Abstract
Lipid peroxidation and ROS generation are the pathogenesis of chronic fluoride toxicity, and its detrimental effects on human reproduction are noted drastically. The aim of the present study was to elucidate the defensive effects of soy protein concentrate (SPC) against sodium fluoride (NaF)-induced uterine dysfunction at biochemical and histological level. Rats were randomly distributed into four groups as control, NaF-treated (200 ppm), and SPC co-administered groups (20 mg and 40 mg/ 100 g body weight) for 16 days. SPC reversed the toxic effects of NaF. SPC significantly ameliorated the NaF-induced alterations of the antioxidant system in the uterus by decreasing lipid peroxidation products and by increasing antioxidant activities. SPC significantly counteracted the adverse effects of NaF on serum level of lactate dehydrogenase (LDH) and inflammatory markers Interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) and nuclear factor kappa-B (NF-κB). Our results also explored that lipid profile was meaningfully altered due to NaF and also focused a diminution of circulating homocysteine (Hcy) and altered lipid profiles along with a diminished quantity of serum B12 and B9. However, both the doses of SPC reverted back serum levels of B12, B9, and Hcy status in similar fashion along with its corrective action on lipid profile. NaF-treated group exhibited a marked degree of reduction in the weights of ovary and uterus with an alteration of normal tissue histology and significant diminution in serum estradiol (ES) levels without fluctuating uterine estradiol receptor-α (ER-α). However, SPC restored the normal tissue histoarchitecture and also increased the functional efficiency and expression of the ER-α receptor by overturning the ES levels in NaF-treated rats. Moreover, both the doses of SPC were effective against NaF-induced alterations, although 40 mg SPC/100 g body weight had better efficacy in ameliorating the NaF-induced adverse effects on the uterus and ovary.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-018-3542-5/MediaObjects/11356_2018_3542_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-018-3542-5/MediaObjects/11356_2018_3542_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-018-3542-5/MediaObjects/11356_2018_3542_Fig3_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-018-3542-5/MediaObjects/11356_2018_3542_Fig4_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-018-3542-5/MediaObjects/11356_2018_3542_Fig5_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-018-3542-5/MediaObjects/11356_2018_3542_Fig6_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-018-3542-5/MediaObjects/11356_2018_3542_Fig7_HTML.png)
Similar content being viewed by others
Abbreviations
- CAT:
-
Catalase
- CD:
-
Conjugated dienes
- ES:
-
Estradiol
- ER-α:
-
Estradiol receptor-α
- GPx:
-
Glutathione peroxidase
- Hcy:
-
Homocysteine
- HDL:
-
High density lipoprotein
- IL-6:
-
Interleukin-6
- LDH:
-
Lactate dehydrogenase
- LDL:
-
Low density lipoprotein
- MDA:
-
Malondialdehyde
- NaF:
-
Sodium fluoride
- NF-κB:
-
Nuclear factor kappa B
- NPSH:
-
Non-protein soluble thiol
- ROS:
-
Reactive oxygen species
- SGOT:
-
Serum glutamic oxaloacetic transaminase
- SGPT:
-
Serum glutamic pyruvic transaminase
- SOD:
-
Superoxide dismutase
- SPC:
-
Soy protein concentrate
- TNF-α:
-
Tumor necrosis factor alpha
References
Afolabi OK, Oyewo EB, Adekunle AS, Adedosu OT, Adedeji AL (2013) Oxidative indices correlate with dyslipidemia and pro-inflammatory cytokine levels in fluoride-exposed rats. Arch Ind Hyg Toxicol 64:521–529
Ali N, Zhang L, Li L, Chan LH, Li B (2015) Effect of pressurized soy protein isolate upon the growth and antioxidants functions of SD rat. Food Nutri Sci 6:501
Al-Khafaji F, Bowron A, Day AP, Scott J, Stansbie D (1998) Stabilization of blood homocysteine by 3-deazaadenosine. Ann Clin Biochem 35:780–782
Anderson JW, Blake JE, Turner J, Smith BM (1998) Effects of soy protein on renal function and proteinuria in patients with type 2 diabetes. Am J Clin Nutr 68:1347–1353
Appelt LC, Reicks MM (1999) Soy induces phase II enzymes but does not inhibit dimethylbenz [a] anthracene-induced carcinogenesis in female rats. J Nutr 129:1820–1826
Atmaca G (2004) Antioxidant effects of sulfur-containing amino acids. Yonsei Med J 45:776–788
Aukema HM, Housini I (2001) Dietary soy protein effects on disease and IGF-I in male and female Han: SPRD-cy rats. Kidney Int 59:52–61
Bachinskiĭ PP, Gutsalenko OA, Naryzhniuk ND, Sidora VD, Shliakhta AI (1985) Action of the body fluorine of healthy persons and thyroidopathy patients on the function of hypophyseal-thyroid the system. Probl Endokrinol (Mosk) 31:25–29
Barbosa AC, Lajolo FM, Genovese MI (2011) Effect of free or protein-associated soy isoflavones on the antioxidant status in rats. J Sci Food Agri 91:721–731
Baum JA, Teng H, Erdman JW Jr, Weigel RM, Klein BP, Persky VW, Freels S, Surya P, Bakhit RM, Ramos E, Shay NF (1998) Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women. Am J Clin Nutr 68:545–551
Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V (2000) Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 23:1227–1231
Bouaziz H, Fetoui H, Ketata S, Jammoussi K, Ellouze F, Zeghal N (2006a) Effects of sodium fluoride ingested by lactating mice on some haematological parameters in suckling pups and dams. Fluoride 39:211–219
Bouaziz H, Ketata S, Jammoussi K, Boudawara T, Ayedi F, Ellouze F, Zeghal N (2006b) Effects of sodium fluoride on hepatic toxicity in adult mice and their suckling pups. Pestic Biochem Physiol 86:124–130
Brandt RB, Laux JE, Spainhour SE, Kline ES (1987) Lactate dehydrogenase in rat mitochondria. Arch Biochem Biophys 259:412–422
Burris RL, Nag HP, Nagarajan S (2014) Soy protein inhibits inflammation-induced VCAM-1 and inflammatory cytokine induction by inhibiting the NF-κB and AKT signaling pathway in apolipoprotein E–deficient mice. Eur J Nutr 53:135–148
Campbell MF, Kraut CW, Yackel WC, Yang HS (1985) Soy protein concentrate. In: Altschul AM, Wilcke HL (eds) New protein foods: seed storage proteins 5. Academic press
CGWB (2015) Groundwater quality scenario in India. In: Central ground water board. Government of India, New Delhi
Collins TF, Sprando RL, Shackelford ME, Black TN, Ames MJ, Welsh JJ, Balmer MF, Olejnik N, Ruggles DI (1995) Developmental toxicity of sodium fluoride in rats. Food Chem Toxicol 33:951–960
Despres JP (2006) Abdominal obesity: the most prevalent cause of the metabolic syndrome and related cardiometabolic risk. Eur Heart J 8(1):B4–B12
Devasagayam TP, Boloor KK, Ramasarma T (2003) Methods for estimating lipid peroxidation: an analysis of merits and demerits. Ind J Biochem Biophys 40:300–308
Dhurvey V, Thakare M (2016) The effect of sodium fluoride intoxication on the estrous cycle and ovarian hormones in rats. Fluoride 49:223
Dhurvey V, Patil V, Thakare M (2017) Effect of sodium fluoride on the structure and function of the thyroid and ovary in albino rats (rattus norvegicus). Fluoroide 50:235–246
Drent M, Cobben NA, Henderson RF, Wouters EF, van Dieijen-Visser M (1996) Usefulness of lactate dehydrogenase and its isoenzymes as indicators of lung damage or inflammation. Eur Respir J 9:1736–1742
Emsley J, Jones DJ, Miller JM, Overill RE, Waddilove RA (1981) An unexpectedly strong hydrogen bond: ab initio calculations and spectroscopic studies of amide-fluoride systems. J Am Chem Soc 103:24–28
FAO/WHO (1989) Protein quality evaluation: report of the joint FAO/WHO expert consultation. Food and Agriculture Organization of the United Nations (Food and Nutrition Paper), Bethesda, p 51
Food and Drug Administration (1999) Food labeling health claims; soy protein and coronary heart disease. Fed Regist 64:57699–57733
Galvez AF, Chen N, Macasieb J, Ben O (2001) Chemopreventive property of a soybean peptide (lunasin) that binds to deacetylated histones and inhibits acetylation. Cancer Res 61:7473–7478
Gawel S, Wardas M, Niedworok E, Wardas P (2004) Malondialdehyde (MDA) as a lipid peroxidation marker. Wiadomoscilekarskie 57:453–455
Ghosh D, Das S, Maiti R, Jana D, Das UB (2002) Testicular toxicity in sodium fluoride treated rats: association with oxidative stress. ReprodToxicol 16:385–390
Ghosh S, Willard B, Comhair SA, Dibello P, Xu W, Shiva S, Aulak KS, Kinter M, Erzurum SC (2013) Disulfide bond as a switch for copper-zinc superoxide dismutase activity in asthma. Antioxid Redox Signal 18(4):412–423
Gudbrandsen OA, Wergedahl H, Mørk S, Liaset B, Espe M, Berge RK (2006) Dietary soya protein concentrate enriched with isoflavones reduced fatty liver, increased hepatic fatty acid oxidation and decreased the hepatic mRNA level of VLDL receptor in obese Zucker rats. Br J Nutr 96:249–257
Hadwan MH (2016) New method for assessment of serum catalase activity. Indian J Sci Technol 9:1–5
Hanson LN, Engelman HM, Alekel DL, Schalinske KL, Kohut ML, Reddy MB (2006) Effects of soy isoflavones and phytate on homocysteine, C-reactive protein, and iron status in postmenopausal women. Am J Clin Nutr 84:774–780
Helmy SA, Emarah HA, Abdelrazek HM (2014) Estrogenic effect of soy phytoestrogens on the uterus of ovariectomized female rats. Clin Pharmacol Biopharmaceut 2:1–7
Hernández-Ledesma B, Hsieh CC, Ben O (2009) Antioxidant and anti-inflammatory properties of cancer preventive peptide lunasin in RAW 2647 macrophages. Biochem Biophys Res Commun 390:803–808
Herrmann W, Obeid R, Hübner U, Jouma M, Geisel J (2004) Homocysteine in relation to C-reactive protein and low-density lipoprotein cholesterol in assessment of cardiovascular risk. Cell Mol Biol 50:895–901
Hirano T, Takahashi T, Saito S, Tajima H, Ebara T, Adachi M (2001) Apoprotein C-III deficiency markedly stimulates triglyceride secretion in vivo: comparison with apoprotein E. Am J Physiol Endocrinol Metab 281:665–669
Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf BM, Tanji N, Ferran LJ, Kohl B, Rao V, Kisiel W, Stern DM (2001) Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 107:675–683
Hubert J, Berger M, Dayde J (2005) Use of simplified HPLC-UV analysis for soya saponin B determination: study of saponin and isoflavones variability in soybean cultivars and soy-based health food products. J Agric Food Chem 53:3923–3930
Jaric I, ZivanoviC J, Miler M, Ajdzanovic V, Blagojevic D, Ristic N, Milosevic V, Nestorovic N (2018) Genistein and daidzein treatments differently affect uterine homeostasis in the ovary-intact middle-aged rats. Toxicol Appl Pharmacol 339:73–84
Jhala DD, Nair SB, Chinoy NJ (2004) Reversible toxicity of fluoride and arsenic in ovary of mice. Fluoride 37:71–79
Kamata H, Honda SI, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649–661
Kamble N, Velhal V (2010) Cytopathological assessment of uterine cells in rattus norvegicus due to induced sodium fluoride. Bioscan 27:301–303
Kojima M, Sekikawa K, Nemoto K, Degawa M (2005) Tumor necrosis factor-alpha independent downregulation of hepatic cholesterol 7alpha hydroxylase gene in mice treated with lead nitrate. Toxicol Sci 87:537–542
Kumar A (2012) Effect of simuastation on paraxonase 1 (PON1) activity and oxidation stress in: Kumar a (ed) significance of lipid profile assay as diagnostic and prognostic tool. CreateSpace Independent Publishing Platform, California, pp 105–109
Lawson PB, Yu MH (2003) Fluoride inhibition of superoxide dismutase (SOD) from the earthworm Eisenia fetida. Fluoride 36:143–151
Liu J, Du J, Zhang Y, Sun W, Smith BJ, Oberley LW, Cullen JJ (2006) Suppression of the malignant phenotype in pancreatic cancer by overexpression of phospholipid hydroperoxide glutathione peroxidase. Hum Gene Ther 17:105–116
Lohakare JD, Pattanaik AK (2013) Effects of addition of fluorine in diets differing in protein content on urinary fluoride excretion, clinical chemistry and thyroid hormones in calves. Rev Bras Zootec 42:751–758
Lu Y, Luo Q, Cui H, Deng H, Kuang P, Liu H, Fang J, Zuo Z, Deng J, Li Y, Wang X (2017) Sodium fluoride causes oxidative stress and apoptosis in the mouse liver. Aging (Albany NY) 9:1623–1639
Luo Q, Cui H, Deng H, Kuang P, Liu H, Lu Y, Fang J, Zuo Z, Deng J, Li Y, Wang X (2017) Sodium fluoride induces renal inflammatory responses by activating NF-κB signaling pathway and reducing anti-inflammatory cytokine expression in mice. Oncotarget 8:80192–80207
Malanovic N, Streith I, Wolinski H, Rechberger G, Kohlwein SD, Tehlivets O (2008) S-adenosyl-L-homocysteine hydrolase, key enzyme of methylation metabolism, regulates phosphatidylcholine synthesis and triacylglycerol homeostasis in yeast implications for homocysteine as a risk factor of atherosclerosis. J Biol Chem 283:23989–23999
Mehdi S, Jarvi ET, Koehl JR, McCarthy JR, Bey P (1990) The mechanism of inhibition of S-adenosyl-L-homocysteine hydrolase by fluorine-containing adenosine analogs. J Enzyme Inhib 4:1–13
Menoyo I, Rigalli A, Puche RC (2005) Effect of fluoride on the secretion of insulin in the rat. Arzneimittelforschung 55:455–460
Michelfelder AJ (2009) Soy: a complete source of protein. Am Fam Physician 79:43–47
Mieyal JJ, Gallogly MM, Qanungo S, Sabens EA, Shelton MD (2008) Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Rignal 10:1941–1988
Milman N (2012) Intestinal absorption of folic acid-new physiologic & molecular aspects. Indian J Med Res 136:725
Minaei M, Fazelipour S, Tootian Z, Minaei M (2017) The effect of cost effective and useful diets on blood parameters in female mice. Food Nutr Sci 8:474–484
Mohammed IA, Al-Okaily BN (2017) Effect of sodium fluoride on liver functions of rats and amelioration by CoQ10. J Entomol Zool Stud 5:887–893
Nagata C, Shimizu H, Takami R, Hayashi M, Takeda N, Yasuda K (2003) Soy product intake is inversely associated with serum homocysteine level in premenopausal Japanese women. J Nutr 133:797–800
Obeid R, Herrmann W (2009) Homocysteine and lipids: S-adenosyl methionine as a key intermediate. FEBS Lett 58:1215–1225
Paglia DE, Valentine WN (1967) Studies on quantitative and qualitative characterization of erythrocyte glutathione peroxidise. J Lab Clin Med 70:158–169
Pattichis K, Louca LL, Glover V (1994) Quantitation of soluble superoxide dismutase in rat Striata, based on the inhibition of nitrite formation from hydroxylammonium chloride. Anal Biochem 221:428–431
Potter SM (1995) Overview of proposed mechanisms for the hypocholesterolemic effect of soy. J Nutr 125:606–611
Reddy KS, Reddy NV, Niharika P, Reddy MA, Reddy H, Daneswari V (2017) Defluoridation of water using natural adsorbents. Int J Pedod Rehabil 2:51–54
Sauerheber R (2013) Physiologic conditions affect toxicity of ingested industrial fluoride. J Environ Public Health 2013:13
Sharma JD, Solanki M, Solanki D (2007) Sodium fluoride toxicity on reproductive organs of female albino rats. Asian J Exp Sci 21:359–364
Shin DS, DiDonato M, Barondeau DP, Hura GL, Hitomi C, Berglund JA, Getzoff ED, Cary SC, Tainer JA (2009) Superoxide dismutase from the eukaryotic thermophile Alvinella pompejana: structures, stability, mechanism, and insights into amyotrophic lateral sclerosis. J Mol Biol 385:1534–1555
Sorescu D, Weiss D, Lassègue B, Clempus RE, Szöcs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR (2002) Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105:1429–1435
Soulsby ME, Phillips B, Chowdhury P (2004) Effects of soy-protein diet on elevated brain lipid peroxide levels induced by simulated weightlessness. Ann Clin Lab Sci 34:103–106
Stubbe J, Nocera DG, Yee CS, Chang MC (2003) Radical initiation in the class I ribonucleotide reductase: long-range proton-coupled electron transfer. Chem Rev 103:2167–2202
Sumona B, Sheetal S, Anil M, Suvarna P (2011) Comparative evaluation of serum folic acid levels in smokers and non-smokers with chronic periodontitis. Bangladesh J Med Sci 10:83–90
Thakare MT, Dhurvey VT (2014) Histopathological changes in the uterus of rats after an administration of sodium fluoride. Int J Scienti Res 3:63–65
Tolba EA (2013) Dietary phytoestrogens reduce the leptin level in ovariectomized female rats. Int J Chem Environ Biol Sci 1:496–500
Vacek J, Klejdus B, Lojková L, Kubán V (2008) Current trends in isolation, separation, determination and identification of isoflavones: a review. J Sep Sci 31:2054–2067
Wang J, Niu R, Sun Z, Lv LH, Smith GW, Wang JD (2008) Effects of protein and calcium supplementation on bone metabolism and thyroid function in protein and calcium deficient rabbits exposed to fluoride. Fluoride 41:283–291
Weydert CJ, Cullen JJ (2010) Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat Protoc 5:51–66
WHO (2004) Guidelines for drinking-water quality: recommendations. World Health Organization
Winarsi H, Purwanto A, Dwiyanti H (2010) Protein and isoflavone content in soybean and soy germ. J Biota 15:186–193
Yamaguti PM, Simões A, Ganzerla E, Souza DN, Nogueira FN, Nicolau J (2013) Effects of single exposure of sodium fluoride on lipid peroxidation and antioxidant enzymes in salivary glands of rats. Oxidative Med Cell Longev 2013:1–7
Zhan S, Ho SC (2005) Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am J Clin Nutr 81:397–408
Zhan XA, Wang M, Xu ZR, Li JX, Li JX (2006) Toxic effects of fluoride on kidney function and histological structure in young pigs. Fluoride 39:22–26
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
Zhou Y, Qiu Y, He J, Chen X, Ding Y, Wang Y, Liu X (2013a) The toxicity mechanism of sodium fluoride on fertlity in female rats. Food Chem Toxicol 56:297–303
Zhuo XG, Melby MK, Watanabe S (2004) Soy isoflavones intake lowers serum LDL cholesterol: a metaanalysis of 8 randomized controlled trials in humans. J Nutr 134:2395–2400
Funding
This research was partially supported by a grant from UGC NET-JRF (Award Letter No. F.15-9(JULY 2016)/2016(NET) and UGC Ref. No.: 1111/(NET-JULY 2016).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
This study was performed following the guidelines of the Institutional Ethical Committee.
Additional information
Responsible editor: Philippe Garrigues
About this article
Cite this article
Jana, L., Maity, P.P., Perveen, H. et al. 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 Res 25, 36462–36473 (2018). https://doi.org/10.1007/s11356-018-3542-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-018-3542-5