Effects of Combined Exposure to Cadmium and High-Fat Diet on Bone Quality in Male Mice


This study investigated the effects of combined exposure to low-dose cadmium and high-fat diet on femoral bone quality in male mice. Eight-week-old male SPF C57BL/6J mice were randomly divided into four groups: normal control group (Con), low-cadmium group (Cd), high-fat diet group (HFD), and high-fat diet plus low-dose cadmium group (HFD + Cd); the second and fourth groups were treated intraperitoneally with CdCl2 (1.0 mg/kg body weight) twice weekly for 20 weeks. Assays related to bone quality were performed. Body weight of HFD plus Cd mice was significantly lower than HFD mice. Femoral length was not different among groups, but femoral weight was decreased in the HFD plus Cd group compared with other three groups. Level of Cd in bone was significantly increased in HFD plus Cd group. There was no difference in cortical BMD among groups; however, cortical bone quality parameters were decreased in HFD plus Cd group. Cd and HFD each reduced trabecular bone quality and together had further detrimental effects on these bone parameters. Based on biomechanical analysis, femoral bone strength was decreased, being more brittle and less resistant to biomechanical forces in the HFD plus Cd mice. HFD plus Cd mice had lower OPG mRNA expression and higher RANKL mRNA expression than others. HFD or Cd can cause adverse effects on bone and together had further detrimental effects associated with RANKL/OPG signaling.

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  1. 1.

    Sugimoto T, Sato M, Dehle FC, Brnabic AJ, Weston A, Burge R (2016) Lifestyle-related metabolic disorders, osteoporosis, and fracture risk in Asia: a systematic review. Value Health Reg Issues 9:49–56. https://doi.org/10.1016/j.vhri.2015.09.005

    Article  PubMed  Google Scholar 

  2. 2.

    Bernabei R, Martone AM, Ortolani E, Landi F, Marzetti E (2014) Screening, diagnosis and treatment of osteoporosis: a brief review. Clin Cases Miner Bone Metab 11(3):201–207

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Cheung CL, Seng BA, Chadha M, Chow SL, Chung YS, Hew FL, Jaisamrarn U, Hou N, Takeuchi Y, Wu CH (2018) An updated hip fracture projection in Asia: the Asian Federation of Osteoporosis Societies study. Osteoporos Sarcopenia 4(1):16–21

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Lu YC, Lin YC, Lin YK, Liu YJ, Chang KH, Chieng PU, Chan WP (2016) Prevalence of osteoporosis and low bone mass in older Chinese population based on bone mineral density at multiple skeletal sites. Sci Rep 6:25206. https://doi.org/10.1038/srep25206

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Cooper C, Cole ZA, Holroyd CR, Earl SC, Harvey NC, Dennison EM, Melton LJ, Cummings SR, Kanis JA (2011) Secular trends in the incidence of hip and other osteoporotic fractures. Osteoporos Int 22(5):1277–1288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Yates J, Barrett-Connor E, Barlas S, Chen YT, Miller PD, Siris ES (2004) Rapid loss of hip fracture protection after estrogen cessation: evidence from the National Osteoporosis Risk Assessment. Obstet Gynecol 103(3):440–446

    Article  CAS  Google Scholar 

  7. 7.

    Hata M, Miyao M, Mizuno Y (2003) Osteoporosis as a lifestyle-related disease. Nihon Rinsho 61(2):305–313

    PubMed  Google Scholar 

  8. 8.

    Kazantzis G (2004) Cadmium, osteoporosis and calcium metabolism. Biometals 17(5):493–498

    Article  CAS  Google Scholar 

  9. 9.

    Kaličanin BM (2009) Determination of very toxic metal — cadmium in natural water samples. Desalination 249(1):58–62

    Article  CAS  Google Scholar 

  10. 10.

    Landrigan PJ (1982) Occupational and community exposures to toxic metals: lead, cadmium, mercury and arsenic. West J Med 137(6):531–539

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Weidenhamer JD, Miller J, Guinn D, Pearson J (2011) Bioavailability of cadmium in inexpensive jewelry. Environ Health Perspect 119(7):1029–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Suwazono Y, Kido T, Nakagawa H, Nishijo M, Honda R, Kobayashi E, Dochi M, Nogawa K (2009) Biological half-life of cadmium in the urine of inhabitants after cessation of cadmium exposure. Biomarkers 14(2):77–81

    Article  CAS  Google Scholar 

  13. 13.

    Bernard A (2004) Renal dysfunction induced by cadmium: biomarkers of critical effects. Biometals 17(5):519–523

    Article  CAS  Google Scholar 

  14. 14.

    Mason HJ, Davison AG, Wright AL, Guthrie CJ, Fayers PM, Venables KM, Smith NJ, Chettle DR, Franklin DM, Scott MC (1988) Relations between liver cadmium, cumulative exposure, and renal function in cadmium alloy workers. Br J Ind Med 45(12):793–802

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Dobson (1992) Cadmium-environmental aspects. World Health Organization, Geneva

    Google Scholar 

  16. 16.

    Järup L, Berglund M, Elinder CG, Nordberg G, Vahter M (1998) Health effects of cadmium exposure—a review of the literature and a risk estimate. Scand J Work Environ Health 24(suppl 1):1–52

    PubMed  Google Scholar 

  17. 17.

    Tinkov AA, Filippini T, Ajsuvakova OP, Aaseth J, Gluhcheva YG, Ivanova JM, Bjørklund G, Skalnaya MG, Gatiatulina ER, Popova EV (2017) The role of cadmium in obesity and diabetes. Sci Total Environ 601-602:741–755

    Article  CAS  Google Scholar 

  18. 18.

    Chen X, Wang G, Li X, Gan C, Zhu G, Jin T, Wang Z (2013) Environmental level of cadmium exposure stimulates osteoclasts formation in male rats. Food Chem Toxicol 60(10):530–535

    Article  CAS  Google Scholar 

  19. 19.

    Rudolph S, Nawrot TS, Tom R, Lutgarde T, Dirk V, Tatiana K, Etienne VH, Roels HA, Staessen JA (2008) Bone resorption and environmental exposure to cadmium in women: a population study. Environ Health Perspect 116(6):777–783

    Article  CAS  Google Scholar 

  20. 20.

    Wallin M, Barregard L, Sallsten G, Lundh T, Karlsson MK, Lorentzon M, Ohlsson C, Dan M (2016) Low-level cadmium exposure is associated with decreased bone mineral density and increased risk of incident fractures in elderly men: the MrOS Sweden study. J Bone Miner Res 31(4):732–741

    Article  CAS  Google Scholar 

  21. 21.

    James KA, Meliker JR (2013) Environmental cadmium exposure and osteoporosis: a review. Int J Public Health 58(5):737–745

    Article  Google Scholar 

  22. 22.

    Trzcinka-Ochocka M, Jakubowski M, Szymczak W, Janasik B, Brodzka R (2010) The effects of low environmental cadmium exposure on bone density. Environ Res 110(3):286–293. https://doi.org/10.1016/j.envres.2009.12.003

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Finkelstein EA, Khavjou OA, Thompson H, Trogdon JG, Pan L, Sherry B, Dietz W (2012) Obesity and severe obesity forecasts through 2030. Am J Prev Med 42(6):563–570

    Article  Google Scholar 

  24. 24.

    Kopelman PG (2000) Obesity as a medical problem. Nature 404(6778):635–643. https://doi.org/10.1038/35007508

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Ruiznúñez B, Pruimboom L, Dijckbrouwer DAJ, Muskiet FAJ (2013) Lifestyle and nutritional imbalances associated with Western diseases: causes and consequences of chronic systemic low-grade inflammation in an evolutionary context. J Nutr Biochem 24(7):1183–1201

    Article  CAS  Google Scholar 

  26. 26.

    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444(7121):860–867. https://doi.org/10.1038/nature05485

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Cao JJ (2011) Effects of obesity on bone metabolism. J Orthop Surg Res 6(1):1–7

    Article  Google Scholar 

  28. 28.

    Halade GV, Rahman MM, Williams PJ, Fernandes G (2010) High fat diet-induced animal model of age-associated obesity and osteoporosis. J Nutr Biochem 21(12):1162–1169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Campos RM, De PA, Da SP, Carnier J, Sanches PL, Corgosinho FC, Masquio DC, Lazaretti-Castro M, Oyama LM, Nascimento CM (2012) The role of pro/anti-inflammatory adipokines on bone metabolism in NAFLD obese adolescents: effects of long-term interdisciplinary therapy. Endocrine 42(1):146–156

    Article  CAS  Google Scholar 

  30. 30.

    Leckaczernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL (2002) Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 143(6):2376–2384

    Article  CAS  Google Scholar 

  31. 31.

    Paula FJ, Rosen CJ (2010) Obesity, diabetes mellitus and last but not least, osteoporosis. Arq Bras Endocrinol Metabol 54(2):150–157

    Article  Google Scholar 

  32. 32.

    Hildebrand T, Rüegsegger P (1997) Quantification of bone microarchitecture with the structure model index. Comput Meth Biomech Biomed Eng 1(1):15–23

    Article  Google Scholar 

  33. 33.

    Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Ralph M (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 25(7):1468–1486

    Article  Google Scholar 

  34. 34.

    Forestierzhang L, Bishop N (2016) Bone strength in children: understanding basic bone biomechanics. Arch Dis Child Educ Pract Ed 101(1):2–7

    Article  Google Scholar 

  35. 35.

    Ashton JR, West JL, Badea CT (2015) In vivo small animal micro-CT using nanoparticle contrast agents. Front Pharmacol 6(256). https://doi.org/10.3389/fphar.2015.00256

  36. 36.

    Carter DR, Hayes WC (1976) Bone compressive strength: the influence of density and strain rate. Science 194(4270):1174–1176

    Article  CAS  Google Scholar 

  37. 37.

    Ito M, Nishida A, Aoyagi K, Uetani M, Hayashi K, Kawase M (2005) Effects of risedronate on trabecular microstructure and biomechanical properties in ovariectomized rat tibia. Osteoporos Int 16(9):1042–1048

    Article  CAS  Google Scholar 

  38. 38.

    Siu WS, Qin L, Cheung WH, Leung KS (2004) A study of trabecular bones in ovariectomized goats with micro-computed tomography and peripheral quantitative computed tomography. Bone 35(1):21–26

    Article  CAS  Google Scholar 

  39. 39.

    Gautam J, Choudhary D, Khedgikar V, Kushwaha P, Singh RS, Singh D, Tiwari S, Trivedi R (2014) Micro-architectural changes in cancellous bone differ in female and male C57BL/6 mice with high-fat diet-induced low bone mineral density. Br J Nutr 111(10):1811–1821

    Article  CAS  Google Scholar 

  40. 40.

    Li W, Xu P, Wang C, Ha X, Gu Y, Wang Y, Zhang J, Xie J (2017) The effects of fat-induced obesity on bone metabolism in rats. Obes Res Clin Pract 11(4):454–463

    Article  Google Scholar 

  41. 41.

    Carvalho AL, Demambro VE, Guntur AR, Le P, Nagano K, Baron R, Fja DP, Motyl KJ (2018) High fat diet attenuates hyperglycemia, body composition changes, and bone loss in male streptozotocin-induced type 1 diabetic mice. J Cell Physiol 233(2):1585–1600

    Article  CAS  Google Scholar 

  42. 42.

    Minematsu A, Nishii Y, Sakata S (2018) High-fat/high-sucrose diet results in higher bone mass in aged rats. Bone Rep 8:18–24

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Pan X, Yin Y, Qingchu LI, Kanghui LI, Wei J, Wenfeng MA, Leng B (2016) Effect of raloxifene on cell survival and expression of 1-α-hydroxylase in cadmium-induced renal tubular epithelial cells. Shandong Med J 56(30):5–8

    Google Scholar 

  44. 44.

    Park JM, Park CY, Han SN (2015) High fat diet-induced obesity alters vitamin D metabolizing enzyme expression in mice. Biofactors 41(3):175–182

    Article  CAS  Google Scholar 

  45. 45.

    Olszowski T, Baranowskabosiacka I, Gutowska I, Chlubek D (2012) Pro-inflammatory properties of cadmium. Acta Biochim Pol 59(4):475–482

    Article  CAS  Google Scholar 

  46. 46.

    Gu Y, Yu S, Lambert JD (2014) Dietary cocoa ameliorates obesity-related inflammation in high fat-fed mice. Eur J Nutr 53(1):149–158

    Article  CAS  Google Scholar 

  47. 47.

    Gunaratnam K, Vidal C, Gimble JM, Duque G (2014) Mechanisms of palmitate-induced lipotoxicity in human osteoblasts. Endocrinology 155(1):108–116

    Article  CAS  Google Scholar 

  48. 48.

    Chen X, Zhu G, Gu S, Jin T, Shao C (2009) Effects of cadmium on osteoblasts and osteoclasts in vitro. Environ Toxicol Pharmacol 28(2):232–236

    Article  CAS  Google Scholar 

  49. 49.

    Weitzmann MN (2013) The role of inflammatory cytokines, the RANKL/OPG axis, and the immunoskeletal interface in physiological bone turnover and osteoporosis. Scientifica 2013,(2013-2-3) 2013 (3):125705:1–29

    Article  CAS  Google Scholar 

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This work was supported by National Natural Science Foundation of China (grant number 81773414) and National Natural Science Foundation of China (grant number 81673151).

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Correspondence to Zengli Zhang.

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Animal care followed the Guide for the Care and Use of Laboratory Animals, and the study protocols were approved by the Soochow University Institutional Animal Care and Use Committee (Permit number: 201801A346).

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The authors declare that they have no conflict of interest.

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Zhang, X., Li, X., Sheng, Z. et al. Effects of Combined Exposure to Cadmium and High-Fat Diet on Bone Quality in Male Mice. Biol Trace Elem Res 193, 434–444 (2020). https://doi.org/10.1007/s12011-019-01713-7

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  • Cadmium
  • High-fat diet
  • Mice
  • Femur
  • Micro-CT