The Metallothionein-Null Phenotype Is Associated with Heightened Sensitivity to Lead Toxicity and an Inability to Form Inclusion Bodies

Qu, Wei; Diwan, Bhalchandra A.; Liu, Jie; Goyer, Robert A.; Dawson, Tammy; Horton, John L.; Cherian, M. George; Waalkes, Michael P.

doi:10.1016/s0002-9440(10)64925-5

Cited by 46 publications

(70 citation statements)

References 39 publications

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“…Increase in creatinine concentration might be due to loss of appreciable loss of kidney function and considered as functional evidence of lead induced nephrotoxicity (Qu, 2002). However significant decrease in creatinine and blood urea nitrogen was reported in lead acetate rats (Rumana et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

Haemato-Biochemical Alterations as Biomarkers of Lead Induced Toxicity in Male Wistar Rats

Okediran

Kasali²,

Omotainse³

et al. 2017

Bangl. J. Vet. Med.

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The present work is devoted to access some of the biomarkers due to lead toxicity in experimental Wistar male rats orally exposed to graded doses of lead (200, 300 and 400 ppm of lead as lead acetate) over a period of four, eight and twelve weeks. A total of sixty Wistar male rats were equally divided into four groups A, B, C and D. Group A served as control. Groups B, C and D were exposed to 200, 300 and 400 ppm of lead as lead acetate respectively. At the end of four, eight and twelve weeks, five animals each were removed from each group; blood sample was obtained via the ocular median canthus for haematological and biochemical studies. The results indicated accumulation of blood lead which was both dose and time dependent, while there was significant decrease (P < 0.05) in packed cell volume and haemoglobin concentration. The erythrocyte indices (mean corpuscular volume, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration) also revealed a significant decrease, revealing microcytic hypochromic anaemia. There was significant decrease (P < 0.05) in both the total plasma protein and albumin while blood urea nitrogen and creatinine revealed a significant increase, giving an indication of compromised liver and kidney functions. It was concluded that oral exposure to lead at vary doses over a period of four, eight and twelve weeks results in alterations of various haematological and biochemical parameters and thus can serve as a sensitive biomarkers in lead toxicity.

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Section: Resultsmentioning

confidence: 99%

Haemato-Biochemical Alterations as Biomarkers of Lead Induced Toxicity in Male Wistar Rats

Okediran

Kasali²,

Omotainse³

et al. 2017

Bangl. J. Vet. Med.

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“…A remarkable characteristic of lead poisoning is the production of a protein-lead complex, which appears in renal cells of poisoned humans or animals as inclusion bodies (1,3,4,13). Lead-induced inclusion bodies are often nuclear, approximately spherical and consist of an electron-dense core with a peripheral fibrillary network (3,4).…”

Section: Introductionmentioning

confidence: 99%

“…Lead-induced inclusion bodies are often nuclear, approximately spherical and consist of an electron-dense core with a peripheral fibrillary network (3,4). Inclusion bodies first form in the cytoplasm and then migrate to the nucleus (3,4,13). Whether inclusion bodies are a permanent structure or decay with cessation of lead exposure is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Lead is highly concentrated in the inclusion bodies, and as much as half of the lead in the kidney may be found here (3,4). It is suspected that these complexes are protective in that they may render lead toxicologically inert, thereby blocking interactions with more sensitive cellular targets (3,4,13,14). Thus, inclusion bodies may play a role in the intracellular partitioning and, possibly, toxicity of lead (4,(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

“…Lead avidly binds to metallothionein under ex vivo conditions (21), and lead appears to bind to metallothionein in human erythrocytes (22,23). Metallothionein mitigates lead toxicity in cultured cells (13,24), and the binding of lead to metallothionein reduces lead-induced inhibition of the enzyme ␦-aminolevulinic acid dehydratase (25). Recently, we studied the role of metallothionein in the subchronic toxicity of lead, with metallothionein-null (metallothionein-I/II double knockout) mice (13), which are unable to synthesize the two major forms of metallothionein, compared with wild-type (WT) mice, which produce metallothionein at normal levels.…”

Section: Introductionmentioning

confidence: 99%

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Metallothionein-I/II Double Knockout Mice Are Hypersensitive to Lead-Induced Kidney Carcinogenesis

et al. 2004

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Lead is an environmental nephrotoxicant and probable human carcinogen. Elucidating factors predisposing populations to lead toxicity is an important public health issue. Recently, we found that metallothionein-I/-II double knockout (metallothionein-null) mice that are unable to produce the major forms of metallothionein do not produce lead inclusion bodies, which are thought to mitigate lead toxicity, and were sensitive to the subchronic toxic effects of lead exposure (10 weeks), showing modestly diminished renal function and nephromegaly compared with wild-type (WT) mice. It is unclear how this knockout might impact lead carcinogenesis. Thus, the effects of lead(II) acetate were tested in groups (n ‫؍‬ 25) of male metallothionein-null and WT mice receiving drinking water with 0, 1,000, 2,000, or 4,000 parts per million lead for up to 104 weeks. Renal proliferative lesions (adenoma and cystic tubular atypical hyperplasia) were much more common and more severe in lead-exposed metallothionein-null mice than in WT mice. A metastatic renal cell carcinoma also occurred in a lead-treated metallothionein-null mouse, whereas none occurred in WT mice. Lead-induced renal proliferative lesions showed marked overexpression of cyclin D1, a common feature of human renal tumors. Renal lead-containing nuclear inclusion bodies were frequently observed in WT mice but did not form in metallothionein-null mice. Metallothionein was often found associated with the outer portion of these inclusion bodies. Thus, the metallothionein-null mice cannot form renal inclusion bodies, even after protracted lead exposure, and this increases the carcinogenic potential of lead. Poor production of metallothionein may predispose human populations to lead carcinogenicity.

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Stable expression of C/EBPα in prostate cancer cells down‐regulates metallothionein and increases zinc‐induced toxicity

2004

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The Metallothionein-Null Phenotype Is Associated with Heightened Sensitivity to Lead Toxicity and an Inability to Form Inclusion Bodies

Cited by 46 publications

References 39 publications

Haemato-Biochemical Alterations as Biomarkers of Lead Induced Toxicity in Male Wistar Rats

Haemato-Biochemical Alterations as Biomarkers of Lead Induced Toxicity in Male Wistar Rats

Metallothionein-I/II Double Knockout Mice Are Hypersensitive to Lead-Induced Kidney Carcinogenesis

Stable expression of C/EBPα in prostate cancer cells down‐regulates metallothionein and increases zinc‐induced toxicity

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