature ovarian failure. Understanding the toxicological effects of chronic fluoride exposure on ovarian function is essential for identifying potential environmental risk factors affecting female reproductive health.

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
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Li M, Qu X, Miao H, Wen S, Hua Z, Ma Z, He Z (2020) Spatial distribution of endemic fluorosis caused by drinking water in a high-fluorine area in Ningxia, China. Environ Sci Pollut Res Int 27(16):20281–20291. https://doi.org/10.1007/s11356-020-08451-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Meena L, Gupta R (2021) Skeletal fluorosis. N Engl J Med 385(16):1510. https://doi.org/10.1056/NEJMicm2103503

    Article  PubMed  Google Scholar 

  3. Saeed M, Malik RN, Kamal A (2020) Fluorosis and cognitive development among children (6–14 years of age) in the endemic areas of the world: a review and critical analysis. Environ Sci Pollut Res Int 27(3):2566–2579. https://doi.org/10.1007/s11356-019-06938-6

    Article  CAS  PubMed  Google Scholar 

  4. Srivastava S, Flora SJS (2020) Fluoride in drinking water and skeletal fluorosis: a review of the global impact. Curr Environ Health Rep 7(2):140–146. https://doi.org/10.1007/s40572-020-00270-9

    Article  CAS  PubMed  Google Scholar 

  5. Wei W, Pang S, Sun D (2019) The pathogenesis of endemic fluorosis: Research progress in the last 5 years. J Cell Mol Med 23(4):2333–2342. https://doi.org/10.1111/jcmm.14185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li M, Cao J, Zhao Y, Wu P, Li X, Khodaei F, Han Y, Wang J (2020) Fluoride impairs ovary development by affecting oogenesis and inducing oxidative stress and apoptosis in female zebrafish (Danio rerio). Chemosphere 256:127105. https://doi.org/10.1016/j.chemosphere.2020.127105

    Article  CAS  PubMed  Google Scholar 

  7. Zhou Y, Qiu Y, He J, Chen X, Ding Y, Wang Y, Liu X (2013) The toxicity mechanism of sodium fluoride on fertility in female rats. Food Chem Toxicol 62:566–572. https://doi.org/10.1016/j.fct.2013.09.023

    Article  CAS  PubMed  Google Scholar 

  8. Zhou Y, Zhang H, He J, Chen X, Ding Y, Wang Y, Liu X (2013) Effects of sodium fluoride on reproductive function in female rats. Food Chem Toxicol 56:297–303. https://doi.org/10.1016/j.fct.2013.02.026

    Article  CAS  PubMed  Google Scholar 

  9. Otsuka F, McTavish KJ, Shimasaki S (2011) Integral role of GDF-9 and BMP-15 in ovarian function. Mol Reprod Dev 78(1):9–21. https://doi.org/10.1002/mrd.21265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Alam MH, Miyano T (2020) Interaction between growing oocytes and granulosa cells in vitro. Reprod Med Biol 19(1):13–23. https://doi.org/10.1002/rmb2.12292

    Article  CAS  PubMed  Google Scholar 

  11. Qin Y, Jiao X, Simpson JL, Chen ZJ (2015) Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update 21(6):787–808. https://doi.org/10.1093/humupd/dmv036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. França MM, Mendonca BB (2022) Genetics of ovarian insufficiency and defects of folliculogenesis. Best Pract Res Clin Endocrinol Metab 36(1):101594. https://doi.org/10.1016/j.beem.2021.101594

    Article  CAS  PubMed  Google Scholar 

  13. Liu MN, Zhang K, Xu TM (2021) The role of BMP15 and GDF9 in the pathogenesis of primary ovarian insufficiency. Hum Fertil (Camb) 24(5):325–332. https://doi.org/10.1080/14647273.2019.1672107

    Article  CAS  PubMed  Google Scholar 

  14. Mondal NK (2021) Diagnosis of fluorosis by analysis of Fluoride Content in Body fluids using Ion Selective Electrode Method. Adv Exp Med Biol 1306:121–127. https://doi.org/10.1007/978-3-030-63908-2_9

    Article  CAS  PubMed  Google Scholar 

  15. Luo M, Huang JC, Yang ZQ, Wang YS, Guo B, Yue ZP (2020) Hydroxysafflor yellow A exerts beneficial effects by restoring hormone secretion and alleviating oxidative stress in polycystic ovary syndrome mice. Exp Physiol 105(2):282–292. https://doi.org/10.1113/ep088147

    Article  CAS  PubMed  Google Scholar 

  16. Luo M, Zheng LW, Wang YS, Huang JC, Yang ZQ, Yue ZP, Guo B (2021) Genistein exhibits therapeutic potential for PCOS mice via the ER-Nrf2-Foxo1-ROS pathway. Food Funct 12(18):8800–8811. https://doi.org/10.1039/d1fo00684c

    Article  CAS  PubMed  Google Scholar 

  17. Luo M, Yang ZQ, Huang JC, Wang YS, Guo B, Yue ZP (2020) Genistein protects ovarian granulosa cells from oxidative stress via cAMP-PKA signaling. Cell Biol Int 44(2):433–445. https://doi.org/10.1002/cbin.11244

    Article  CAS  PubMed  Google Scholar 

  18. Kumah EA, Eskandari F, Azevedo LB, John S, Zohoori FV (2022) Mapping the evidence for monitoring fluoride exposure in community prevention programmes for oral health using nail clippings and spot urine samples: a scoping review. BMC Oral Health 22(1):575. https://doi.org/10.1186/s12903-022-02615-2

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liang C, Gao Y, He Y, Han Y, Manthari RK, Tikka C, Chen C, Wang J, Zhang J (2020) Fluoride induced mitochondrial impairment and PINK1-mediated mitophagy in Leydig cells of mice: in vivo and in vitro studies. Environ Pollut 256:113438. https://doi.org/10.1016/j.envpol.2019.113438

    Article  CAS  PubMed  Google Scholar 

  20. Liang S, Zhao MH, Ock SA, Kim NH, Cui XS (2016) Fluoride impairs oocyte maturation and subsequent embryonic development in mice. Environ Toxicol 31(11):1486–1495. https://doi.org/10.1002/tox.22153

    Article  CAS  PubMed  Google Scholar 

  21. Chaulagain R, Chhatkuli A, Shrestha AR, Chhetri BK, Pandey S (2022) Mean Fluoride Concentration in drinking Water sources of a municipality: a descriptive cross-sectional study. JNMA J Nepal Med Assoc 60(255):947–951. https://doi.org/10.31729/jnma.7898

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fordyce FM, Vrana K, Zhovinsky E, Povoroznuk V, Toth G, Hope BC, Iljinsky U, Baker J (2007) A health risk assessment for fluoride in Central Europe. Environ Geochem Health 29(2):83–102. https://doi.org/10.1007/s10653-006-9076-7

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was funded by Natural Science Research Project of Guizhou Provincial Education Office (KY2012037), Health Commission of Henan Province (LHGJ20210766) and Zhengzhou Central Hospital Affiliated to Zhengzhou University (KYQDJJ2021002).

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China

    Xiaoke Tang, Hongjuan Li, Yali Wang, Yajun Qu, Hui Yang, Xiaolin Zhang, Yanmin Li & Man Luo

  2. Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China

    Man Luo

  3. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guizhou Traditional Chinese Medicine University, Guiyang, China

    Li Zeng & Qi Zhou

  4. Department of Obstetrics and Gynecology, Tongliang District People’s Hospital, Chongqing, China

    Ling Long

  5. Department of Pathology, Guizhou Medical University, Guiyang, China

    Yanni Yu

Authors
  1. Xiaoke Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongjuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yali Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ling Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yajun Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaolin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yanmin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yanni Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qi Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Man Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by X.T., M.L., H.L., Y. W., L. Z., L. L. and Y. Q. The first draft of the manuscript was written by H. Y., X. Z., Y. L., Y. Y., Q. Z. and M. L. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Qi Zhou or Man Luo.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, X., Li, H., Wang, Y. et al. Chronic Fluoride Exposure Induces Ovarian Dysfunction and Potential Association with Premature Ovarian Failure in Female Rats. Biol Trace Elem Res (2023). https://doi.org/10.1007/s12011-023-03914-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12011-023-03914-7

Keywords

Search

Navigation