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Effect of Sodium Fluoride on Reproductive Function Through Regulating Reproductive Hormone Level and Circulating SIRT1 in Female Rats.
| Biological Trace Element Research | Dong S, Yang Y, He B, Xu Z, Zhou Z, Wang J, Chen C, Chen Q. | [Epub ahead of print]
Fertility Ovary/Uterus Reproductive Toxicity Animal Study
References Kabir H, Gupta AK, Tripathy S (2020) Fluoride and human health: systematic appraisal of sources, exposures, metabolism, and toxicity. Crit Rev Env Sci Tec 50(11):1116–1193. https://doi.org/10.1080/10643389.2019.1647028 CAS  Article  Google Scholar Choubisa SL (2015) Industrial fluorosis in domestic goats (Capra hircus), Rajasthan. India Fluoride 48(2):105–112 CAS  Google Scholar Szczuko M, Splinter J, Zapalowska-Chwyc M, Zietek M, Maciejewska D

Abstract

Fluorosis causes female reproductive dysfunction with reduced fertility without established pathogenesis. To clarify the mechanism, Sprague–Dawley female rats were selected with drinking water containing 0, 50 (low), 100 (moderate), and 150 mg/L (high) sodium fluoride (NaF) for a short (2 months), medium (4 months), and long term (6 months). The water consumption and body weight of female rats were recorded daily. The effect of NaF on the estrous cycle was examined by vaginal smears and recorded in different term treatments. Female and male rats were mated in a 2:1 ratio for 1 week at 2-, 4-, and 6-month treatment time for mating performance and fertility rate. Selected female rats were executed for tissue and blood collection at different treatment terms. Twenty-four-hour urine sample from each female rat was collected using the metabolic cage. The levels of steroid hormones and silent information regulator 2 homolog 1 (SIRT1) in serum were measured by appropriate ELISA kits. Body weight of the high NaF group was significantly less during short-term treatment than that of other treatment groups or control group. Urinary fluoride concentration was increased linearly with treatment time. Treatment of NaF significantly decreased steroid hormone level while increased SIRT1 level in the serum. In addition, NaF treatment significantly decreased pregnancy rate. It is concluded that NaF inhibits the secretion of hormone and estradiol (E2) release from the ovary, thereby reducing the rate of pregnant. SIRT1 may be involved in this NaF-induced reproductive dysfunction in female rats through regulating reproductive hormone, FSH, and LH secretion.

Data Availability

The data underlying this article are available in the article and in its online supplementary material.

*Original abstract online at https://link.springer.com/article/10.1007/s12011-022-03283-7

Excerpt:

References

  1. Kabir H, Gupta AK, Tripathy S (2020) Fluoride and human health: systematic appraisal of sources, exposures, metabolism, and toxicity. Crit Rev Env Sci Tec 50(11):1116–1193. https://doi.org/10.1080/10643389.2019.1647028

    CAS  Article  Google Scholar

  2. Choubisa SL (2015) Industrial fluorosis in domestic goats (Capra hircus), Rajasthan. India Fluoride 48(2):105–112

    CAS  Google Scholar

  3. Szczuko M, Splinter J, Zapalowska-Chwyc M, Zietek M, Maciejewska D (2019) Fluorine may intensify the mechanisms of polycystic ovary syndrome (PCOS) development via increased insulin resistance and disturbed thyroid-stimulating hormone (TSH) synthesis even at reference levels. Med Hypotheses 128:58–63. https://doi.org/10.1016/j.mehy.2019.05.007

    CAS  Article  PubMed  Google Scholar

  4. Sen A, Hoffmann HM (2020) Role of core circadian clock genes in hormone release and target tissue sensitivity in the reproductive axis. Mol Cell Endocrinol 501:110655. https://doi.org/10.1016/j.mce.2019.110655

    CAS  Article  PubMed  Google Scholar

  5. Meethal SV, Liu T, Chan HW, Ginsburg E, Wilson AC, Gray DN, Bowen RL, Vonderhaar BK, Atwood CS (2009) Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors. J Neurochem 110(3):1014–1027. https://doi.org/10.1111/j.1471-4159.2009.06192.x

    CAS  Article  PubMed  PubMed Central  Google Scholar

  6. Bosch E, Alviggi C, Lispi M, Conforti A, Hanyaloglu AC, Chuderland D, Simoni M, Raine-Fenning N, Crepieux P, Kol S, Rochira V, D’Hooghe T, Humaidan P (2021) Reduced FSH and LH action: implications for medically assisted reproduction. Hum Reprod 36(6):1469–1480. https://doi.org/10.1093/humrep/deab065

    CAS  Article  PubMed  PubMed Central  Google Scholar

  7. Randolph JF, Ginsburg KA, Leach RE, Blacker CM, Moghissi KS, Diamond MP, Reame NE (2003) Elevated early follicular gonadotropin levels in women with unexplained infertility do not provide evidence for disordered gonadotropin-releasing hormone secretion as assessed by luteinizing hormone pulse characteristics. Fertil Steril 80(2):320–327. https://doi.org/10.1016/S0015-0282(03)00612-5

    Article  PubMed  Google Scholar

  8. Xu M, Jiang H, Zhang L, Sun X, Luo D, Fu Y, Gao Y, Yuan B, Zhang J (2018) MiR-29b affects the secretion of PROG and promotes the proliferation of bovine corpus luteum cells. PLoS ONE 13(4):e0195562. https://doi.org/10.1371/journal.pone.0195562

    CAS  Article  PubMed  PubMed Central  Google Scholar

  9. Selvaggi M, Carbonara C, Ciotola F, Albarella S, Aiudi G, Tufarelli V, Dario C (2019) Determination of a possible relationship between a single nucleotide polymorphism (SNP) in the promoter region of the SIRT1 gene and production and reproduction traits in the Agerolese cattle breed. Arch Anim Breed 62(1):107–112. https://doi.org/10.5194/aab-62-107-2019

    Article  PubMed  PubMed Central  Google Scholar

  10. 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

    CAS  Article  PubMed  Google Scholar

  11. Liu G, Zhang W, Jiang P, Li X, Liu C, Chai C (2012) Role of nitric oxide and vascular endothelial growth factor in fluoride-induced goitrogenesis in rats. Environ Toxicol Phar 34(2):209–217. https://doi.org/10.1016/j.etap.2012.04.003

    CAS  Article  Google Scholar

  12. El-Sayyad HIH, Al-Haggar MMS, El-Ghawet HA, Bakr IHM (2014) Effect of maternal diabetes and hypercholesterolemia on fetal liver of albino Wistar rats. Nutrition 30(3):326–336. https://doi.org/10.1016/j.nut.2013.08.016

    CAS  Article  PubMed  Google Scholar

  13. Reimer JN, Schuster CJ, Knight CG, Pang DSJ, Leung VSV (2020) Intraperitoneal injection of sodium pentobarbital has the potential to elicit pain in adult rats (Rattus norvegicus). PLoS ONE 15(9):e0238123. https://doi.org/10.1371/journal.pone.0238123

    CAS  Article  PubMed  PubMed Central  Google Scholar

  14. Wang A, Ma Q, Gong B, Sun L, Afrim F, Sun R, He T, Huang H, Zhu J, Zhou G, Ba Y (2021) DNA methylation and fluoride exposure in school-age children: epigenome-wide screening and population-based validation. Ecotox Environ Safe 223:112612. https://doi.org/10.1016/j.ecoenv.2021.112612

    CAS  Article  Google Scholar

  15. Weng Q, Yi F, Yu Y, Ge S, Liu S, Zhang Y (2021) Altered miRNA expression profiling in enamel organ of fluoride affected rat embryos. Ecotox Environ Safe 210:111876. https://doi.org/10.1016/j.ecoenv.2020.111876

    CAS  Article  Google Scholar

  16. Gaspar RS, Alves Benevides RO, de Lima Fontelles JL, Vale CC, Franca LM, Silva Barros PDT, de Andrade Paes AM (2016) Reproductive alterations in hyperinsulinemic but normoandrogenic MSG obese female rats. J Endocrinol 229(2):61–72. https://doi.org/10.1530/JOE-15-0453

    CAS  Article  PubMed  Google Scholar

  17. Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA (2012) National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. Plos Med 9(12):e1001356. https://doi.org/10.1371/journal.pmed.1001356

    Article  PubMed  PubMed Central  Google Scholar

  18. 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

    CAS  Article  PubMed  Google Scholar

  19. Lynn DA, Brown GR (2009) The ontogeny of exploratory behavior in male and female adolescent rats (Rattus norvegicus). Dev Psychobiol 51(6):513–520. https://doi.org/10.1002/dev.20386

    Article  PubMed  PubMed Central  Google Scholar

  20. Jana L, Maity PP, Perveen H, Dash M, Jana S, Dey A, De SK, Chattopadhyay S (2018) Attenuation of utero-toxicity, metabolic dysfunction and inflammation by soy protein concentrate in rats exposed to fluoridated water: consequence of hyperlipidemia in parallel with hypohomocysteinemia. Environ Sci Pollut R 25(36SI):36462–36473. https://doi.org/10.1007/s11356-018-3542-5

    CAS  Article  Google Scholar

  21. Yan L, Bai X, Fang Z, Che L, Xu S, Wu D (2013) Effect of different dietary omega-3/omega-6 fatty acid ratios on reproduction in male rats. Lipids Health Dis 12:33. https://doi.org/10.1186/1476-511X-12-33

    CAS  Article  PubMed  PubMed Central  Google Scholar

  22. Faria TDS, Brasil FDB, Sampaio FJB, Ramos CDF (2010) Effects of maternal undernutrition during lactation on estrogen and androgen receptor expressions in rat ovary at puberty. Nutrition 26(10):993–999. https://doi.org/10.1016/j.nut.2009.09.027

    CAS  Article  Google Scholar

  23. Perera-Marin G, Gutierrez CG, Murcia C, Leon H, Gonzalez-Padilla E (2008) Progesterone and the distribution of pituitary gonadotropin isoforms in cattle. Anim Reprod Sci 104(2–4):164–176. https://doi.org/10.1016/j.anireprosci.2007.02.015

    CAS  Article  PubMed  Google Scholar

  24. Ulloaaguirre A, Espinoza R, Damianmatsumura P, Larrea F, Flores A, Morales L, Dominguez R (1988) Studies on the microheterogeneity of anterior-pituitary follicle-stimulating-hormone in the female rat – isoelectric-focusing pattern throughout the estrous-cycle. Biol Reprod 38(1):70–78. https://doi.org/10.1095/biolreprod38.1.70

    CAS  Article  Google Scholar

  25. Hunter MG, Robinson RS, Mann GE, Webb R (2004) Endocrine and paracrine control of follicular development and ovulation rate in farm species. Anim Reprod Sci 82–3(SI):461–477. https://doi.org/10.1016/j.anireprosci.2004.05.013

    CAS  Article  Google Scholar

  26. Liu YX, Hsueh A (1986) Synergism between granulosa and theca-interstitial cells in estrogen biosynthesis by gonadotropin-treated rat ovaries – studies on the 2-cell, 2-gonadotropin hypothesis using steroid antisera. Biol Reprod 35(1):27–36. https://doi.org/10.1095/biolreprod35.1.27

    CAS  Article  PubMed  Google Scholar

  27. Shah AB, Nivar I, Speelman DL (2018) Elevated androstenedione in young adult but not early adolescent prenatally androgenized female rats. PLoS ONE 13(5):e0196862. https://doi.org/10.1371/journal.pone.0196862

    CAS  Article  PubMed  PubMed Central  Google Scholar

  28. Oke OA, Oke BO (1999) Vaginal cytological changes during the oestrous cycle of the adult female African giant rat (Cricetomys gambianus Waterhouse). Trop Vet 17(3–4):169–180

    Google Scholar

  29. Zhao MX, Zhou GY, Zhu JY, Gong B, Hou JX, Zhou T, Duan LJ, Ding Z, Cui LX, Ba Y (2015) Fluoride exposure, follicle stimulating hormone receptor gene polymorphism and hypothalamus-pituitary-ovarian axis hormones in Chinese women. Biomed Environ Sci 28(9):696–700. https://doi.org/10.3967/bes2015.099

    CAS  Article  PubMed  Google Scholar

  30. D’Angelo S, Mele E, Di Filippo F, Viggiano A, Meccariello R (2021) Sirt1 activity in the brain: simultaneous effects on energy homeostasis and reproduction. Int J Env Res Pub He 18(3):1243. https://doi.org/10.3390/ijerph18031243

    CAS  Article  Google Scholar

  31. Haigis MC, Sinclair DA (2010) Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 5:253–295. https://doi.org/10.1146/annurev.pathol.4.110807.092250

    CAS  Article  PubMed  PubMed Central  Google Scholar

  32. Khawar M, Sohail A, Li W (2022) SIRT1: a key player in male reproduction. Life 12(2):318. https://doi.org/10.3390/life12020318

    CAS  Article  PubMed  PubMed Central  Google Scholar

  33. Tatone C, Di Emidio G, Barbonetti A, Carta G, Luciano AM, Falone S, Amicarelli F (2018) Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility. Hum Reprod Update 24(3):267–289. https://doi.org/10.1093/humupd/dmy003

    CAS  Article  PubMed  Google Scholar

  34. Kolthur-Seetharam U, Teerds K, de Rooij DG, Wendling O, Mcburney M, Sassone-Corsi P, Davidson I (2009) The histone deacetylase SIRT1 controls male fertility in mice through regulation of hypothalamic-pituitary gonadotropin signaling. Biol Reprod 80(2):384–391. https://doi.org/10.1095/biolreprod.108.070193

    CAS  Article  PubMed  Google Scholar

  35. Choi I, Rickert E, Fernandez M, Webster N (2019) SIRT1 in astrocytes regulates glucose metabolism and reproductive function. Endocrinology 160(6):1547–1560. https://doi.org/10.1210/en.2019-00223

    CAS  Article  PubMed  PubMed Central  Google Scholar

  36. Zhao Q, Tian Z, Zhou G, Niu Q, Chen J, Li P, Dong L, Xia T, Zhang S, Wang A (2020) SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of resveratrol against neurodevelopment damage by fluoride. Theranostics 10(11):4822–4838. https://doi.org/10.7150/thno.42387

    CAS  Article  PubMed  PubMed Central  Google Scholar

  37. Li W, Dong S, Chen Q, Chen C, Dong Z (2020) Selenium may suppress peripheral blood mononuclear cell apoptosis by modulating HSP70 and regulate levels of SIRT1 through reproductive hormone secretion and oxidant stress in women suffering fluorosis. Eur J Pharmacol 878:173098. https://doi.org/10.1016/j.ejphar.2020.173098

    CAS  Article  PubMed  Google Scholar

  38. Bodis J, Sulyok E, Koszegi T, Godony K, Premusz V, Varnagy A (2019) Serum and follicular fluid levels of sirtuin 1, sirtuin 6, and resveratrol in women undergoing in vitro fertilization: an observational, clinical study. J Int Med Res 47(2):772–782. https://doi.org/10.1177/0300060518811228

    CAS  Article  PubMed  Google Scholar

  39. Smedlund KB, Hill JW (2020) The role of non-neuronal cells in hypogonadotropic hypogonadism. Mol Cell Endocrinol 518:110996. https://doi.org/10.1016/j.mce.2020.110996

    CAS  Article  PubMed  Google Scholar

  40. Gu X, Han D, Chen W, Zhang L, Lin Q, Gao J, Fanning S, Han B (2016) SIRT1-mediated FoxOs pathways protect against apoptosis by promoting autophagy in osteoblast-like MC3T3-E1 cells exposed to sodium fluoride. Oncotarget 7(40):65218–65230. https://doi.org/10.18632/oncotarget.11573

    Article  PubMed  PubMed Central  Google Scholar

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Funding

This work was funded by the National Natural Science Foundation of China (grant numbers 82073496 and 81673115), Huimin Project of Ministry of Science and Technology of China (grant number 2012GS610101), Department of Health of Shaanxi Province (grant number 2018D050), and International Cooperation Foundation of Shaanxi province (2020KW-057). CC was supported by NHMRC and The University of Queensland.

Author information

Author notes

  1. Siyuan Dong and Yanni Yang contributed equally to this manuscript.

Affiliations

  1. Guipei Class s0141, Xi’an Jiaotong University Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China

    Siyuan Dong

  2. Xianyang Central Hospital, Xianyang, People’s Republic of China

    Yanni Yang

  3. Class 0128#, Xi’an Jiaotong University Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China

    Biqi He

  4. School of Chemistry, Xi’an Jiaotong University, Xi’an, People’s Republic of China

    Zhao Xu

  5. University of California-Davis, Davis, CA, 95616, USA

    Zhaoqiang Zhou

  6. Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China

    Jinhai Wang

  7. Endocrinology, School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia

    Chen Chen

  8. Institute of Endemic Diseases, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People’s Republic of China, Key Laboratory for Disease Prevention and Control and Health Promotion of Shaanxi Province, Xi’an Jiaotong University Health Science Center, No. 76, Yanta Western Road, Shaanxi, 710061, Xi’an, People’s Republic of China

    Qun Chen

Contributions

Qun Chen designed the experiments, analyzed the data, and wrote the manuscript. Biqi He, Yanni Yang, and Siyuan Dong performed the experiments. Zhaoqiang Zhou and Jinhai Wang provided intellectual inputs. Zhao Xu interpreted the results and critically reviewed the manuscript. Chen Chen was involved in the result interpretation, manuscript writing, and reviewing and editing.

Corresponding author

Correspondence to Qun Chen.