Heavy Metal Metabolism Research Articles

Autism: A form of lead and mercury toxicity

AimAutism is a developmental disability characterized by severe deficits in social interaction and communication. The definite cause of autism is still unknown. The aim of this study is to find out the relation between exposure to Lead and/or mercury as heavy metals and autistic symptoms, dealing with the heavy metals with chelating agents can improve the autististic symptoms. MethodBlood and hair samples were obtained from 45 children from Upper Egypt with autism between the ages of 2 and 10 years and 45 children served as controls in the same age range, after taken an informed consent and fill a questionnaire to assess the risk factors. The samples were analyzed blindly for lead and mercury by using atomic absorption and ICP-MS. Data from the two groups were compared, then follow up of the autistic children after treatment with chelating agents were done. ResultsThe results obtained showed significant difference among the two groups, there was high level of mercury and lead among those kids with autism. Significant decline in the blood level of lead and mercury with the use of DMSA as a chelating agent. In addition, there was decline in the autistic symptoms with the decrease in the lead and mercury level in blood. ConclusionLead and mercury considered as one of the main causes of autism. Environmental exposure as well as defect in heavy metal metabolism is responsible for the high level of heavy metals. Detoxification by chelating agents had great role in improvement of those kids.

Molecular Evolution and Functional Divergence of the Metallothionein Gene Family in Vertebrates

The metallothionein (MT) gene superfamily consists of metal-binding proteins involved in various metal detoxification and storage mechanisms. The evolution of this gene family in vertebrates has mostly been studied in mammals using sparse taxon or gene sampling. Genomic databases and available data on MT protein function and expression allow a better understanding of the evolution and functional divergence of the different MT types. We recovered 77 MT coding sequences from 20 representative vertebrates with annotated complete genomes. We found multiple MT genes, also in reptiles, which were thought to have only one MT type. Phylogenetic and synteny analyses indicate the existence of a eutherian MT1 and MT2, a tetrapod MT3, an amniote MT4, and fish MT. The optimal gene-tree/species-tree reconciliation analyses identified the best root in the fish clade. Functional analyses reveal variation in hydropathic index among protein domains, likely correlated with their distinct flexibility and metal affinity. Analyses of functional divergence identified amino acid sites correlated with functional divergence among MT types. Uncovering the number of genes and sites possibly correlated with functional divergence will help to design cost-effective MT functional and gene expression studies. This will permit further understanding of the distinct roles and specificity of these proteins and to properly target specific MT for different types of functional studies. Therefore, this work presents a critical background on the molecular evolution and functional divergence of vertebrate MTs to carry out further detailed studies on the relationship between heavy metal metabolism and tolerances among vertebrates.

城市生活垃圾代谢的研究进展

Urban ecological metabolism is the sum of society,economy and technology during the city development,energy production and waste emissions. Municipal solid waste management was a typical complex system combines social-economicnatural factors. Municipal solid waste management was effected by managing mechanism,technical level and environmental conscious of inhabitants. Municipal solid waste run through the urban metabolism processes of production,consumption, logistics and recycling,and even more,waste has a close relationship of natural environmental such as water body,soil, air,biology and mines. In this paper,we reviewed the literatures about municipal solid waste emission,transfer,and dump of carbon,heavy metal,energy and nutrients in the framework of urban ecological metabolism,and gave the important researching directions and contents in this area. Main findings were: 1) Carbon metabolism of municipal solid waste was important in the researches of urban carbon cycle,current researches were focus on the carbon emission regulation of waste treatment,comparison studies on carbon emission between different cities,carbon emission and transfer inside the cities, carbon detecting and accounting of solid waste and waste management for low carbon emissions. 2) Heavy metal metabolism was paid attentions by researchers,current researches were focus on the inputs and outputs of heavy metals through urban metabolism,source analysis of heavy metals in different municipal solid wastes,transferring and migrating of different heavy metals through different treating and disposing processes,migrating of heavy metal in soil-plant system brought from waste compost,and impacts to heavy metal metabolism by different collection separating and transporting system. 3) Nutrients and energy metabolism of municipal solid waste were reported less than carbon and heavy metals. Inputs,output and the balance of typical nutrients,such us nitrogen and phosphorus,were studied,and nutrients metabolism from municipal solid waste were important substrate flows in the process of urban metabolism. Energy indicators such as emergy and exergy were introduced to analyze the systemic metabolism efficiency of different municipal solid waste treatment and mangement systems. Based on the review of current researches,some important researching areas has been putting forward: 1) metabolism of municipal solid waste based on the rural-urban geographic and season differences,these researches could promote the progress on researching geography-ecology processes of urban ecological systems; 2) producing,transferring and fate models of carbon,heavy metals,nutrients and energy metabolism,and typical Chinese parameters for accounting and simulating the urban metabolism of municipal solid waste,these researches could promote the systemic and comparing studies of different waste metabolism systems; 3) experimental researches on key processes for carbon,heavy metals, nutrients and energy metabolism of municipal solid waste,for example,the deposit,transfer and emission processes of carbon cycle through collecting,separating,transporting and treating of municipal solid waste; and the quantitative studies on the heavy metals transferring processes impacting by different waste components,environmental temperature,pH value. The researches of energy transfer,material cycling and metabolism efficiency of municipal solid waste managing system could give scientific basis of assessment, planning, engineering and management of urban municipal solid waste management systems.

MicroRNA mediated regulation of metal toxicity in plants: present status and future perspectives

The human population is increasing at an alarming rate, whereas heavy metals (HMs) pollution is mounting serious environmental problem, which could lead to serious concern about the future sufficiency of global food production. Some HMs such as Mn, Cu, and Fe, at lower concentration serves as an essential vital component of plant cell as they are crucial in various enzyme catalyzed biochemical reactions. At higher concentration, a vast variety of HMs such as Mn, Cu, Cd, Fe, Hg, Al and As, impose toxic reaction in the plant system which greatly affect the crop yield. Recently, microRNAs (miRNAs) that are small class of non-coding riboregulator have emerged as central regulator of numerous abiotic stresses including HMs. Increasing reports indicate that plants have evolved specialized inbuilt mechanism viz. signal transduction, translocation and sequestration to counteract the toxic response of HMs. Combining computational and wet laboratory approaches have produced sufficient evidences concerning active involvement of miRNAs during HMs toxicity response by regulating various transcription factors and protein coding genes involved in plant growth and development. However, the direct role of miRNA in controlling various signaling molecules, transporters and chelating agents of HM metabolism is poorly understood. This review focuses on the latest progress made in the area of direct involvement of miRNAs in signaling, translocation and sequestration as well as recently added miRNAs in response to different HMs in plants.

Research on cadmium toxicity mechanism during maize germination

为了深入探讨重金属胁迫下植物重金属代谢过程及机理, 采用有一定重金属镉耐受能力的农作物玉米为试验材料, 综合研究了不同镉浓度(5~100 μmol·L^-1)及不同处理时间下玉米幼苗发芽、不同组织部位镉含量及分布、镉中毒前后液相色谱 质谱联用谱图(HPLC-MS)、核磁共振氢谱图(1H NMR)和总蛋白氨基酸含量。结果表明, 低于50 μmol·L^-1的镉浓度能促进玉米发芽, 高于此浓度可明显抑制发芽。镉在胚乳、根、茎、芽等新鲜组织部位的分布不均, 其分布情况为: 胚乳>根>茎>芽。HPLC-MS和¹H NMR分析结果表明, 玉米中镉以金属螯合剂(PC)形式络合。总蛋白氨基酸含量分析说明镉胁迫影响营养物质的吸收及合成。重金属镉在整个玉米幼苗中传输积累过程为: 大量镉吸附在胚乳中, 部分直接吸附在根表面; 部分镉以游离形式存在, 部分以植物金属螯合剂螯合形式存在; 镉在细胞中与各种蛋白作用, 在胞液、液泡、胞间连丝等细胞器间传递; 镉经根、茎传输到芽, 此过程主要受浓度梯度影响; 镉的传输过程很可能遵循顺浓度梯度的协助扩散过程, 试验证明了此过程的合理性。

Isolation of Metallothionein Genes and in silico Structural Characterization of Their Proteins Using Molecular Modeling from Yak (Bos grunniens)

Yak metallothioneins (BgMTs) are cysteine-rich metal-chelating proteins with highly conserved cysteine residues in their amino acid sequences. The 3D structures of the Cd(7)-BgMTs reconstructed by molecular modeling included two domains: the β-domain with M(3)(S(cys))(9) metal-thiolate clusters and the α-domain with M(4)(S(cys))(11) metal-thiolate clusters. An unusual variant was found at position 30 (Cys30→Ser30) in BgMT-III, which is usually conserved in the mammalian MT-I/-II (Cys29) and MT-III (Cys30). The variant residue of BgMT-III may play a key role in yak genetic evolution, metal-binding activity, dynamic conformation, and heavy metal metabolism. BgMT-III contained a Thr insertion at position 5 (T(5)), which may loosen the structure of the β-domain of BgMT-III, and a conserved C(6)PCP(9) motif, which may provide an interacting surface for protein-protein interactions. There is also an acidic hexapeptide insertion (E(55)GAEAE(60)) that could regulate the particular interdomain interactions and lead to the conformational change in the β-domain.

Effects of duration of exposure to dietary lead on rumen metabolism and the accumulation of heavy metals in sheep

The duration of exposure of sheep to dietary Pb may affect their ability to manage the toxic effects of the Pb, as well as influencing the metabolism of other heavy metals. Sheep were exposed to a supplement of 34mg Pb/kg basal diet DM for 3, 6 or 9 weeks. Compared with 3-week exposure, rumen contents after 6 weeks had increased Pb content (P=0.02), and after 9 weeks had reduced Cu (P=0.01) and Cr (P=0.04) concentrations. The longer exposure periods reduced digestion of long particles, and increased the alkali buffering potential in the rumen, but duration of exposure to Pb did not affect its proportional absorption (P=0.26). Most additional Pb was excreted in faeces or accumulated in the bones and spleen, and urinary Pb output was increased (P<0.01) after exposure for 6 or 9 weeks. Proportional absorption of Cd was increased after 6 and 9 weeks of Pb exposure, compared to 3 weeks (P<0.01), and after 6 weeks renal Cd had increased from 4 to 9mg/kg (P<0.01), which is above the normally accepted legal maximum concentration of 4.8mg/kg. After 9 weeks of Pb exposure Cd had declined in the kidney and increased in blood cells. It is concluded that duration of exposure to Pb did not affect its absorption, and there was no evidence of protective mechanisms, but extended exposure caused increased accumulation of Cd that rendered renal concentrations above legal limits.

Arsenate, Cadmium and Lead affect the plant detoxifi cation cascade for organic pollutants

Multiple sites of moderate to low pollution with heavy metals or organic xenobiotics have been identified throughout Europe, and those where no immediate pressure exists for further use, may well be remediated by plant based technologies. Hence, phytoremediation has become a green sustainable technology that has gained increasing attention during the last decade. Municipal and industrial waste water treatment plants can be optimized by the addition of lagoons with aquatic macrophytes. However, it is obvious, that quite a number of remediation projects failed due to insufficient plant performance. In this paper, we present evidence that Typha and Phragmites, two widely used plant species in phytoremediation, are capable of removal and metabolism of heavy metals and organic pollutants from water and sediments to some extent, but will fail at higher concentrations. We show also that pollution with heavy metals will interfere with both, the oxidative stress defence in plants, and with their ability to conjugate and detoxify organic xenobiotics. Despite plant species dependent differences, the general reactions seem to include oxidative stress and an induction of antioxidative enzymes. Both species respond to trace elements with oxidative stress and decay of central physiological functions. In non-hyperaccumulators like the chosen species, photosynthesis, growth, but also defense will cease at higher concentrations or prolonged exposure to heavy metals. Interestingly, defense reactions against organic xenobiotics, so far considered unrelated to heavy metal stress will also be impaired by mixed pollution, especially cadmium. Here, direct interactions with enzyme proteins are possible, but influence on transcription is frequently observed. For the practical use of plants in phytoremediation, it is discussed that only species with proven stress resistance or mixed plant consortia with differential resistances and uptake can be recommended.

Metallothionein: a new soldier in the fight against chronic renal hypoxia?

Sustained hypoxia appears to be an early and pivotal condition in the pathogenesis of chronic kidney disease, and may induce a number of adaptive/protective or harmful cellular responses. Kojima and colleagues found an upregulation of metallothioneins (MTs) among dozens of altered expression patterns. They demonstrated the astonishing properties of MTs within major intracellular signaling pathways beyond their notorious functions in heavy metal metabolism, detoxification, and ROS scavenging-HRE stimulation during normoxia and hypoxia together with ERK phosphorylation and mTOR activation.

The Dual Nature of Metallothioneins in the Metabolism of Heavy Metals and Reactive Oxygen Species in Aquatic Organisms: Implications of Use as a Biomarker of Heavy-Metal Effects in Field Investigations

The purpose of this study was to examine the function of metallothioneins (MT) in respect to the mobilization of heavy metals and superoxide anion (O2–) scavenging in aquatic organisms. Using an O2– generating system, liberation of free zinc from native and zinc MT (Zn-MT) was measured in vitro. Addition of the O2– generating system and H2O2 readily increased the di- and trimeric forms of MT as determined by gel electrophoresis analysis. To determine whether the proportion of oxidized MT could change in contaminated environments, metal-contaminated Mya arenaria clams were collected from a harbour in the St. Lawrence Estuary. The levels of labile zinc, superoxide dismutase (O2– scavenging enzyme), lipid peroxidation (LPO) and the oxidized/metallic form of MT were determined in the digestive gland. The results revealed that the induction of total MT levels was the result of increased oxidized MT at the expense of the reduced or metallic form of MT. Both superoxide dismutase (SOD) and labile zinc (Zn) levels were induced and they were significantly correlated with the oxidized form of MT, but not the metallic form, in feral clam populations. We concluded that the level of total MT was related to Zn mobility and the activation of antioxidant mechanisms such as SOD, and corresponded to the levels of oxidized MT. The metallic form of MT was negatively associated with Zn mobility but positively associated with oxidative damage such as LPO. Overall, the oxidized fraction of MT appeared to be more closely related to detoxification, while the metallic form of MT was associated with metal mobility and toxicity via oxidative damage. The protective effect of MT during heavy-metal contamination depends on the availability of metals and on its capacity to sequester reactive oxygen species.

Stress response in the central nervous system of a transgenic mouse model of bovine spongiform encephalopathy

An immunohistochemical study was performed to evaluate the stress-related proteins heat shock protein 25 (HSP25) and metallothionein 1 + 2 (MT1 + 2) in the brains of a murine model of bovine spongiform encephalopathy (BSE). Transgenic mice (BoTg110) expressing the bovine cellular prion protein were intracerebrally inoculated with brainstem homogenate from BSE infected cattle. PrP BSE deposits were found in the brain as early as 150 days post-inoculation (dpi) and in mice sacrificed terminally at 290–320 dpi. Glial proliferation and spongiform change were associated with an increase in glial immunostaining of MT1 + 2 and HSP25, respectively. These proteins are associated with oxidative stress and heavy metal metabolism, which may have a role in the pathogenesis of BSE.

Toxicological effects of primary-treated urban wastewaters, before and after ozone treatment, on freshwater mussels ( Elliptio complanata)

This study examined the toxic potential of a primary-treated municipal effluent, before and after ozonation, in freshwater mussels. Animals were exposed to various concentrations (0, 1, 3, 10 and 20% v/v) of a primary-treated effluent and also after a treatment with ozone at 10 mg/L in continuous flow-through mode for seven weeks. A suite of biomarkers was used to assess the potential toxic effects of various contaminants typically present in municipal wastewaters: heavy metal metabolism (metallothioneins and labile zinc), cytochrome P4501A1 and 3A4, glutathione S-transferase activities (biotransformation of organic compounds), lipid peroxidation and xanthine oxidoreductase (oxygen radical scavenging), DNA damage, mitochondrial electron transport activity at various temperatures and gonad lipid levels (cellular energy allocation) and aspartate transcarbamoylase and dihydrofolate reductase (gonad activity). On the one hand, some biomarkers, including metallothioneins, labile zinc, glutathione S-transferase, cytochrome P4503A4 activity, dehydrofolate reductase and aspartate transcarbamoylase, were readily decreased. In contrast, these biomarkers, cytochrome P4501A1, gill lipid peroxidation, DNA strand breaks in gills and digestive gland, mitochondrial electron transport at high and low temperatures (temperature-dependent activity) and total gonad lipids, were readily increased. In general, ozone treatment reduced adverse effects by either decreasing the intensity of the toxic responses or increasing the threshold concentration. For gill lipid peroxidation, however, intensity was greater at a higher threshold concentration. Ozone treatment eliminated the temperature sensitivity of the mitochondrial electron transport system, indicating a loss of interaction between temperature and urban pollution in terms of energy expenditure in mussels. Ozone treatment could significantly decrease either the toxic potency or intensity of urban pollutants at the expense of increased oxidative stress in gills of freshwater mussels.

A Cadmium-transporting P1B-type ATPase in Yeast Saccharomyces cerevisiae

Detoxification and homeostatic acquisition of metal ions are vital for all living organisms. We have identified PCA1 in yeast Saccharomyces cerevisiae as an overexpression suppressor of copper toxicity. PCA1 possesses signatures of a P1B-type heavy metal-transporting ATPase that is widely distributed from bacteria to humans. Copper resistance conferred by PCA1 is not dependent on catalytic activity, but it appears that a cysteine-rich region located in the N terminus sequesters copper. Unexpectedly, when compared with two independent natural isolates and an industrial S. cerevisiae strain, the PCA1 allele of the common laboratory strains we have examined possesses a missense mutation in a predicted ATP-binding residue conserved in P1B-type ATPases. Consistent with a previous report that identifies an equivalent mutation in a copper-transporting P1B-type ATPase of a Wilson disease patient, the PCA1 allele found in laboratory yeast strains is nonfunctional. Overexpression or deletion of the functional allele in yeast demonstrates that PCA1 is a cadmium efflux pump. Cadmium as well as copper and silver, but not other metals examined, dramatically increase PCA1 protein expression through post-transcriptional regulation and promote subcellular localization to the plasma membrane. Our study has revealed a novel metal detoxification mechanism in yeast mediated by a P1B-type ATPase that is unique in structure, substrate specificity, and mode of regulation.

Differences in apolipoprotein E3/3 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease

Apolipoprotein E4 (APOE4) allele is a major risk factor for late-onset familial and sporadic Alzheimer disease (AD). The mechanism of action of APOE in the etiology of AD remains unclear. Using gene expression (microarray) analysis of human hippocampus from APOE3/3 AD and APOE4/4 AD cases, we found different gene transcription patterns between APOE4/4 and APOE3/3 AD cases. The expression of APOE4/4 alleles, in comparison to APOE3/3, is associated with upregulation of multiple gene transcripts encoding cell growth suppresser or arrest, signal transduction, myelinogenesis, cell adhesion and migration, heavy metal metabolism and detoxification. Whereas the APOE4 gene expression is associated with downregulation of gene transcripts involved in mitochondrial oxidative phosphorylation and energy metabolism, synaptic vesicle docking and fusing, and synaptic plasticity compared to APOE3. These mechanisms may contribute increased risk for AD and for cognitive dysfunction in AD patients who carry the APOE4 allele(s).

Regulation of metallothionein and zinc transporter expression in human prostate cancer cells and tissues.

Prostate glands contain heavy metals such as zinc and cadmium, and epidemiological studies showed that both metals were associated with prostate cancer development. To understand the heavy metal metabolism in prostate glands, we investigated the regulation of metallothionein (MT), metal-responsive promoter element-binding transcription factor (MTF) and zinc transporter (ZnT) in human prostate cells and tissues. Growth of human prostate cancer cells, LNCaP and PC-3 cells, was suppressed by zinc or cadmium treatment in a dose-dependent manner. LNCaP cells expressed MT-1A, 1X and 2A mRNA, and PC-3 cells expressed MT-1X and 2A mRNA. Zinc or cadmium treatment up-regulated MTs, MTF-1 and ZnT-1 gene expression levels in both cell lines. In PC-3 cells, ZnT-1 protein was detected, and was up-regulated by the metal treatment. Human prostate cancer tissues expressed significantly lower levels of ZnT-1 gene in comparison with hyperplastic tissues. We demonstrated the ZnT-1 expression in human prostate for the first time. The present study showed that heavy metal-metabolizing proteins were involved in human prostate homeostasis, and that the metal metabolizing system might be different in malignant tissues.

Heavy metals and the origin of life

The functional value of heavy metals in proto-cells was immense and involved critical roles in catalysis of molecular synthesis, translation, electrical neutrality and conduction, energy capture, cross-linking and precipitation (stabilizers of protective cell walls), and to a limited extent, osmotic pressure control. Metals must have modulated the evolutionary choices of the types of building blocks, such as ribose sugars as a constituent of RNA, or the the chirality and enantiopurity of many biomolecules. The formation of an enclosing membrane led to intracellular prokaryotic life (believed to have originated in an anaerobic environment) and much enhanced control over primary metabolism, the uptake and incorporation of heavy metals and the management of biomolecules (especially RNA, DNA and proteins) that were formed. Cells of the most primitive organisms (archaebacteria) reveal complex mechanisms designed specifically to deal with selective pressures from metal-containing environments including intra- and extra-cellular sequestration, exclusion by cell wall barrier, removal through active efflux pumps, enzymatic detoxification, and reduction in sensitivity of cellular targets to metal ions. Adaptation to metals using a variety of chromosomal, and transposon and plasmid-mediated systems began early in the evolution of life on Earth. Recent studies, however, show that the roles played by many heavy metals have changed over time. Divalent lead, for instance, has relinquished its unique catalytic role in the conversion of carbohydrates into ribose in the prebiotic world. The putative elements that dominated the primordial biochemistry were V, Mo, W, Co, Fe(II) and Ni; with the development of oxygenated atmosphere, these elements gave way to Zn, Cu and Fe(III) in their metabolic functions.

The "metal transcription factor" MTF-1: biological facts and medical implications.

Metallothioneins (MTs) are a class of small, cysteine-rich proteins that have an important function in heavy metal metabolism and detoxification and in the management of various forms of cell stress. Several lines of evidence suggest a role for metallothioneins in therapy resistance of malignant tumours, regulation of blood pressure and protection against some neurological diseases. Basal and heavy metal-induced expression of the stress-inducible metallothionein-I and -II genes and some other stress-regulated genes depends on the zinc-finger transcription factor MTF-1. MTF-1 acts as a cellular stress-sensor protein and, besides its crucial role in metallothionein expression, is essential for liver development since mice null mutant for MTF-1 die in utero due to hepatocyte degeneration. Under pathological conditions, MTF-1 seems to be involved in clinically important processes such as tumour angiogenesis and drug resistance. It thus seems generally advisable to monitor MTF-1 activity in stress-related processes including aging and carcinogenesis.

The "metal transcription factor" MTF-1: biological facts and medical implications.

Metallothioneins (MTs) are a class of small, cysteine-rich proteins that have an important function in heavy metal metabolism and detoxification and in the management of various forms of cell stress. Several lines of evidence suggest a role for metallothioneins in therapy resistance of malignant tumours, regulation of blood pressure and protection against some neurological diseases. Basal and heavy metal-induced expression of the stress-inducible metallothionein-I and -II genes and some other stress-regulated genes depends on the zinc-finger transcription factor MTF-1. MTF-1 acts as a cellular stress-sensor protein and, besides its crucial role in metallothionein expression, is essential for liver development since mice null mutant for MTF-1 die in utero due to hepatocyte degeneration. Under pathological conditions, MTF-1 seems to be involved in clinically important processes such as tumour angiogenesis and drug resistance. It thus seems generally advisable to monitor MTF-1 activity in stress-related processes including aging and carcinogenesis.

Putting its fingers on stressful situations: the heavy metal-regulatory transcription factor MTF-1.

It has been suggested that metallothioneins, discovered about 45 years ago, play a central role in heavy metal metabolism and detoxification, and in the management of various forms of stress. The metal-regulatory transcription factor-1 (MTF-1) was shown to be essential for basal and heavy metal-induced transcription of the stress-responsive metallothionein-I and metallothionein-II. Recently it has become obvious that MTF-1 has further roles in the transcriptional regulation of genes induced by various stressors and might even contribute to some aspects of malignant cell growth. Furthermore, MTF-1 is an essential gene, as mice null-mutant for MTF-1 die in utero due to liver degeneration. We describe here the state of knowledge on the complex activation of MTF-1, and propose a model with MTF-1 as an interconnected cellular stress-sensor protein involved in heavy metal metabolism, hepatocyte differentiation and detoxification of toxic agents.

The Drosophila homolog of mammalian zinc finger factor MTF-1 activates transcription in response to heavy metals.

Metallothioneins (MTs) are short, cysteine-rich proteins for heavy metal homeostasis and detoxification; they bind a variety of heavy metals and also act as radical scavengers. Transcription of mammalian MT genes is activated by heavy metal load via the metal-responsive transcription factor 1 (MTF-1), an essential zinc finger protein whose elimination in mice leads to embryonic lethality due to liver decay. Here we characterize the Drosophila homolog of vertebrate MTF-1 (dMTF-1), a 791-amino-acid protein which is most similar to its mammalian counterpart in the DNA-binding zinc finger region. Like mammalian MTF-1, dMTF-1 binds to conserved metal-responsive promoter elements (MREs) and requires zinc for DNA binding, yet some aspects of heavy metal regulation have also been subject to divergent evolution between Drosophila and mammals. dMTF-1, unlike mammalian MTF-1, is resistant to low pH (6 to 6.5). Furthermore, mammalian MT genes are activated best by zinc and cadmium, whereas in Drosophila cells, cadmium and copper are more potent inducers than zinc. The latter species difference is most likely due to aspects of heavy metal metabolism other than MTF-1, since in transfected mammalian cells, dMTF-1 responds to zinc like mammalian MTF-1. Heavy metal induction of both Drosophila MTs is abolished by double-stranded RNA interference: small amounts of cotransfected double-stranded RNA of dMTF-1 but not of unrelated control RNA inhibit the response to both the endogenous dMTF-1 and transfected dMTF-1. These data underline an important role for dMTF-1 in MT gene regulation and thus heavy metal homeostasis.