Abstract
Excessive fluoride levels in drinking water poses serious global health issues. Decreased male fertility rates are reported from fluorosis endemic regions globally. This study aimed to examine potential impacts of chronic exposure to fluoride in drinking water on male reproductive parameters. The case–control study was based on recruits from a fluorosis endemic region, Anuradhapura, and a non-endemic region, Colombo, (n = 15 fertile with proven paternity and 15 subfertile, from each region) in Sri Lanka. Seminal fluid analysis (SFA) was performed according to WHO guidelines. Fluoride ion-selective electrodes quantified serum fluoride levels, while sandwich ELISAs assayed seminal IL-4 and IL-1β cytokines. SFA between the fertile groups did not differ significantly (p > 0.05). Compared to the non-endemic subfertile group (NESG), the endemic subfertile group (ESG) manifested highly significant higher serum fluoride concentration, percentage of morphologically normal spermatozoa (p < 0.001), and liquefaction time (p < 0.02), while the contrary was true of semen volume (p < 0.001). Significantly lower spermatozoa count (p < 0.02), motility (p < 0.001), and viability (p < 0.002) detected in the ESG compared to the NESG, was reiterated by significant negative correlation established between serum fluoride concentration and aforementioned three spermatozoa parameters in ESG (p < 0.05). Seminal plasma IL-4 and IL-1β levels did not significantly differ between ESG and NESG (p > 0.05). The source of drinking water significantly differed in ESG (67% well water) and NESG (60% pipe-borne water) (p < 0.02). These findings were indicative of serum fluoride concentration as an important contributory factor for male factor subfertility in a fluorosis endemic region in Sri Lanka.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The data set analysed and used during the current study is available with the corresponding author upon reasonable request.
References
Adimalla N, Li P (2019) Occurrence, health risks, and geochemical mechanisms of fluoride and nitrate in groundwater of the rock-dominant semi-arid region, Telangana State, India. Hum Ecol Risk Assess Int J 25:81–103. https://doi.org/10.1080/10807039.2018.1480353
Amarasekara DS, Wijerathna S, Fernando C, Udagama PV (2014) Cost-effective diagnosis of male oxidative stress using the nitroblue tetrazolium test: useful application for the developing world. Andrologia 46:73–79. https://doi.org/10.1111/and.12043
An N, Zhu J, Ren L, Liu X, Zhou T, Huang H, Sun L, Ding Z, Li Z, Cheng X, Ba Y (2019) Trends of SHBG and ABP levels in male farmers: Influences of environmental fluoride exposure and ESR alpha gene polymorphisms. Ecotoxicol Environ Saf 172:40–44. https://doi.org/10.1016/j.ecoenv.2019.01.062
ATSDR (2003) Toxicological profile for fluorides, hydrogen fluoride, and fluorine (update). Agency for Toxic Substances and Disease Registry, Georgia, USA
Ayoob S, Gupta AK (2006) Fluoride in drinking water: a review on the status and stress effects. Crit Rev Environ Sci Technol 36:433–487. https://doi.org/10.1080/10643380600678112
Azenabor A, Ekun AO, Akinloye O (2015) Impact of inflammation on male reproductive tract. J Reprod Infert 16:123
Balasooriya S, Munasinghe H, Herath AT, Diyabalanage S, Ileperuma OA, Manthrithilake H, Daniel C, Amann K, Zwiener C, Barth JAC, Chandrajith R (2019) Possible links between groundwater geochemistry and chronic kidney disease of unknown etiology (CKDu): an investigation from the Ginnoruwa region in Sri Lanka. Exposure Health. https://doi.org/10.1007/s12403-019-00340-w
Barbier O, Arreola-Mendoza L, Del Razo LM (2010) Molecular mechanisms of fluoride toxicity. Chem Biol Interact 188:319–333. https://doi.org/10.1016/j.cbi.2010.07.011
Cabral Pinto MMS, Ferreira da Silva EA (2019) Heavy Metals of Santiago Island (Cape Verde) Alluvial Deposits: Baseline Value Maps and Human Health Risk Assessment. Int J Environ Res Public Health 16:2. https://doi.org/10.3390/ijerph16010002
Cabral Pinto MMS, Silva MMV, Ferreira da Silva EA, Marinho-Reis AP (2017) The cancer and non-cancer risk of Santiago Island (Cape Verde) population due to potential toxic elements exposure from soils. Geosciences 7:78. https://doi.org/10.3390/geosciences7030078
Carey CM (2014) Focus on fluorides: update on the use of fluoride for the prevention of dental caries. J Evid Based Dental Pract 14:95–102. https://doi.org/10.1016/j.jebdp.2014.02.004
Chaithra B, Sarjan HN, Shivabasavaiah, (2020) A comparative analysis of fluoride-contaminated groundwater and sodium fluoride-induced reproductive toxicity and its reversibility in male rats. Biol Trace Elem Res 197:507–521. https://doi.org/10.1007/s12011-019-01994-y
Chandrajith R, Abeypala U, Dissanayake CB, Tobschall HJ (2007) Fluoride in Ceylon tea and its implications to dental health. Environ Geochem Health 29:429–434. https://doi.org/10.1007/s10653-007-9087-z
Chandrajith R, Padmasiri JP, Dissanayake CB, Prematilaka KM (2012) Spatial distribution of fluoride in groundwater of Sri Lanka. J Natl Sci Found. https://doi.org/10.4038/jnsfsr.v40i4.5044
Chandrajith R, Diyabalanage S, Dissanayake CB (2020) Geogenic fluoride and arsenic in groundwater of Sri Lanka and its implications to community health. Groundw Sustain Dev 10:100359. https://doi.org/10.1016/j.gsd.2020.100359
Chandrajith R, Bhagya S, Diyabalanage S, Wimalasiri S, Ranatunga MAB, Barth JAC (2021) Exposure assessment of fluoride intake through commercially available black tea (Camellia sinensis L.) from areas with high incidences of chronic kidney disease with undetermined origin (CKDu) in Sri Lanka. Biol Trace Elem Res. https://doi.org/10.1007/s12011-021-02694-2
Chauhan AA, Singh VP, Mishra S, Tripathi S, Tiwari M, Tomar A (2013) Influence of fluoride exposure on hypothalamic pitutary gonadal axis hormones and semen quality. Asian J Biol Life Sci 2:201–206
Chinoy NJ, Narayana MV (1994) In vitro fluoride toxicity in human spermatozoa. Reprod Toxicol 8:155–159. https://doi.org/10.1016/0890-6238(94)90022-1
Chinoy NJ, Sequeira E (1989) Effects of fluoride on the histoarchitecture of reproductive organs of the male mouse. Reprod Toxicol 3:261–267. https://doi.org/10.1016/0890-6238(89)90020-8
Daesslé LW, Ruiz-Montoya L, Tobschall HJ, Chandrajith R, Camacho-Ibar VF, Mendoza-Espinosa LG, Quintanilla-Montoya AL, Lugo-Ibarra KC (2009) Fluoride, nitrate and water hardness in groundwater supplied to the rural communities of Ensenada County, Baja California, Mexico. Environ Geol 58:419–429. https://doi.org/10.1007/s00254-008-1512-9
Dharmagunawardhane HA, Dissanayake CB (1993) Fluoride problems in Sri Lanka. Environ Manag Health. https://doi.org/10.1108/09566169310033422
Dissanayake C (2005) Of stones and health: medical geology in Sri Lanka. Science 309:883–885. https://doi.org/10.1126/science.1115174
Dissanayake CB, Chandrajith R (2007) Medical geology in tropical countries with special reference to Sri Lanka. Environ Geochem Health 29:155–162. https://doi.org/10.1007/s10653-006-9070-0
Dissanayake CB, Chandrajith R (2009) Introduction to medical geology. Springer, Berlin. https://doi.org/10.1007/978-3-642-00485-8
Dissanayake CB, Chandrajith R (2018) The hydrogeological and geochemical characteristics of groundwater of Sri Lanka. In: A. M (ed) Groundwater of South Asia. vol Springer Hydrogeology. Springer, Singapore
Dissanayake CB, Chandrajith R (2019) Fluoride and hardness in groundwater of tropical regions-review of recent evidence indicating tissue calcification and calcium phosphate nanoparticle formation in kidney tubules. Ceylon J Sci 48:197–207. https://doi.org/10.4038/cjs.v48i3.7643
Dong C, Cao J, Cao C, Han Y, Wu S, Wang S, Wang J (2016) Effects of fluoride and aluminum on expressions of StAR and P450scc of related steroidogenesis in guinea pigs’ testis. Chemosphere 147:345–351. https://doi.org/10.1016/j.chemosphere.2015.12.064
Dunipace AJ, Zhang W, Noblitt TW, Li Y, Stookey GK (1989) Genotoxic evaluation of chronic fluoride exposure: micronucleus and sperm morphology studies. J Dent Res 68:1525–1528. https://doi.org/10.1177/00220345890680111101
Edmunds WM, Smedley PL (2013) Fluoride in natural waters. In: O. S (ed) Essentials of medical geology, vol Springer, Dordrecht, pp 311–336. https://doi.org/10.1007/978-94-007-4375-5_13
Feng D, Huang H, Yang Y, Yan T, Jin Y, Cheng X, Cui L (2015) Ameliorative effects of N-acetylcysteine on fluoride-induced oxidative stress and DNA damage in male rats’ testis. Mutat Res 792:35–45. https://doi.org/10.1016/j.mrgentox.2015.09.004
Fernando WBNT, Nanayakkara N, Gunarathne L, Chandrajith R (2020) Serum and urine fluoride levels in populations of high environmental fluoride exposure with endemic CKDu: a case–control study from Sri Lanka. Environ Geochem Health 42:1497–1504. https://doi.org/10.1007/s10653-019-00444-x
Fraczek M, Kurpisz M (2015) Cytokines in the male reproductive tract and their role in infertility disorders. J Reprod Immunol 108:98–104. https://doi.org/10.1016/j.jri.2015.02.001
Gadani SP, Cronk JC, Norris GT, Kipnis J (2012) IL-4 in the Brain: a cytokine to remember. J Immunol 189:4213–4219. https://doi.org/10.4049/jimmunol.1202246
Gerardo B, Cabral Pinto M, Nogueira J, Pinto P, Almeida A, Pinto E, Marinho-Reis P, Diniz L, Moreira PI, Simões MR, Freitas S (2020) Associations between trace elements and cognitive decline: an exploratory 5-Year follow-up study of an elderly cohort. Int J Environ Res Public Health 17:6051. https://doi.org/10.3390/ijerph17176051
Ghosh D, Das S, Maiti R, Jana D, Das UB (2002) Testicular toxicity in sodium fluoride treated rats: association with oxidative stress. Reprod Toxicol 16:385–390. https://doi.org/10.1016/S0890-6238(02)00038-2
Giri A, Bharti VK, Angmo K, Kalia S, Kumar B (2016) Fluoride induced oxidative stress, immune system and apoptosis in animals: a review. Int J Bioassays 5:5174–5178
Gupta RS, Khan TI, Agrawal D, Kachhawa JBS (2007) The toxic effects of sodium fluoride on the reproductive system of male rats. Toxicol Ind Health 23:507–513. https://doi.org/10.1177/0748233708089041
Han Y, Yu Y, Liang C, Shi Y, Zhu Y, Zheng H, Wang J, Zhang J (2019) Fluoride-induced unrestored arrest during haploid period of spermatogenesis via the regulation of DDX25 in rats. Environ Pollut 253:538–551. https://doi.org/10.1016/j.envpol.2019.06.107
Hedger MP, Meinhardt A (2003) Cytokines and the immune-testicular axis. J Reprod Immunol 58:1–26. https://doi.org/10.1016/S0165-0378(02)00060-8
Karunanidhi D, Aravinthasamy P, Subramani T, Wu J, Srinivasamoorthy K (2019) Potential health risk assessment for fluoride and nitrate contamination in hard rock aquifers of Shanmuganadhi River basin, South India. Hum Ecol Risk Assess Int J 25(1–2):250–270. https://doi.org/10.1080/10807039.2019.156885
Kim J, Kwon W-S, Rahman MS, Lee J-S, Yoon S-J, Park Y-J, You Y-A, Pang M-G (2015) Effect of sodium fluoride on male mouse fertility. Andrology 3:544–551. https://doi.org/10.1111/andr.12006
Kumar N, Sood S, Arora B, Singh M (2010) Effect of duration of fluoride exposure on the reproductive system in male rabbits. J Hum Reprod Sci 3:148
Li J, Shi Y, Fan H, Li Y, Zhu Y, Lin X, Zhang J (2018) Effects of fluoride on surface structure of primary culture Leydig cells in mouse. Biol Trace Elem Res 183:123–127. https://doi.org/10.1007/s12011-017-1121-0
Li P, He X, Li Y (2019) Occurrence and health implication of fluoride in groundwater of loess aquifer in the Chinese loess plateau: a case study of Tongchuan, Northwest China. Expo Health 11:95–107. https://doi.org/10.1007/s12403-018-0278-x
Liang C, Gao Y, He Y, Han Y, Manthari RK, Tikka C, Chen C, Wang J, Zhang J (2020a) 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
Liang C, He Y, Liu Y, Gao Y, Han Y, Li X, Zhao Y, Wang J, Zhang J (2020b) Fluoride exposure alters the ultra-structure of sperm flagellum via reducing key protein expressions in testis. Chemosphere 246:125772. https://doi.org/10.1016/j.chemosphere.2019.125772
Liu L, Wu J, He S (2021) Occurrence and distribution of groundwater fluoride and manganese in the Weining plain (China) and their probabilistic health risk quantification. Expo Health. https://doi.org/10.1007/s12403-021-00434-4
Liu Y, Liang C, Gao Y, Jiang S, He Y, Han Y, Olfati A, Manthari RK, Wang J, Zhang J (2019) Fluoride interferes with the sperm fertilizing ability via downregulated SPAM1, ACR, and PRSS21 expression in rat epididymis. J Agric Food Chem 67:5240–5249. https://doi.org/10.1021/acs.jafc.9b01114
Loveland KL, Klein B, Pueschl D, Indumathy S, Bergmann M, Loveland BE, Hedger MP, Schuppe HC (2017) Cytokines in male fertility and reproductive pathologies: immunoregulation and beyond. Front Endocrinol 8:307. https://doi.org/10.3389/fendo.2017.00307
Nanayakkara D, Chandrasekara M, Wimalasiri WR (1999) Dental fluorosis and caries incidence in rural children residing in a high fluoride area in the dry zone of Sri Lanka.
Nanayakkara S, Senevirathna STMLD, Harada KH, Chandrajith R, Nanayakkara N, Koizumi A (2020) The Influence of fluoride on chronic kidney disease of uncertain aetiology (CKDu) in Sri Lanka. Chemosphere 257:127186. https://doi.org/10.1016/j.chemosphere.2020.127186
Ortiz-Pérez D, Rodrı́guez-Martı́nez M, Martı́nez F, Borja-Aburto VcH, Castelo J, Grimaldo JI, de la Cruz E, Carrizales L, Dı́az-Barriga F (2003) Fluoride-induced disruption of reproductive hormones in men. Environ Res 93:20–30. https://doi.org/10.1016/S0013-9351(03)00059-8
Papadimas J, Goulis DG, Sotiriades A, Daniilidis M, Fleva A, Bontis JN, Tourkantonis A (2002) Interleukin-1 beta and tumor necrosis factor-alpha in normal/infertile men. Arch Androl 48:107–113. https://doi.org/10.1080/014850102317267418
Pervez A, Sinha MK, Yadav M (2016) Implications of fluoride toxicity on the male reproductive system: a review. J Mt Res 11:1–7
Pushpalatha T, Srinivas M, Reddy PS (2005) Exposure to high fluoride concentration in drinking water will affect spermatogenesis and steroidogenesis in male albino rats. Biometals 18:207–212. https://doi.org/10.1007/s10534-005-0336-2
Rafique T, Ahmed I, Soomro F, Khan M, Shirint K (2015) Fluoride levels in urine, blood plasma and serum of people living in an endemic fluorosis serum in the thar desert, Pakistan. J Chem Soc Pak 37(06):1223–1230
Ranasinghe N, Kruger E, Chandrajith R, Tennant M (2019) The heterogeneous nature of water well fluoride levels in Sri Lanka: an opportunity to mitigate the dental fluorosis. Commun Dent Oral Epidemiol 47:236–242. https://doi.org/10.1111/cdoe.12449
Roberts M, Jarvi K (2009) Steps in the investigation and management of low semen volume in the infertile man. Can Urol Assoc J 3:479
Rubasinghe R, Gunatilake SK, Chandrajith R (2015) Geochemical characteristics of groundwater in different climatic zones of Sri Lanka. Environ Earth Sci 74:3067–3076. https://doi.org/10.1007/s12665-015-4339-1
Saalu LC (2010) The incriminating role of reactive oxygen species in idiopathic male infertility: an evidence based evaluation. Pak J Biol Sci 13:413
Skare JA, Schrotel KR, Nixon GA (1986) Lack of DNA-strand breaks in rat testicular cells after in vivo treatment with sodium fluoride. Mutat Res 170:85–92. https://doi.org/10.1016/0165-1218(86)90085-6
Sprando RL, Collins TFX, Black T, Olejnik N, Rorie J (1998) Testing the potential of sodium fluoride to affect spermatogenesis: a morphometric study. Food Chem Toxicol 36:1117–1124. https://doi.org/10.1016/S0278-6915(98)00085-4
Subba Rao N, Ravindra B, Wu J (2020) Geochemical and health risk evaluation of fluoride rich groundwater in Sattenapalle Region, Guntur district, Andhra Pradesh, India. Hum Ecol Risk Assess Int J 26(9):2316–2348. https://doi.org/10.1080/10807039.2020.1741338
Sun Z, Zhang W, Xue X, Zhang Y, Niu R, Li X, Li B, Wang X, Wang J (2016) Fluoride decreased the sperm ATP of mice through inhabiting mitochondrial respiration. Chemosphere 144:1012–1017. https://doi.org/10.1016/j.chemosphere.2015.09.061
Sun Z, Li S, Yu Y, Chen H, Ommati MM, Manthari RK, Niu R, Wang J (2018) Alterations in epididymal proteomics and antioxidant activity of mice exposed to fluoride. Arch Toxicol 92:169–180. https://doi.org/10.1007/s00204-017-2054-2
Tang W, Zheng X, Li D, Xiao Y, Yang C, Shang S, Shi M, Zhu Y (2018) Effects of sodium fluoride on the reproductive development of Bombyx mori. Environ Toxicol Pharmacol 64:41–47. https://doi.org/10.1016/j.etap.2018.09.009
Thermo scientific orion fluoride ion selective electrode (2016) https://assets.thermofisher.com/TFS-Assets/LSG/manuals/D15872~.pdf
Vithanage M, Bhattacharya P (2015) Fluoride in the environment: sources, distribution and defluoridation. Environ Chem Lett 13:131–147. https://doi.org/10.1007/s10311-015-0496-4
Wan S, Zhang J, Wang J, Shanxi B (2006) Effects of high fluoride on sperm quality and testicular histology in male rats. Fluoride 39:17–21
WHO (2004) Guidelines for drinking-water quality. Recommendations, vol 1. World Health Organization, Geneva
WHO (2010) WHO laboratory manual for the examination and processing of human semen, 5th edn. World Health Organization, Geneva
Yadav KK, Kumar S, Pham QB, Gupta N, Rezania S, Kamyab H, Yadav S, Vymazal J, Kumar V, Tri DQ, Talaiekhozani A, Prasad S, Reece LM, Singh N, Maurya PK, Cho J (2019) Fluoride contamination, health problems and remediation methods in Asian groundwater: a comprehensive review. Ecotoxicol Environ Saf 182:109362. https://doi.org/10.1016/j.ecoenv.2019.06.045
Yu Y-J, Zhu W-Q, Xu L-N, Ming P-P, Shao S-Y, Qiu J (2019) Osseointegration of titanium dental implant under fluoride exposure in rabbits: Micro-CT and histomorphometry study. Clin Oral Implant Res 30:1038–1048. https://doi.org/10.1111/clr.13517
Zakrzewska H, Udała J (2006) In vitro influence of sodium fluoride on adenosine triphosphate (ATP) content in ram semen. In: Annales Academiae Medicae Stetinensis, pp 109–111
Zhang X, Sun Z, Yue B, Li W, Wang J, Niu R (2020) Fluoride reduced CRISP2 expression in testis and epididymal sperm of rats. Fluoride 53:239–248
Acknowledgements
This study was funded by the University of Colombo, Sri Lanka. Relevant staff members of the "Vindana” Reproductive Health Centre, Colombo, and of Durdans Laboratory, Anuradhapura, and Ms. Shakila Rathnayake and Mr. JLRA Jayakody of the Department of Zoology and Environment Sciences, Faculty of Science, University of Colombo are sincerely thanked for their help in sample collection, and technical help.
Funding
Financial assistance by the University of Colombo, Sri Lanka is acknowledged.
Author information
Authors and Affiliations
Contributions
Conceptualization and fund acquisition: CBD, PVU, CRG. Sample collection: SW, JKP. Sample analyses: CRG, RC. Data analyses: CRG, DSA. Draft preparation: CRG. Reviewing and editing: PVU, RC.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest.
Ethical Approval and Consent to Participate
Ethical clearance for the study was obtained from the Ethics Review Committee of the Faculty of Medicine, University of Colombo, Sri Lanka (EC-19–049; 22/08/2019). Participants provided written informed consent before their recruitment for the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gulegoda, C.R., Dissanayake, C.B., Amarasekara, D.S. et al. Impact of Fluoride Exposure on Male Reproductive Parameters: A Pilot Case–Control Study in Sri Lanka. Expo Health 14, 447–457 (2022). https://doi.org/10.1007/s12403-022-00465-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12403-022-00465-5