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Published in: International Archives of Occupational and Environmental Health 3/2007

01-01-2007 | Original Article

Changes in tubular dysfunction marker levels in parallel with the levels of copper, rather than cadmium, in urine of middle-aged women in non-polluted areas

Authors: Masayuki Ikeda, Fumiko Ohashi, Yoshinari Fukui, Shiro Takada, Jiro Moriguchi, Takafumi Ezaki

Published in: International Archives of Occupational and Environmental Health | Issue 3/2007

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Abstract

Objective

This study was initiated to investigate if and to what extent the elevations in urinary α1- and β2-microglobulins (α1-MG and β2-MG, respectively) are specific to Cd nephro-toxicity.

Methods

Stored urine samples, collected from 1,000 adult women in 11 prefectures all over Japan, were analysed for eight elements (Ca, Cd, Co, Cu, Mg, Mn, Ni and Zn), α1-MG, β2-MG, creatinine (CR) and specific gravity (SG); the data were cited from previous publications. The levels of eight elements and two MGs were expressed as observed and after correction for CR or SG (1.016). Age, CR and SG distributed normally, whereas two MGs and eight elements distributed log-normally. The 1,000 cases were classified into quartiles (i.e., 250 cases/group) of the lowest to the highest values (Groups A to D) for each element.

Results

α1-MG and β2-MG increased as a function of Ca, Cd and Cu when corrected for CR, and the two MGs increased in parallel only with Cd and Cu after SG correction. Prevalence of α1-MG-uria (cut-off values; 5.3 and 6.5 mg/g cr or l) and β2-MG-uria (cut-off values; 300 and 400 μg/g cr or l) was elevated with increasing Ca, Cd and Cu when corrected for CR, but only with Cd and Cu when corrected for SG. Multiple regression analysis of 353 cases of 50–59 year-old women with the eight element levels as independent variables and one of the two MGs as a dependent variable showed that Cu was the most influential element, and both Cd and Zn were less influential.

Conclusions

Urinary levels of α1-MG and β2-MG among women with no environmental Cd exposure correlated more closely with Cu levels than Cd levels in urine. The observation suggests that sub-clinical elevation in α1-MG and β2-MG is not always attributable to nephro-toxicity of Cd, and that consideration on possible effects of other elements such as Cu is necessary.
Literature
go back to reference Agata T (1997) Mantel-extention method. In: Basic medical statistics (in Japanese). Chugai-Igaku Publishers, Tokyo, pp 114–118 Agata T (1997) Mantel-extention method. In: Basic medical statistics (in Japanese). Chugai-Igaku Publishers, Tokyo, pp 114–118
go back to reference Araya M, Olivares M, Pizarro F, González M, Speisky H, Uauy R (2003) Copper exposure and potential biomarkers of copper metabolism. BioMetals 16:199–204PubMedCrossRef Araya M, Olivares M, Pizarro F, González M, Speisky H, Uauy R (2003) Copper exposure and potential biomarkers of copper metabolism. BioMetals 16:199–204PubMedCrossRef
go back to reference Arisawa K, Nakano A, Saito H, Liu X-J, Yokoo M, Soda M, Koba T, Takahashi T, Kinoshita K (2001) Mortality and cancer incidence among a population previously exposed to environmental cadmium. Int Arch Occup Environ Health 74:255–262PubMedCrossRef Arisawa K, Nakano A, Saito H, Liu X-J, Yokoo M, Soda M, Koba T, Takahashi T, Kinoshita K (2001) Mortality and cancer incidence among a population previously exposed to environmental cadmium. Int Arch Occup Environ Health 74:255–262PubMedCrossRef
go back to reference Beliles RP (1994) Copper. In: Clayton GD, Clayton FE (eds) Patty’s industrial hygiene and toxicology, 4th edn, vol 2, Part C Toxicology. Wiley, New York, pp 1999–2006 Beliles RP (1994) Copper. In: Clayton GD, Clayton FE (eds) Patty’s industrial hygiene and toxicology, 4th edn, vol 2, Part C Toxicology. Wiley, New York, pp 1999–2006
go back to reference Beneš B, Spěváčková V, Šmíd J, Čejchanová M, Kaplanová E, Černá M, Gajewská V, Blatný J (2002) Determinatnion of normal concentration levels of Cd, Pb, Hg, Cu, Zn and Se in urine of the population in the Czech Republic. Cent Eur J publ Health 1–2:3–5 Beneš B, Spěváčková V, Šmíd J, Čejchanová M, Kaplanová E, Černá M, Gajewská V, Blatný J (2002) Determinatnion of normal concentration levels of Cd, Pb, Hg, Cu, Zn and Se in urine of the population in the Czech Republic. Cent Eur J publ Health 1–2:3–5
go back to reference Bremner I, Marshall RB (1974) Hepatic copper- and zinc-binding proteins in ruminants. 2. Relationship between Cu and Zn concentrations and occurrence of metallothionein-like fraction. Br J Nutr 32:293–300PubMedCrossRef Bremner I, Marshall RB (1974) Hepatic copper- and zinc-binding proteins in ruminants. 2. Relationship between Cu and Zn concentrations and occurrence of metallothionein-like fraction. Br J Nutr 32:293–300PubMedCrossRef
go back to reference Browning E (1969) Copper, Chapter 15. Toxicology of industrial metals. Butterworth, London, pp 145–152 Browning E (1969) Copper, Chapter 15. Toxicology of industrial metals. Butterworth, London, pp 145–152
go back to reference Buchwald H (1964) The expression of urine analysis results—observations on the use of specific gravity correction. Ann Occup Hyg 7:125–136PubMed Buchwald H (1964) The expression of urine analysis results—observations on the use of specific gravity correction. Ann Occup Hyg 7:125–136PubMed
go back to reference Ezaki T, Tsukahara T, Moriguchi J, Furuki K, Fukui Y, Ukai H, Okamoto S, Sakurai H, Honda S, Ikeda M (2003a) Analysis for threshold levels of cadmium in urine that induce tubular dysfunction among women in non-polluted areas in Japan. Int Arch Occup Environ Health 76:197–204PubMed Ezaki T, Tsukahara T, Moriguchi J, Furuki K, Fukui Y, Ukai H, Okamoto S, Sakurai H, Honda S, Ikeda M (2003a) Analysis for threshold levels of cadmium in urine that induce tubular dysfunction among women in non-polluted areas in Japan. Int Arch Occup Environ Health 76:197–204PubMed
go back to reference Ezaki T, Tsukahara T, Moriguchi J, Furuki K, Fukui Y, Ukai H, Okamoto S, Sakurai H, Honda S, Ikeda M (2003b) No clear-cut evidence for cadmium-induced tubular dysfunction among over 10,000 women in the Japanese general population; a nationwide large-scale survey. Int Arch Occup Environ Health 76:186–196PubMed Ezaki T, Tsukahara T, Moriguchi J, Furuki K, Fukui Y, Ukai H, Okamoto S, Sakurai H, Honda S, Ikeda M (2003b) No clear-cut evidence for cadmium-induced tubular dysfunction among over 10,000 women in the Japanese general population; a nationwide large-scale survey. Int Arch Occup Environ Health 76:186–196PubMed
go back to reference Hambidge M (2003) Biomarkers of trace mineral intake and status. J Nutr 133(Suppl3):948S–955SPubMed Hambidge M (2003) Biomarkers of trace mineral intake and status. J Nutr 133(Suppl3):948S–955SPubMed
go back to reference Honda R, Nogawa K (1987) Cadmium, zinc,and copper relationships in kidney and liver of humans exposed to environmental cadmium. Arch Toxicol 59:437–442PubMedCrossRef Honda R, Nogawa K (1987) Cadmium, zinc,and copper relationships in kidney and liver of humans exposed to environmental cadmium. Arch Toxicol 59:437–442PubMedCrossRef
go back to reference Ichihara K (1990) Comparison of two correlation coefficients. In: Ichihara K (ed) Statistics for bioscience (in Japanese). Nankodo Publishers, Tokyo, p233 Ichihara K (1990) Comparison of two correlation coefficients. In: Ichihara K (ed) Statistics for bioscience (in Japanese). Nankodo Publishers, Tokyo, p233
go back to reference Ikeda M, Ezaki T, Tsukahara T, Moriguchi J, Furuki K, Fukui Y, Okamoto S, Ukai H, Sakurai H (2003) Bias induced by the use of creatinine-corrected values in evaluation of β2-microglobulin levels. Toxicol Lett 145:197–207PubMedCrossRef Ikeda M, Ezaki T, Tsukahara T, Moriguchi J, Furuki K, Fukui Y, Okamoto S, Ukai H, Sakurai H (2003) Bias induced by the use of creatinine-corrected values in evaluation of β2-microglobulin levels. Toxicol Lett 145:197–207PubMedCrossRef
go back to reference Jackson S (1966) Creatinine in urine as an index of urinary excretion rate. Health Phys 12:843–850PubMedCrossRef Jackson S (1966) Creatinine in urine as an index of urinary excretion rate. Health Phys 12:843–850PubMedCrossRef
go back to reference Klaassen CD, Liu J (1998) Metallothionein transgenic and knock-out mouse models in the study of cadmium toxicity. J Toxicol Sci 23(Suppl 2):97–102PubMed Klaassen CD, Liu J (1998) Metallothionein transgenic and knock-out mouse models in the study of cadmium toxicity. J Toxicol Sci 23(Suppl 2):97–102PubMed
go back to reference Kobayashi E (1981a) Copper levels in serum and urine of cadmium-exposed people (in Japanese with English abstract). J Kanazawa Med Univ 6:119–122 Kobayashi E (1981a) Copper levels in serum and urine of cadmium-exposed people (in Japanese with English abstract). J Kanazawa Med Univ 6:119–122
go back to reference Kobayashi E (1981b) Zinc levels in serum and urine of cadmium-exposed people (in Japanese with English abstract). J Kanazawa Med Univ 6:123–126 Kobayashi E (1981b) Zinc levels in serum and urine of cadmium-exposed people (in Japanese with English abstract). J Kanazawa Med Univ 6:123–126
go back to reference Liu X, Jin T, Nordberg GF, Sjöström M, Zhou Y (1994) Influence of zinc and copper administration on metal disposition in rat with cadmium–metallothionein-induced nephrotoxicy. Toxicol Appl Pharmacol 126:84–90PubMedCrossRef Liu X, Jin T, Nordberg GF, Sjöström M, Zhou Y (1994) Influence of zinc and copper administration on metal disposition in rat with cadmium–metallothionein-induced nephrotoxicy. Toxicol Appl Pharmacol 126:84–90PubMedCrossRef
go back to reference McArdle HJ, Mercer JFB, Sargeson AM, Danks DM (1990) Effects of cellular copper content on copper uptake and metallothionein and ceruloplasmin mRNA levels in mouse hepatocytes. J Nutr 120:1370–1375PubMed McArdle HJ, Mercer JFB, Sargeson AM, Danks DM (1990) Effects of cellular copper content on copper uptake and metallothionein and ceruloplasmin mRNA levels in mouse hepatocytes. J Nutr 120:1370–1375PubMed
go back to reference Milne DB, Nielsen FH (1996) Effects of a diet low in copper on copper-status indicators in postmenopausal women. Am J Clin Nutr 63:358–364PubMed Milne DB, Nielsen FH (1996) Effects of a diet low in copper on copper-status indicators in postmenopausal women. Am J Clin Nutr 63:358–364PubMed
go back to reference Ministry of Health, Labour and Welfare, the Government of Japan (2004) The national nutrition survey in Japan, 2002 (in Japanese). Dai0ichi Shuppan Publishers, Tokyo, p79 Ministry of Health, Labour and Welfare, the Government of Japan (2004) The national nutrition survey in Japan, 2002 (in Japanese). Dai0ichi Shuppan Publishers, Tokyo, p79
go back to reference Minoia C, Sabbioni E, Apostoli P, Pietra R, Pozzoli L, Gallorini M, Nicolaou G, Alessio L, Capodaglio E (1990) Trace element reference values in tissues from inhabitans of the European Community I. A study of 46 elements in urine, blood and serum of Italian subjects. Sci Total Environ 95:89–105PubMedCrossRef Minoia C, Sabbioni E, Apostoli P, Pietra R, Pozzoli L, Gallorini M, Nicolaou G, Alessio L, Capodaglio E (1990) Trace element reference values in tissues from inhabitans of the European Community I. A study of 46 elements in urine, blood and serum of Italian subjects. Sci Total Environ 95:89–105PubMedCrossRef
go back to reference Mitane Y, Tohyama C, Saito H (1986) The role of metallothionein in the elevated excretion of copper in urine from people living in a cadmium-polluted area. Fundam Appl Toxicol 6:285–291PubMedCrossRef Mitane Y, Tohyama C, Saito H (1986) The role of metallothionein in the elevated excretion of copper in urine from people living in a cadmium-polluted area. Fundam Appl Toxicol 6:285–291PubMedCrossRef
go back to reference Moriguchi J, Ezaki T, Tsukahara T, Fukui Y, Ukai H, Okamoto S, Shimbo S, Sakurai H, Ikeda M (2005a) Effects of aging on cadmium and tubular dysfunction markers in urine from adult women in non-polluted areas. Int Arch Occup Environ Health 78:446–451PubMedCrossRef Moriguchi J, Ezaki T, Tsukahara T, Fukui Y, Ukai H, Okamoto S, Shimbo S, Sakurai H, Ikeda M (2005a) Effects of aging on cadmium and tubular dysfunction markers in urine from adult women in non-polluted areas. Int Arch Occup Environ Health 78:446–451PubMedCrossRef
go back to reference Moriguchi J, Ezaki T, Tsukahara T, Fukui Y, Ukai H, Okamoto S, Shimbo S, Sakurai H, Ikeda M (2005b) Decrease in urine specific gravity and urinary creatinine in elderly women. Int Arch Occup Environ Health 78:438–445PubMedCrossRef Moriguchi J, Ezaki T, Tsukahara T, Fukui Y, Ukai H, Okamoto S, Shimbo S, Sakurai H, Ikeda M (2005b) Decrease in urine specific gravity and urinary creatinine in elderly women. Int Arch Occup Environ Health 78:438–445PubMedCrossRef
go back to reference Moriguchi J, Ezaki T, Tsukahara T, Furuki K, Fukui Y, Okamoto S, Ukai H, Sakurai H, Ikeda M (2005c) α1-Microglobulin levels and correlation with cadmium and other metals in urine of non-smoking women among general populations in Japan. Toxicol Environ Chem 87:119–133 Moriguchi J, Ezaki T, Tsukahara T, Furuki K, Fukui Y, Okamoto S, Ukai H, Sakurai H, Ikeda M (2005c) α1-Microglobulin levels and correlation with cadmium and other metals in urine of non-smoking women among general populations in Japan. Toxicol Environ Chem 87:119–133
go back to reference Nishijo M, Nakagawa H, Morikawa Y, Kuriwaki J, Miura K, Kido T, Nogawa K (2004) Mortality in a cadmium polluted area in Japan. BioMetals 17:533–538CrossRef Nishijo M, Nakagawa H, Morikawa Y, Kuriwaki J, Miura K, Kido T, Nogawa K (2004) Mortality in a cadmium polluted area in Japan. BioMetals 17:533–538CrossRef
go back to reference Nogawa K, Yamada Y, Honda R, Tsuritani I, Kobayashi E, Ishizaki M (1984) Copper and zinc levels in serum and urine of cadmium-exposed people with special reference to renal tubular damage. Environ Res 33:29–38PubMedCrossRef Nogawa K, Yamada Y, Honda R, Tsuritani I, Kobayashi E, Ishizaki M (1984) Copper and zinc levels in serum and urine of cadmium-exposed people with special reference to renal tubular damage. Environ Res 33:29–38PubMedCrossRef
go back to reference Nordberg M, Nordberg GF (2000) Toxicological aspects of metallothionein. Cell Molec Biol 46:451–463 Nordberg M, Nordberg GF (2000) Toxicological aspects of metallothionein. Cell Molec Biol 46:451–463
go back to reference Ohashi F, Fukui Y, Takada S, Moriguchi J, Ezaki T, IkedaM (2006) Reference values for cobalt, copper, manganese and nickel in urine among general populations in Japan. Int Arch Occup Environ Health (in press) Ohashi F, Fukui Y, Takada S, Moriguchi J, Ezaki T, IkedaM (2006) Reference values for cobalt, copper, manganese and nickel in urine among general populations in Japan. Int Arch Occup Environ Health (in press)
go back to reference Rainsford SG, Lloyd Davies TA (1965) Urinary excretion of phenol by men exposed to vapour of benzene; a screening test. Br J Ind Med 22:21–26PubMed Rainsford SG, Lloyd Davies TA (1965) Urinary excretion of phenol by men exposed to vapour of benzene; a screening test. Br J Ind Med 22:21–26PubMed
go back to reference Satarug S, Baker JR, Reilly PEB, Moore MR, Williams DJ (2001) Changes in zinc and copper homeostasis in human livers and kidneys associated with exposure to environmental cadmium. Hum Exp Toxicol 20:205–213PubMedCrossRef Satarug S, Baker JR, Reilly PEB, Moore MR, Williams DJ (2001) Changes in zinc and copper homeostasis in human livers and kidneys associated with exposure to environmental cadmium. Hum Exp Toxicol 20:205–213PubMedCrossRef
go back to reference Simpkins CO (2000) Metallothionein in human disease. Cell Mol Biol 46:465–488PubMed Simpkins CO (2000) Metallothionein in human disease. Cell Mol Biol 46:465–488PubMed
go back to reference Steinebach OM, Wolterbeek HT (1994) Role of cytosolic copper, metallothionein and glutathione in copper toxicity in rat hepatoma tissue culture cells. Toxicology 92:75–90PubMedCrossRef Steinebach OM, Wolterbeek HT (1994) Role of cytosolic copper, metallothionein and glutathione in copper toxicity in rat hepatoma tissue culture cells. Toxicology 92:75–90PubMedCrossRef
go back to reference Tapiero H, Townsend DM, Tew KD (2003) Trace elements in human physiology and pathology. Copper Biomed Pharmacother 57:386–398CrossRef Tapiero H, Townsend DM, Tew KD (2003) Trace elements in human physiology and pathology. Copper Biomed Pharmacother 57:386–398CrossRef
go back to reference Task group on metal interaction (1978) Factors influencing metabolism and toxicity of metals: a consensus report. Environ Health Perspect 25:3–41 Task group on metal interaction (1978) Factors influencing metabolism and toxicity of metals: a consensus report. Environ Health Perspect 25:3–41
go back to reference Tohyama C, Shaikh ZA, Nogawa K, Kobayashi E, Honda R (1982) Urinary metallothionein as a new index of renal dysfunction in ‘Itai-itai’ disease patients and other Japanese women environmentally exposed to cadmium. Arch Toxicol 50:159–166PubMedCrossRef Tohyama C, Shaikh ZA, Nogawa K, Kobayashi E, Honda R (1982) Urinary metallothionein as a new index of renal dysfunction in ‘Itai-itai’ disease patients and other Japanese women environmentally exposed to cadmium. Arch Toxicol 50:159–166PubMedCrossRef
go back to reference Tsukahara T, Ezaki T, Moriguchi J, Furuki K, Fukui Y, Ukai H, Okamoto S, Sakurai H, Ikeda M (2003) No significant effect of iron deficiency on cadmium body burden or kidney dysfunction among women in the general population in Japan. Int Arch Occup Environ Health 76:275–281PubMed Tsukahara T, Ezaki T, Moriguchi J, Furuki K, Fukui Y, Ukai H, Okamoto S, Sakurai H, Ikeda M (2003) No significant effect of iron deficiency on cadmium body burden or kidney dysfunction among women in the general population in Japan. Int Arch Occup Environ Health 76:275–281PubMed
go back to reference Willis MS, Monaghan SA, Miller ML, Miller ML, McKenna RW, Perkins WD, Levinson BS, Bhushan V, Kroft SH (2005) Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination. Am J Clin Pathol 123:125–131PubMedCrossRef Willis MS, Monaghan SA, Miller ML, Miller ML, McKenna RW, Perkins WD, Levinson BS, Bhushan V, Kroft SH (2005) Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination. Am J Clin Pathol 123:125–131PubMedCrossRef
go back to reference Yamagami T, Ezaki T, Moriguchi J, Fukui Y, Okamoto S, Ukai H, Sakurai H, Aoshima K, Ikeda M (2006) Low-level cadmium exposure in Toyama City and its surroundings in Toyama prefecture, Japan, with references to possible contribution of shellfish intake to increased urinary cadmium levels. Sci Total Environ 362:56–67PubMedCrossRef Yamagami T, Ezaki T, Moriguchi J, Fukui Y, Okamoto S, Ukai H, Sakurai H, Aoshima K, Ikeda M (2006) Low-level cadmium exposure in Toyama City and its surroundings in Toyama prefecture, Japan, with references to possible contribution of shellfish intake to increased urinary cadmium levels. Sci Total Environ 362:56–67PubMedCrossRef
go back to reference Yamanaka O, Kobayashi E, Nogawa K, Suwazono Y, Sakurada I, Kido T (1998) Association between renal effects ans cadmium exposure in cadmium-nonexposed area in Japan. Environ Res 77:1–8PubMedCrossRef Yamanaka O, Kobayashi E, Nogawa K, Suwazono Y, Sakurada I, Kido T (1998) Association between renal effects ans cadmium exposure in cadmium-nonexposed area in Japan. Environ Res 77:1–8PubMedCrossRef
Metadata
Title
Changes in tubular dysfunction marker levels in parallel with the levels of copper, rather than cadmium, in urine of middle-aged women in non-polluted areas
Authors
Masayuki Ikeda
Fumiko Ohashi
Yoshinari Fukui
Shiro Takada
Jiro Moriguchi
Takafumi Ezaki
Publication date
01-01-2007
Publisher
Springer-Verlag
Published in
International Archives of Occupational and Environmental Health / Issue 3/2007
Print ISSN: 0340-0131
Electronic ISSN: 1432-1246
DOI
https://doi.org/10.1007/s00420-006-0117-4

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