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Biological Trace Element Research

, Volume 181, Issue 2, pp 272–280 | Cite as

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

  • Vivek K. Saroj
  • Udayraj P. Nakade
  • Abhishek Sharma
  • Soumen Choudhury
  • Sunil W. Hajare
  • Satish K. GargEmail author
Article

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.

Keywords

Cadmium Myometrium VDCC Calcium Phenylephrine 

Notes

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).

Compliance with Ethical Standards

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.

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 24:1–51CrossRefPubMedGoogle 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 222:221–226CrossRefPubMedGoogle 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 104:85–95CrossRefPubMedGoogle Scholar
  6. 6.
    Pochwałowski M (2001) Cadmium concentration in uterine myomas, myometrium and peripheral blood from women living in Lower Silesia. Ginekol Pol 72:1055–1058PubMedGoogle 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 132:328–333CrossRefPubMedGoogle 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 30:370–376CrossRefPubMedGoogle 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 7:195–204CrossRefPubMedPubMedCentralGoogle 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:e92152CrossRefPubMedPubMedCentralGoogle 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 9:1081–1084CrossRefPubMedGoogle Scholar
  12. 12.
    Gundacker C, Hengstschlager M (2012) The role of placenta in foetal exposure to heavy metals. Wien Med Wochenschr 162:201–206CrossRefPubMedGoogle Scholar
  13. 13.
    Egawa M, Yasuda K, Nakajima T et al (2003) Smoking enhances oxytocin-induced rhythmic myometrial contraction. Biol Reprod 68:2274–2280CrossRefPubMedGoogle 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 74:93–96CrossRefPubMedGoogle 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 27:529–534Google 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 7:51–60CrossRefPubMedGoogle 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 41:488–499CrossRefPubMedPubMedCentralGoogle 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 75:561–567CrossRefPubMedPubMedCentralGoogle 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 162:157–170CrossRefPubMedGoogle 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 21:423–440CrossRefPubMedGoogle 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 9:251–256CrossRefPubMedPubMedCentralGoogle 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 264:7115–7118PubMedGoogle 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 56:1023–1028CrossRefPubMedPubMedCentralGoogle 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 48:464–469CrossRefPubMedGoogle 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 28:97–106CrossRefPubMedPubMedCentralGoogle 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 8:463–468PubMedGoogle 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 102:537–545CrossRefPubMedGoogle 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 188:186–191CrossRefPubMedGoogle 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 251:137–145CrossRefPubMedGoogle Scholar
  31. 31.
    Mikolić A, Piasek M (2010) Oral cadmium exposure and placental steroidogenesis in rats. Toxicol Lett 196:S302–S302CrossRefGoogle Scholar
  32. 32.
    Ghosh MN (2005) Fundamentals of experimental pharmacology, 3rd edn. Hilton & Company, McLean, pp 24–37Google 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 17:493–498CrossRefGoogle 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 59:77–80CrossRefPubMedGoogle Scholar
  36. 36.
    Chedrese PJ, Piasek M, Henson MC (2006) Cadmium as endocrine disruptor in the reproductive system. Immunol Endocr Metab Agents Med Chem 6:27–35CrossRefGoogle Scholar
  37. 37.
    Thompson J, Bannigan J (2008) Cadmium: toxic effects on the reproductive system and the embryo. Reprod Toxicol 25:304–315CrossRefPubMedGoogle 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 179:187–190CrossRefGoogle 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 19:114–117Google 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 15–33Google 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 57:1563–1577CrossRefPubMedGoogle Scholar
  42. 42.
    Martin MB, Reiter R, Pham T et al (2003) Estrogen-like activity of metals in MCF-7 breast cancer cells. Endocrinology 144:2425–2436CrossRefPubMedGoogle 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 203:297–303CrossRefPubMedGoogle 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 777:191–202CrossRefPubMedGoogle 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.Google Scholar
  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 5:48–51Google 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 216:20–28CrossRefPubMedGoogle 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 27:827–832CrossRefPubMedGoogle 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 89:73–79CrossRefGoogle 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 143:189–195CrossRefPubMedGoogle 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 536:123–131CrossRefPubMedPubMedCentralGoogle 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):323–328CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Vivek K. Saroj
    • 1
  • Udayraj P. Nakade
    • 2
  • Abhishek Sharma
    • 2
  • Soumen Choudhury
    • 2
  • Sunil W. Hajare
    • 1
  • Satish K. Garg
    • 3
    Email author
  1. 1.Department of Pharmacology and Toxicology, Post Graduate Institute of Veterinary and Animal SciencesAkola, MAFSUNagpurIndia
  2. 2.Experimental Pharmacology Laboratory, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal HusbandryU.P. Pandit Deen Dayal Upadhyaya Veterinary UniversityMathuraIndia
  3. 3.College of Veterinary Science and Animal HusbandryDUVASUMathuraIndia

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