Skip to main content
SpringerLink
Log in

Involvement of Zn Depletion in Cd-Induced Toxicity on Prenatal Bone Formation in Rat

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

This study explored the potential toxicity of Cd on the Zn bone depletion in prenatal bone formation. Female rats received either tap water, Cd, Zn, or Cd + Zn in their drinking water during gestation, and some markers of bone formation were studied in their fetuses removed at the 20th day of pregnancy (GD20). Cd exposure induced maternal hypozincemia and Zn depletion in the femur of the fetuses. A striking inhibition of bone formation in fetuses, expressed by decreases in femur length, width, and area, by the shortening of diaphysis, and by a decrease in length and area of distal and proximal proliferative zones, was observed in fetuses from Cd-exposed mothers. At the molecular level, Cd caused upregulation of MT-1 and ZIP2 genes and significantly depressed the expression of the ZnT5, colα1, osteocalcin, and ALP genes in the femur. Interestingly, Zn treatment ameliorated the Cd-induced maternal hypozincemia and femoral changes and partially restored the normal histomorphometry of the femur. These results suggest that the observed toxic effects of Cd are, at least in part, mediated by the disruption of maternal Zn metabolism during pregnancy leading to Zn depletion and thus to perturbation of prenatal bone formation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. World Health Organisation, Environmental Health Criteria 134, Cadmium. International Programme on Chemical Safety (IPCS) WHO, Geneva. (1992)

  2. Brzóska MM, Roszczenko A, Galażyn-Sidorczuk M, Majewska K (2011) Zinc supplementation can protect from enhanced risk of femoral neck fracture in male rats chronically exposed to cadmium. Exp Toxicol Pathol 63:491–498

    Article  PubMed  Google Scholar 

  3. Engström A, Michaëlsson K, Vahter M, Julin B, Wolk A, Åkesson A (2012) Associations between dietary cadmium exposure and bone mineral density and risk of osteoporosis and fractures among women. Bone 50:1372–1378

    Article  PubMed  Google Scholar 

  4. Youness ER, Mohammed NA, Morsy FA (2012) Cadmium impact and osteoporosis: mechanism of action. Toxicol Mec Methods 22:560–567

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Ogoshi K, Moriyama T, Nanzai Y (1989) Decrease in the mechanical strength of bones of rats administered cadmium. Arch Toxicol 6:320–324

    Article  Google Scholar 

  7. Ogoshi K, Nanzai Y, Moriyama T (1992) Decrease in bone strength of cadmium-treated young and old rats. Arch Toxicol 66:315–320

    Article  CAS  PubMed  Google Scholar 

  8. Bhattacharyya MH, Whelton BD, Stern PH, Peterson DP (1988) Cadmium accelerates bone loss in ovariectomized mice and fetal rat limb bones in culture. Proc Nail Acad Sci USA 85:8761–8765

    Article  CAS  Google Scholar 

  9. Ovesen J, Moller-Madsen B, Thomsen JS, Canscher G, Mosekilde L (2001) The positive effects of zinc on skeletal strength in growing rats. Bone 29:565–570

    Article  CAS  PubMed  Google Scholar 

  10. Rossi L, Migliaccio S, Corsi A, Marzia M, Bianco P, Teti A (2001) Reduced growth and skeletal changes in zinc-deficient growing rats are due to impaired growth plate activity and inanition. J Nutr 13:1142–1146

    Google Scholar 

  11. Wang X, Fosmire GJ, Gay CV, Leach M (2002) Short-term zinc deficiency inhibits chondrocyte proliferation and induces cell apoptosis in the epiphyseal growth plate of young chickens. J Nutr 132:665–673

    CAS  PubMed  Google Scholar 

  12. Kwun IS, Cho YE, Lomeda RAR, Shin HI, Choi Y, Kang YH, Beattie JH (2010) Zinc deficiency suppresses matrix mineralization and retards osteogenesis transiently with catch-up possibly through Runx 2 modulation. Bone 46:732–741

    Article  CAS  PubMed  Google Scholar 

  13. Fong L, Tan K, Tran C, Cool J, Scherer MA, Elovaris R, Coyle P, Foster BK, Rofe AM, Xian CJ (2009) Interaction of dietary zinc and intracellular binding protein metallothionein in postnatal bone growth. Bone 44:1151–1162

    Article  CAS  PubMed  Google Scholar 

  14. Suzuki T, Ishihara K, Magaki H, Matsurra W, Kohda A, Okumura K (2005) Zinc transporters, ZnT5 and ZnT7, are required for the activation of alkaline phosphatases, zinc-requiring enzymes that are glycosyl phosphatidyl inositol-anchored to the cytoplasmic membrane. J Biol Chem 280:637–643

    Article  CAS  PubMed  Google Scholar 

  15. King LM, Banks WA, George WJ (2000) Differential zinc transport into the testis and brain of cadmium-sensitive and -resistant murine strains. J Androl 21:656–663

    CAS  PubMed  Google Scholar 

  16. Dalton TP, He L, Wang MB, Miller L, Jin L, Stringer KF (2005) Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. PNAS 102:3401–3406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chemek M, Boughammoura S, Ben Mimouna S, Chouchene L, Banni M, Messaoudi I (2015) Changes of the mRNA expression pattern of Zn transporters: a probable mechanism for cadmium retention and zinc redistribution in the suckling rat tissues. Biol Trace Elem Res 165:173–182

    Article  CAS  PubMed  Google Scholar 

  18. Chemek M, Ben Mimouna S, Boughammoura S, Delbès G, Messaoudi I (2016) Protective role of zinc against the toxicity induced by exposure to cadmium during gestation and lactation on testis development. Reprod Toxicol 63:151–160

    Article  CAS  PubMed  Google Scholar 

  19. Barański B (1986) Effect of maternal cadmium exposure on postnatal development and tissue cadmium, copper and zinc concentrations in rats. Arch Toxicol 58:255–260

    Article  PubMed  Google Scholar 

  20. Messaoudi I, Banni M, Saïd L, Saïd K, Kerkeni A (2010) Evaluation of involvement of testicular metallothionein gene expression in the protective effect of zinc against cadmium-induced testicular pathophysiology in rat. Reprod Toxicol 29:339–345

    Article  CAS  PubMed  Google Scholar 

  21. Miralles-Flores C, Delgado-Baeza E (1992) Histomorphometric analysis of the epiphyseal growth plate in rats after prenatal alcohol exposure. J Orthop Res 10:325–336

    Article  CAS  PubMed  Google Scholar 

  22. Banni M, Negri A, Mignone F, Boussetta H, Viarengo A, Dondero F (2011) Gene expression rhythms in the mussel Mytilus galloprovincialis (Lam.) across an annual cycle. PLoS One 6:e18904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30:e36

    Article  PubMed  PubMed Central  Google Scholar 

  24. Brzoska MM, Moniuszko-Jakoniuk J, Jurczuk M, Gaazyn-Sidorczuk M (2002) Cadmium turnover and changes of zinc and copper body status of rats continuously exposed to cadmium and ethanol. Alcohol Alcohol 37:213–221

    Article  CAS  PubMed  Google Scholar 

  25. Banni M, Messaoudi I, Said L, El Heni J, Kerkeni A, Said K (2010) Metallothionein gene expression in liver of rats exposed to cadmium and supplemented with zinc and selenium. Arch Environ Contam Toxicol 59:513–519

    Article  CAS  PubMed  Google Scholar 

  26. Brzoska MM, Moniuszko-Jakoniuk J (2001) Interactions between cadmium and zinc in the organism. Food Chem Toxicol 39:967–980

    Article  CAS  PubMed  Google Scholar 

  27. Kelly EJ, Quaife CJ, Froelick G, Palmiter RD (1996) Metallothionein I and II protect against zinc deficiency and zinc toxicity in mice. J Nutr 126:1782–1790

    CAS  PubMed  Google Scholar 

  28. Mikolic A, Piasek M, Sulimanec A, Grgec VM, Varnai Stasenko S, Kralik Oguic S (2015) Oral cadmium exposure during rat pregnancy: assessment of transplacental micronutrient transport and steroidogenesis at term. J Appl Toxicol 35:508–519

    Article  CAS  PubMed  Google Scholar 

  29. Kuriwaki J, Nishijo M, Honda R, Tawara K, Nakagawa H, Hori E, Nishijo H (2005) Effects of cadmium exposure during pregnancy on trace elements in fetal rat liver and kidney. Toxicol Lett 156:369–376

    Article  CAS  PubMed  Google Scholar 

  30. Eberle J, Schmidmayer S, Erben RG, Stangassinger M, Roth HP (1999) Skeletal effects of zinc deficiency in growing rats. J Trace Elem Med Biol 13:21–26

    Article  CAS  PubMed  Google Scholar 

  31. Oner G, Bhaumick B, Bala RM (1984) Effect of zinc deficiency on serum somatomedin levels and skeletal growth in young rats. Endocrinology 114:1860–1863

    Article  CAS  PubMed  Google Scholar 

  32. Tran CD, Butler RN, Howarth GS, Philcox JC, Rofe AM, Coyle P (1999) Regional distribution and localization of zinc and metallothionein in the intestine of rats fed diets differing in zinc content. Scand J Gastroenterol 34:689–695

    Article  CAS  PubMed  Google Scholar 

  33. Cousins RJ (1979) Metallothionein synthesis and degradation: relationship to cadmium metabolism. Environ Health Perspect 28:131–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chouchene L, Banni M, Kerkeni A, Saïd K, Messaoudi I (2011) Cadmium-induced ovarian pathophysiology is mediated by change in gene expression pattern of zinc transporters in zebrafish (Danio rerio). Chem Biol Interact 193:172–179

    Article  CAS  PubMed  Google Scholar 

  35. Yamaguchi A, Komori T, Suda T (2000) Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocr Rev 21:393–411

    Article  CAS  PubMed  Google Scholar 

  36. Sims NA, Vrahnas C (2014) Regulation of cortical and trabecular bone mass by communication between osteoblasts, osteocytes and osteoclasts. Arch Biochem Biophy 561:22–28

    Article  CAS  Google Scholar 

  37. Komori T (2006) Regulation of osteoblast differentiation by transcription factors. J Cell Biochem 99:1233–1239

    Article  CAS  PubMed  Google Scholar 

  38. Moss DW (1992) Perspectives in alkaline phosphatase research. Clin Chem 38:2486–2492

    CAS  PubMed  Google Scholar 

  39. Hie M, Iitsuka N, Otsuka T, Nakanishi A, Tsukamoto I (2011) Zinc deficiency decreases osteoblasts and osteoclasts associated with the reduced expression of Runx2 and RANK. Bone 49:1152–1159

    Article  CAS  PubMed  Google Scholar 

  40. Takiguchi M, Cherrington NJ, Hartley DP, Klaassen CD, Waalkes MP (2001) Cyproterone acetate induces a cellular tolerance to cadmium in rat liver epithelial cells involving reduced cadmium accumulation. Toxicology 165:13–25

    Article  CAS  PubMed  Google Scholar 

  41. Liu Z, Li H, Soleimani M, Girijashanker K, Reed JM, He L (2008) Cd2+ versus Zn2+ uptake by the ZIP8 HCO3− dependent symporter: kinetics, electrogenicity and trafficking. Biochem Biophys Res Commun 2365:814–820

    Article  Google Scholar 

  42. Haumont S (1967) Distribution of zinc in bone tissue. J Histochem Cytochem 9:141–145

    Article  Google Scholar 

  43. Yamaguchi M, Weitzmann MN (2011) Zinc stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-kappa B activation. Mol Cell Biochem 355:179–186

    Article  CAS  PubMed  Google Scholar 

  44. Hall SL, Dimai HP, Farley JR (1999) Effects of zinc on human skeletal alkaline phosphatase activity in vitro. Calcif Tissue Int 64:163–172

    Article  CAS  PubMed  Google Scholar 

  45. Nagata M, Lönnerdal B (2011) Role of zinc in cellular zinc trafficking and mineralization in a murine osteoblast-like cell line. J NutrBiochem 22:172–178

    CAS  Google Scholar 

  46. Favus MJ, Christakos S editors (2003) Primer on the metabolic bone diseases and disorders of mineral metabolism, 5th ed. Washington, DC: American Society for Bone and Mineral Research.

  47. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein S, Gundberg C, Bradley A, Karsenty G (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382:448–452

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the Ministry of Higher Education, Scientific Research and Technology of Tunisia. The funding sources were not involved in the design of the study, or collection and analysis of data. The authors declare no competing financial interests or conflicts of interest. The authors would like to thank Pr Martine Cohen-Solal, Director of the Inserm U1132 unit, for his assistance and his permission to use the HistoLab software for the fetal femur histomorphometric analyses.

Author information

Authors and Affiliations

  1. LR11ES41: Génétique, Biodiversité et Valorisation des Bioressources, Institut de Biotechnologie, Université de Monastir, 5000, Monastir, Tunisia

    Sana Boughammoura, Marouane Chemek, Safa Ben Mimouna & Imed Messaoudi

  2. Laboratoire de Biochimie et Toxicologie Environnementale, ISA Chott-Mariem, 4042, Sousse, Tunisia

    Mohamed Banni

Authors
  1. Sana Boughammoura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marouane Chemek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Safa Ben Mimouna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohamed Banni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Imed Messaoudi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Imed Messaoudi.

Ethics declarations

Conflict of Interest

The authors declare that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boughammoura, S., Chemek, M., Mimouna, S.B. et al. Involvement of Zn Depletion in Cd-Induced Toxicity on Prenatal Bone Formation in Rat. Biol Trace Elem Res 180, 70–80 (2017). https://doi.org/10.1007/s12011-017-0981-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-017-0981-7

Keywords

Search

Navigation