Fluoride Action Network


Arsenic and fluoride are two of the major groundwater pollutants. To better understand the liver damage induced during development, 24 male rats exposed to fluoride (F), arsenic (As), and their combination (As + F) from the prenatal stage to 90 days after birth were selected for analysis. Histopathological results showed vacuolar degeneration in the As and As + F groups. Compared to those in the control group, aspartate aminotransferase and alanine aminotransferase levels were significantly increased in the combined group. Catalase activity significantly decreased in the treatment groups compared to that in the controls, and the malondialdehyde content in the As and As + F groups was significantly higher than those in the control group. We further evaluated whether this damage is linked to endoplasmic reticulum stress and its related pathways. The mRNA expression levels of PERK, GRP78, EIF2?, ATF4, and CHOP as well as the protein levels of CHOP was significantly increased in the As + F group compared with the control group. These results demonstrate that As, F, and their combination could lead to liver function damage and reduce the antioxidant capacity of the liver to cause oxidative damage to tissues. Moreover, the combination of As and F triggers endoplasmic reticulum stress-induced apoptosis in liver cells by activating the PERK pathway in the unfolded protein response. As and F seem to have different independent effects, whereas their combination resulted in more severe effects overall.


  1. 1.
    Wang SX, Wang ZH, Cheng XT, Li J, Sang ZP, Zhang XD, Han LL, Qiao XY, Wu ZM, Wang ZQ (2007) Arsenic and fluoride exposure in drinking water: children’s IQ and growth in Shanyin County, Shanxi Province, China. Environ Health Perspect 115(4):643–647PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Rocha-Amador D, Navarro ME, Carrizales L, Morales R, Calderón J (2007) Decreased intelligence in children and exposure to fluoride and arsenic in drinking water. Cadernos De Saúde Pública 23(1):S579PubMedCrossRefGoogle Scholar
  3. 3.
    Levy DB, Schramke JA, Esposito KJ, Erickson TA, Moore JC (1999) The shallow ground water chemistry of arsenic, fluorine, and major elements: Eastern Owens Lake, California. Appl Geochem 14(1):53–65CrossRefGoogle Scholar
  4. 4.
    Bretzler A, Lalanne F, Nikiema J, Podgorski J, Pfenninger N, Berg M, Schirmer M (2017) Groundwater arsenic contamination in Burkina Faso, West Africa: predicting and verifying regions at risk. Sci Total Environ 584:958–970PubMedCrossRefGoogle Scholar
  5. 5.
    IPCS (2002) Fluorides. Environmental Health Criteria 227. World Health Organization, Geneva http://www.who.int Google Scholar
  6. 6.
    Yan X, Yang X, Hao X, Ren Q, Gao J, Wang Y, Chang N, Qiu Y, Song G (2015) Sodium fluoride induces apoptosis in H9c2 cardiomyocytes by altering mitochondrial membrane potential and intracellular ROS level. Biol Trace Elem Res 166(2):210–215PubMedCrossRefGoogle Scholar
  7. 7.
    Zhu YP, Xi SH, Li MY, Ding TT, Liu N, Cao FY, Zeng Y, Liu XJ, Tong JW, Jiang SF (2017) Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats. Neurotoxicology 59:56–64PubMedCrossRefGoogle Scholar
  8. 8.
    Chattopadhyay A, Podder S, Agarwal S, Bhattacharya S (2011) Fluoride-induced histopathology and synthesis of stress protein in liver and kidney of mice. Arch Toxicol 85(4):327–335PubMedCrossRefGoogle Scholar
  9. 9.
    Lu Y, Luo Q, Cui H, Deng H, Kuang P, Liu H, Fang J, Zuo Z, Deng J, Li Y (2017) Sodium fluoride causes oxidative stress and apoptosis in the mouse liver. Aging 9(6):1623–1639PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Naujokas MF, Beth A, Habibul A, H Vasken A, Graziano JH, Claudia T, Suk WA (2013) The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environ Health Perspect 121 (3):295-302PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Manthari RK, Tikka C, Ommati MM et al (2018) Arsenic induces autophagy in developmental mouse cerebral cortex and hippocampus by inhibiting PI3K/Akt/mTOR signaling pathway: involvement of blood–brain barrier’s tight junction proteins. Arch Toxicol 92(11):3255–3275PubMedCrossRefGoogle Scholar
  12. 12.
    Zhao Y, Li Y, Wang J, Manthari RK, Wang J (2018) Fluoride induces apoptosis and autophagy through the IL-17 signaling pathway in mice hepatocytes. Arch ToxicolGoogle Scholar
  13. 13.
    Yong H, Yu C, Yao M, Lei W, Bing L, Zhang B, Huang X, Zhang A (2018) The PKC?-Nrf2-ARE signalling pathway may be involved in oxidative stress in arsenic-induced liver damage in rats. In: Environmental Toxicology & Pharmacology 62Google Scholar
  14. 14.
    Prakash C, Kumar V (2016) Chronic arsenic exposure-induced oxidative stress is mediated by decreased mitochondrial biogenesis in rat liver. Biol Trace Elem Res 173(1):87–95PubMedCrossRefGoogle Scholar
  15. 15.
    Chen Y, Ahsan H (2004) Cancer burden from arsenic in drinking water in Bangladesh. Am J Public Health 94(5):741–744PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Bodaghi-Namileh V, Sepand MR, Omidi A, Aghsami M, Seyednejad SA, Kasirzadeh S, Sabzevari O (2017) Acetyl-l-carnitine attenuates arsenic-induced liver injury by abrogation of mitochondrial dysfunction, inflammation, and apoptosis in rats. Environ Toxicol Pharmacol 58:11PubMedCrossRefGoogle Scholar
  17. 17.
    Niu R, Han H, Zhang Y et al (2016) Changes in liver antioxidant status of offspring mice induced by maternal fluoride exposure during gestation and lactation. Biol Trace Elem Res 172(1):172–178PubMedCrossRefGoogle Scholar
  18. 18.
    Ferreira SAC, Sena BDS, Couto SF et al (2018) Arsenic aggravates oxidative stress causing hepatic alterations and inflammation in diabetic rats. Life Sci 209:472–480CrossRefGoogle Scholar
  19. 19.
    Zhou BH, Zhao J, Liu J, Zhang JL, Li J, Wang HW (2015) Fluoride-induced oxidative stress is involved in the morphological damage and dysfunction of liver in female mice. Chemosphere 139:504–511PubMedCrossRefGoogle Scholar
  20. 20.
    Pereira HABDS, Dionizio AS, Araujo TT, Fernandes MDS, Iano FG, Buzalaf MAR (2018) Proposed mechanism for understanding the dose- and time-dependency of the effects of fluoride in the liver. Toxicol Appl Pharmacol 358:68–75PubMedCrossRefGoogle Scholar
  21. 21.
    Kallen CJHVD, Greevenbroek MMJV, Stehouwer CDA, Schalkwijk CG (2009) Endoplasmic reticulum stress-induced apoptosis in the development of diabetes: is there a role for adipose tissue and liver. Apoptosis 14(12):1424–1434PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Higa A, Chevet E (2012) Redox signaling loops in the unfolded protein response. Cell Signal 24(8):1548–1555PubMedCrossRefGoogle Scholar
  23. 23.
    Sun F, Li X, Yang C, Lv P, Li G, Xu H (2014) A role for PERK in the mechanism underlying fluoride-induced bone turnover. Toxicology 325:52–66PubMedCrossRefGoogle Scholar
  24. 24.
    Tian XL, Feng J, Dong NS, Lyu Y, Wei CL, Li B, Ma YQ, Xie JX, Qiu YL, Song GH, Ren XF, Yan XY (2019) Subchronic exposure to arsenite and fluoride from gestation to puberty induces oxidative stress and disrupts ultrastructure in the kidneys of rat offspring. Sci Total Environ 686:1229–1237PubMedCrossRefGoogle Scholar
  25. 25.
    Sankar P, Gopal TA, Kalaivanan R, Karunakaran V, Manikam K, Sarkar SN (2015) Effects of nanoparticle-encapsulated curcumin on arsenic-induced liver toxicity in rats. Environ Toxicol 30(6):628–637PubMedCrossRefGoogle Scholar
  26. 26.
    Mittal M, Flora SJS (2006) Effects of individual and combined exposure to sodium arsenite and sodium fluoride on tissue oxidative stress, arsenic and fluoride levels in male mice. Chem Biol Interact 162(2):128–139PubMedCrossRefGoogle Scholar
  27. 27.
    Flora SJS, Pachauri V, Mittal M, Kumar D (2011) Interactive effect of arsenic and fluoride on cardio-respiratory disorders in male rats: possible role of reactive oxygen species. Biometals 24(4):615–628PubMedCrossRefGoogle Scholar
  28. 28.
    Flora SJS, Mittal M, Mishra D (2009) Co-exposure to arsenic and fluoride on oxidative stress, glutathione linked enzymes, biogenic amines and DNA damage in mouse brain. J Neurol Sci 285(1):198–205PubMedCrossRefGoogle Scholar
  29. 29.
    Li C, Xu J, Li F et al (2011) Unfolded protein response signaling and MAP kinase pathways underlie pathogenesis of arsenic-induced cutaneous inflammation. Cancer Prev Res 4(12):2101–2109CrossRefGoogle Scholar
  30. 30.
    Lu TH, Tseng TJ, Su CC et al (2014) Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways. Toxicol Lett 224(1):130–140PubMedCrossRefGoogle Scholar
  31. 31.
    Yen CC, Ho TJ, Wu CC et al (2011) Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway. Arch Toxicol 85(6):565–575PubMedCrossRefGoogle Scholar
  32. 32.
    Chou YH, Chao PL, Tsai MJ et al (2008) Arsenite-induced cytotoxicity in dorsal root ganglion explants. Free Radic Biol Med 44(8):1553–1561PubMedCrossRefGoogle Scholar
  33. 33.
    Srivastava RK, Li C, Chaudhary SC et al (2013) Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption. Toxicol Appl Pharmacol 272(3):879–887PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Li K, Zhang L, Xiang X et al (2013) Arsenic trioxide alleviates airway hyperresponsiveness and promotes apoptosis of CD4 + T lymphocytes: evidence for involvement of the ER stress–CHOP pathway. Ir J Med Sci 182(4):573–583PubMedCrossRefGoogle Scholar
  35. 35.
    Chiu HW, Tseng YC, Hsu YH et al (2015) Arsenic trioxide induces programmed cell death through stimulation of ER stress and inhibition of the ubiquitin–proteasome system in human sarcoma cells. Cancer Lett 356(2):762–772PubMedCrossRefGoogle Scholar
  36. 36.
    Zhang XY, Yang SM, Zhang HP, Yang Y, Sun SB, Chang JP, Tao XC, Yang TY, Liu C, Yang YM (2015) Endoplasmic reticulum stress mediates the arsenic trioxide-induced apoptosis in human hepatocellular carcinoma cells. Int J Biochem Cell Biol 68:158–165PubMedCrossRefGoogle Scholar
  37. 37.
    Yang X, An L, Li X (2014) Arsenic trioxide induced endoplasmic reticulum stress in laryngeal squamous cell line Hep-2 cells. Auris Nasus Larynx 41(1):81–83PubMedCrossRefGoogle Scholar
  38. 38.
    Li X, Meng L, Wang F, Hu X, Yu Y Sodium fluoride induces apoptosis and autophagy via the endoplasmic reticulum stress pathway in MC3T3-E1 osteoblastic cells. In: Molecular and Cellular Biochemistry, pp 1–9Google Scholar
  39. 39.
    Zhang Y, Zhang KQ, Ma L, Gu HF, Li J, Lei S (2016) Fluoride induced endoplasmic reticulum stress and calcium overload in ameloblasts. Arch Oral Biol 69:95–101PubMedCrossRefGoogle Scholar
  40. 40.
    Deng H, Kuang P, Cui H, Chen L, Luo Q, Fang J, Zuo Z, Deng J, Wang X, Zhao L (2016) Sodium fluoride (NaF) induces the splenic apoptosis via endoplasmic reticulum (ER) stress pathway y in vivo and in vitro. Aging 8(12):3552PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Yang Y, Lin X, Huang H, Feng D, Ba Y, Cheng X, Cui L (2015) Sodium fluoride induces apoptosis through reactive oxygen species-mediated endoplasmic reticulum stress pathway in Sertoli cells. J Environ Sci 30(4):81–89CrossRefGoogle Scholar
  42. 42.
    Niu Q, Chen J, Xia T, Li P, Zhou G, Xu C, Zhao Q, Dong L, Zhang S, Wang A (2016) Excessive ER stress and the resulting autophagic flux dysfunction contribute to fluoride-induced neurotoxicity. Environ Pollut 233:S026974911732465XGoogle Scholar