Dose-Dependent Differential Effects of In Vivo Exposure of Cadmium on Myometrial Activity in Rats: Involvement of VDCC and Ca2+-Mimicking Pathways

Abstract

Present study was undertaken to study the effect of 28-days exposure of female adult rats to cadmium (Cd) in drinking water @ 3, 10 and 30 parts per million (ppm) on myometrial responsiveness to different spasmogens and unravel the possible mechanism of alterations in myometrial activity. Cadmium and Ca2+ levels in blood and uterus were measured by atomic absorption spectroscopy while isometric tension in myometrial strips was measured using data acquisition system-based physiograph. Dose-dependent increase in levels of cadmium was observed in both blood and uterus while calcium was increased only in the uterus as compared to those in control. Significant increase in absolute tension and mean integral tension along with non-significant increase in frequency of myometrial contraction was observed in rats of Cd-treated groups. As compared to the control, cadmium decreased and increased the effects of calcium chloride, 80 mM KCl, histamine (0.1 μM) and oxytocin (10−2 IU/ml) in lower-dose (3 ppm) and higher-dose groups (10 and 30 ppm), respectively. Cadmium potentiated and inhibited the relaxant response to phenylephrine in myometrium of rats at lower-dose (3 ppm) and highest-dose (30 ppm) Cd-treated groups, respectively. Results of our study revealed that Cd accumulates in the myometrium of rats and alters its responsiveness to oxytocin, histamine, 80 mM KCl, calcium chloride and phenylephrine, and these effects are differentially mediated depending on levels of exposure possibly through voltage-dependent calcium channel (VDCC) and Ca2+-mimicking pathways.

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

Fig. 1
Fig. 2

References

  1. 1.

    World Health Organization (1993) International Agency for Research on Cancer monographs on the evaluation of carcinogenic risks to humans: beryllium, cadmium, mercury, and exposures the glass manufacturing industry. 58. http://monographs.iarc.fr/ENG/Monographs/vol58/index.php.

  2. 2.

    Jarup 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 24:1–51

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    ASTDR (2012) ToxGuideTM for cadmium. U.S. Department of Health and Human Services Public Health Service, Division of Toxicology and Human Health Sciences, Environmental Toxicology Branch, pp-1. CAS# 7440–43-9. http://www.atsdr.cdc.gov/toxguides/toxguide-5.pdf

  4. 4.

    Kippler M, Ekström EC, Lönnerdal B, Goessler W, Åkesson A, El Arifeen S, Persson LA, Vahter M (2007) Influence of iron and zinc status on cadmium accumulation in Bangladeshi women. Toxicol Appl Pharmacol 222:221–226

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Vahter M, Åkesson A, Lidén C, Ceccatelli C, Berglund M (2007) Gender differences in the disposition and toxicity of metals. Environ Res 104:85–95

    Article  CAS  Google Scholar 

  6. 6.

    Pochwałowski M (2001) Cadmium concentration in uterine myomas, myometrium and peripheral blood from women living in Lower Silesia. Ginekol Pol 72:1055–1058

    PubMed  Google Scholar 

  7. 7.

    Rzymski P, Rzymski P, Tomczyk K, Niedzielski P, Jakubowski K, Poniedziałek B, Opala T (2014) Metal status in human endometrium: relation to cigarette smoking and histological lesions. Environ Res 132:328–333

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Helmestam M, Stavreus-Evers A, Olovsson M (2010) Cadmium chloride alters mRNA levels of angiogenesis related genes in primary human endometrial endothelial cells grown in vitro. Reprod Toxicol 30:370–376

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Samuel JB, Stanley JA, Princess RA, Shanthi P, Sebastian MS (2011) Gestational cadmium exposure-induced ovotoxicity delays puberty through oxidative stress and impaired steroid hormone levels. J Med Toxicol 7:195–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Pollack AZ, Sjaarda L, Ahrens KA, Mumford SL, Browne RW, Wactawski-Wende J, Schisterman EF (2014) Association of cadmium, lead and mercury with paraoxonase 1 activity in women. PLoS One 9:e92152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Johnson MD, Kenney N, Stoica A et al (2003) Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nat Med 9:1081–1084

    Article  CAS  Google Scholar 

  12. 12.

    Gundacker C, Hengstschlager M (2012) The role of placenta in foetal exposure to heavy metals. Wien Med Wochenschr 162:201–206

    Article  Google Scholar 

  13. 13.

    Egawa M, Yasuda K, Nakajima T et al (2003) Smoking enhances oxytocin-induced rhythmic myometrial contraction. Biol Reprod 68:2274–2280

    Article  CAS  Google Scholar 

  14. 14.

    Sipowicz M, Kostrzewska A, Laudanski T, Akerlund M (1995) Effects of cadmium on myometrial activity of the non-pregnant human. Interactions with calcium and oxytocin. Acta Obstet Gynecol Scand 74:93–96

    Article  CAS  Google Scholar 

  15. 15.

    Haki K, Kadir S, Yaflar A (2003) Effects of cadmium on uterine contractions in different species in vitro. Turk J Vet Anim Sci 27:529–534

    Google Scholar 

  16. 16.

    Saroj VK, Nakade UP, Sharma A, Yadav RS, Hajare SW, Garg SK (2016) Functional involvement of L-type calcium channels and cyclic nucleotide-dependent pathways in cadmium-induced myometrial relaxation in rats. Hum Exp Toxicol. doi:10.1177/09603271 16646840

  17. 17.

    Niwa A, Suzuki A (1982) Effects of cadmium on the tension of isolated rat aorta (a possible mechanism for cadmium-induced hypertension). J Toxicol Sci 7:51–60

    Article  CAS  Google Scholar 

  18. 18.

    Schnieden H, Small RC (1971) Spasmolytic effects of cadmium and zinc ions upon the guinea-pig isolated ileum preparation. Br J Pharmacol 41:488–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Asai F, Nishimura M, Satoh E, Urakawa N (1982) Mechanism of cadmium-induced contraction in ileal longitudinal muscle of guinea-pig. Br J Pharmacol 75:561–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Skoczynska A, Wróbel J, Andrzejak R (2001) Lead-cadmium interaction effect on the responsiveness of rat mesenteric vessels to norepinephrine and angiotensin II. Toxicology 162:157–170

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Ozdem SS, Ogutman C (1999) The effects of short-term nifedipine treatment on responsiveness of aortic rings of cadmium hypertensive rats. Clin Exp Hypertens 21:423–440

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Takahashi Y, Poteser M, Masui H, Koizumi N, Wakabayashi I (2004) Effects of cadmium in vitro on contractile and relaxant responses of isolated rat aortas. Environ Health Prev Med 9:251–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Smith JB, Dwyer SD, Smith L (1989) Cadmium evokes inositol polyphosphate formation and calcium mobilization. Evidence for a cell surface receptor that cadmium stimulates and zinc antagonizes. J Biol Chem 264:7115–7118

    CAS  PubMed  Google Scholar 

  24. 24.

    Huang Y, Quayle JM, Worley JF, Standen NB, Nelson MT (1989) External cadmium and internal calcium block of single calcium channels in smooth muscle cells from rabbit mesenteric artery. Biophys J 56:1023–1028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Da Costa R, Botana D, Piñero S, Proverbio F, Marín R (2016) Cadmium inhibits motility, activities of plasma membrane Ca(2+)-ATPase and axonemal dynein-ATPase of human spermatozoa. Andrologia 48:464–469

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Petering HG, Choudhury H, Stemmer KL (1979) Some effects of oral ingestion of cadmium on zinc, copper and iron metabolism. Environ Health Perspect 28:97–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ali MM, Murthy RC, Chandra SV (1986) Developmental and longterm neurobehavioral toxicity of low level in-utero cadmium exposure in rats. Neurobehav Toxicol Teratol 8:463–468

    CAS  PubMed  Google Scholar 

  28. 28.

    Sorell TL, Graziano JH (1990) Effect of oral cadmium exposure during pregnancy on maternal and fetal zinc metabolism in the rat. Toxicol Appl Pharmacol 102:537–545

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Ronco AM, Urrutia M, Montenegro M, Llanos MN (2009) Cadmium exposure during pregnancy reduces birth weight and increases maternal and foetal glucocorticoids. Toxicol Lett 188:186–191

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Ronco AM, Montenegro M, Castillo P, Urrutia M, Saez D, Hirsch S, Zepeda R, Llanos MN (2011) Maternal exposure to cadmium during gestation perturbs the vascular system of the adult rat offspring. Toxicol Appl Pharmacol 251:137–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Mikolić A, Piasek M (2010) Oral cadmium exposure and placental steroidogenesis in rats. Toxicol Lett 196:S302–S302

    Article  Google Scholar 

  32. 32.

    Ghosh MN (2005) Fundamentals of experimental pharmacology, 3rd edn. Hilton & Company, McLean, pp 24–37

    Google Scholar 

  33. 33.

    Nakade UP, Sharma A, Choudhury S, Yadav RS, Garg SK (2016) Lead modulates calcium entry and beta-adrenoceptors signalling to produce myometrial relaxation in rats. Biol Trace Elem Res. doi:10.1007/s12011-016-0813-1

  34. 34.

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

    Article  Google Scholar 

  35. 35.

    Haouem S, Hmad N, Najjar MF, El Hani A, Sakly R (2007) Accumulation of cadmium and its effects on liver and kidney functions in rats given diet containing cadmium polluted radish bulb. Exp Toxicol Pathol 59:77–80

    Article  CAS  Google Scholar 

  36. 36.

    Chedrese PJ, Piasek M, Henson MC (2006) Cadmium as endocrine disruptor in the reproductive system. Immunol Endocr Metab Agents Med Chem 6:27–35

    Article  CAS  Google Scholar 

  37. 37.

    Thompson J, Bannigan J (2008) Cadmium: toxic effects on the reproductive system and the embryo. Reprod Toxicol 25:304–315

    Article  CAS  Google Scholar 

  38. 38.

    Tanrıkut E, Karaer A, Celik O, Celik E, Otlu B, Yilmaz E, Ozgul O (2014) Role of endometrial concentrations of heavy metals (cadmium, lead, mercury and arsenic) in the aetiology of unexplained infertility. Eur J Obstet Gynecol 179:187–190

    Article  CAS  Google Scholar 

  39. 39.

    Toman R, Massányi P, Uhrin V (2002) Changes in the testis and epididymis of rabbits after an intraperitoneal and per-oral administration of cadmium. Trace Elem Electrolytes 19:114–117

    CAS  Google Scholar 

  40. 40.

    Bernard A, Roels H, Buchet JP, Cardenas A, Lauwerys R (1992) Cadmium and health, the Belgian experience, Vol. 118. IARC Scientific Publications, Lyon, pp 15–33

    Google Scholar 

  41. 41.

    Langendijk P, Bouwman EG, Soede NM, Taverne MA, Kemp B (2002) Myometrial activity around estrus in sows: spontaneous activity and effects of estrogens, cloprostenol, seminal plasma and clenbuterol. Theriogenology 57:1563–1577

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Martin MB, Reiter R, Pham T et al (2003) Estrogen-like activity of metals in MCF-7 breast cancer cells. Endocrinology 144:2425–2436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Branham WS, Zehr DR, Sheehan DM (1993) Differential sensitivity of rat uterine growth and epithelium hypertrophy to estrogens and anti-estrogens. Proc Soc Exp Biol Med 203:297–303

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Diel P, Schmidt S, Vollmer G (2002) In vivo test systems for the quantitative and qualitative analysis of the biological activity of phytoestrogens. J Chromatogr B Analyt Technol Biomed Life Sci 777:191–202

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    OECD (Organisation for Economic Co-operation and Development) (2007) OECD guidelines for the testing of chemicals. Test no. 440. Uterotrophic bioassay in rodents: a short-term screening test for oestrogenic properties. ENV/EPOC (2007)10. Paris: OCD.

  46. 46.

    Zeneli L, Daci N, Paçarizi H, Daci-Ajvazi M (2010) Interaction between cadmium and calcium in human blood at the smokers. J Pharmacol Exp Ther 5:48–51

    CAS  Google Scholar 

  47. 47.

    Silva E, Lopez-Espinoza MJ, Molina-Molina JM, Fernandez M, Olea N, Kortenkamp A (2006) Lack of activity of cadmium in in vitro estrogenicity assays. Toxicol Appl Pharmacol 216:20–28

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Shmygol A, Gullam J, Blanks A, Thornton S (2006) Multiple mechanisms involved in oxytocin-induced modulation of myometrial contractility. Acta Pharmacol Sin 27:827–832

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Benoff S, Auborn K, Marmar JL, Hurley IR (2008) Link between low-dose environmentally relevant cadmium exposures and asthenozoospermia in a rat model. Fertil Steril 89:73–79

    Article  Google Scholar 

  50. 50.

    Long GJ (1997) The effect of cadmium on cytosolic free calcium, protein kinase C, and collagen synthesis in rat osteosarcoma (ROS17/2.8) cells. Toxicol Appl Pharmacol 143:189–195

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Mhaouty-Kodja S, Houdeau E, Cohen-Tannoudji J, Legrand C (2001) Catecholamines are not linked to myometrial phospholipase C and uterine contraction in late pregnant and parturient mouse. J Physiol 536:123–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Washington B, Williams S, Armstrong P, Mtshali C, Robinson JT, Myles EL (2006) Cadmium toxicity on arterioles vascular smooth muscle cells of spontaneously hypertensive rats. Int J Environ Res Public Health 3(4):323–328

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Indian Council of Agriculture Research (ICAR), New Delhi, under Niche Area of Excellence programme to the Department of Veterinary Pharmacology and Toxicology, DUVASU, Mathura, India (Grant No:10(10)/2012-EPD, dated: 23rd March, 2012).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Satish K. Garg.

Ethics declarations

All the experimental studies were undertaken after approval of the Institutional Animal Ethics Committee, DUVASU, Mathura, as per the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA).

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saroj, V.K., Nakade, U.P., Sharma, A. et al. Dose-Dependent Differential Effects of In Vivo Exposure of Cadmium on Myometrial Activity in Rats: Involvement of VDCC and Ca2+-Mimicking Pathways. Biol Trace Elem Res 181, 272–280 (2018). https://doi.org/10.1007/s12011-017-1040-0

Download citation

Keywords

  • Cadmium
  • Myometrium
  • VDCC
  • Calcium
  • Phenylephrine