Academic journal article Environmental Health Perspectives

Blood Metallothionein Transcript as a Biomarker for Metal Sensitivity: LowBlood Metallothionein Transcripts in Arsenicosis Patients from Guizhou, China

Academic journal article Environmental Health Perspectives

Blood Metallothionein Transcript as a Biomarker for Metal Sensitivity: LowBlood Metallothionein Transcripts in Arsenicosis Patients from Guizhou, China

Article excerpt

BACKGROUND: Because metallothionein (MT) is a metal-binding protein that protects against metal intoxication, it could be a biomarker for individual sensitivity to metal toxicity.

OBJECTIVE: We assessed the use of bloodborne MT transcript as a reflection of tissue MT levels and examined the potential role of MT in arsenic toxicity in an environmentally exposed human population.

METHOD: Rodents were treated with zinc or nonmetallic MT inducers for 4 days, and the blood and tissues were collected for MT transcript analysis by real-time reverse transcriptase-polymerase chain reaction and MT protein determination by the cadmium-hemoglobin assay. Blood and buccal cell samples were collected from arsenicosis patients and healthy subjects residing in Guizhou, China, and total RNA was isolated for MT transcript analysis.

RESULTS: There was a positive correlation between blood MT-1 and MT-2 transcripts and corresponding hepatic or renal MT transcript levels in rats and mice. Furthermore, there was a positive correlation between blood MT-1 and MT-2 transcript and tissue MT protein levels in these animals. A positive correlation also occurred between human blood MT and buccal cell MT transcript levels. MT-1A and MT-2A were the major isoform transcripts in human blood and buccal cells, and significantly lower MT levels were seen in arsenicosis patients compared with healthy subjects.

CONCLUSIONS: Blood MT transcript appears to be a useful biomarker of tissue MT levels. Arsenicosis patients in Guizhou show significantly lower MT transcript levels in blood, which may have predisposed this population to arsenic intoxication.

KEY WORDS: arsenicosis patients, biomarker, blood, buccal cells, metallothionein. Environ Health Perspect 115:1101-1106 (2007). doi:10.1289/ehp.10035 available via http://dx.doi.org/ [Online 18 April 2007]

Metallothionein (MT) is a low-molecularweight metal-binding protein (Kagi 1991). MT plays important roles in the detoxication of heavy metals, in the homeostasis of essential metals, and in the scavenging of free radicals (Kagi 1991; Klaassen et al. 1999). Moreover, MT expression can be greatly increased by exposure to a variety of agents and physiologic stimuli (Kagi 1991). This includes a variety of metallic agents that can activate MT gene expression. There are at least four mammalian major MT isoforms. The MT-1 and MT-2 isoforms are most widely expressed, whereas MT-3 is largely brain-specific and MT-4 is located mainly in stratified squamous epithelia (Cherian et al. 2003; Quaife et al. 1994).

Deficiency of MT clearly predisposes animals to metal intoxication and carcinogenesis. For example, MT-1/2-double knockout (MT-null) mice are more sensitive than wildtype mice to the toxicity of cadmium (Klaassen et al. 1999), mercury (Yoshida et al. 2004), arsenic (Liu et al. 2000), cisplatin (Satoh et al. 1997), and zinc and copper (Park et al. 2001). MT-null mice are also more susceptible to carcinogenic effects of lead (Waalkes et al. 2004), cisplatin (Waalkes et al. 2006), and cadmium (Waalkes MP et al., unpublished observation). Thus, the levels of MT appear to be a key factor in determining sensitivity to toxicity and carcinogenicity for various metals.

In humans for reasons that are not fully understood, there is great individual variation in MT expression (Allan et al. 2000; Wu et al. 2000). For example, in one study, MT protein levels in human liver without any pathology varied from 0 to 104 [micro]g/g tissue (Sillevis Smitt et al. 1992). Various other authors have seen similar wide-ranging discrepancies in MT expression in human populations (Bem et al. 1988; Onosaka et al. 1986). It also appears that polymorphisms for human MT-2A gene can significantly affect MT expression (Kita et al. 2006). On the basis of these findings, we hypothesize that individuals with a low ability for MT expression may be susceptible to metal toxicity.

MT synthesis can be increased by arsenicals in mice or rats (Albores et al. …

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