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At least 19 recordsLinked to original sources
PubMed1977

Metabolic interrelationships between arsenic and selenium.

In 1938, Moxon discovered that arsenic protected against selenium toxicity. Since that time it has been shown that this protective effect of arsenic against selenium poisoning can be demonstrated in many different animal species under a wide variety of conditions. Antagonistic effects between arsenic and selenium have also been noted in teratologic experiments. Early metabolic studies showed that arsenic inhibited the expiration of volatile selenium compounds by rats injected with acutely toxic doses of both elements. This was puzzling since pulmonary excretion had long been regarded as a means by which animals could rid themselves of excess selenium. However, later work demonstrated that arsenic increased the biliary excretion of selenium. Not only did arsenic stimulate the excretion of selenium in the bile, but selenium also stimulated the excretion of arsenic in the bile. This increased biliary excretion of selenium caused by arsenic provides a reasonable rationale for the ability of arsenic to counteract the toxicity of selenium, although the chemical mechanism by which arsenic does this is not certain. The most satisfactory explanation is that these two elements react in the liver to form a detoxication conjugate which is then excreted into the bile. This is consistent with the fact that both arsenic and selenium each increase the biliary excretion of the other. Several other metabolic interactions between arsenic and selenium have been demonstrated in vitro, but their physiological significance is not clear. Although arsenic decreased selenium toxicity under most conditions, there is a pronounced synergistic toxicity between arsenic and two methylated selenium metabolites, trimethylselenonium ion or dimethyl selenide. The ecological consequences of these synergisms are largely unexplored, although it is likely that selenium methylation occurs in the environment. All attempts to promote or prevent selenium deficiency diseases in animals by feeding arsenic have been unsuccessful. Over 30 years ago it was suggested that industrial hygienists use arsenic as a tonic to prevent or cure selenium poisoning in workers exposed to this hazard. Organic arsenical feed additives were tried as partial antidotes against selenium poisoning in livestock raised in seleniferous agricultural areas but were not found to be practical.

Animals↗
PubMed2026

ARR1 and ARR12 negatively regulate arsenic stress tolerance by controlling flavonoid metabolism in Arabidopsis.

ARR1/12-mediated cytokinin signaling negatively regulates the accumulation of glycosylated flavonoids, thereby increasing plant susceptibility to As(III) stress. Cytokinins negatively regulate arsenic stress tolerance in plants through cytokinin-signaling type-B Arabidopsis response regulators (B-ARRs), specifically ARR1 and ARR12. However, the mechanism by which cytokinin signaling regulates plant metabolite dynamics, particularly antioxidant flavonoids, in response to arsenic toxicity remains largely unknown. Here, we hypothesized that ARR1/12-mediated cytokinin signaling modulates flavonoid metabolism to regulate arsenite [As(III)] tolerance. By comparing the global metabolic changes in roots of the arr1 12 double mutant (rD) and wild-type (WT) plants, we found that As(III) stress globally reduced metabolite abundance in WT roots. Importantly, the rD mutant accumulated significantly more flavonoids, most in glycosylated forms, than WT under As(III) exposure, which was supported by the specific upregulation of UDP-glycosyltransferase genes involved in flavonoid glycosylation. Accordingly, exogenous application of the glycosylated quercitrin-enhanced As(III) tolerance in WT roots, strengthening that the increase of glycosylated flavonoids in rD roots was beneficial for plant survival under As(III) exposure. Our data collectively strongly support that the increased glycosylation of flavonoids in the rD mutant improves their antioxidant functionality, thereby enhancing the As(III) stress tolerance. This study provides a new insight into the negative role of cytokinin signaling in repressing glycosylated flavonoid accumulation, causing increased susceptibility of plants to As(III) stress. Manipulation of cytokinin signaling or flavonoid glycosylation is, therefore, a promising approach for heavy metal stress mitigation in crops.

Arabidopsis↗
PubMed2024

Prenatal arsenic exposure alters EZH2-H3K27me3 occupancy at TNF-α promoter leading to insulin resistance and metabolic syndrome in a mouse model.

The global prevalence of Metabolic Syndrome (MetS) is continuously rising and exposure to environmental toxicants such as arsenic could be contributing to this rapid surge. In this study, we have assessed the effects of prenatal arsenic exposure on insulin resistance and MetS parameters in a mouse model, and an underlying mechanism was identified. We found that prenatal arsenic exposure promotes insulin resistance and adipocyte dysfunction which leads to the early onset of MetS in male offspring. Primary adipocytes isolated from 20-week-old arsenic-exposed offspring showed hypertrophy, elevated basal lipolysis, and impaired insulin response along with enhanced expression of Tumor necrosis factor-alpha (TNF-α). TNF-α levels were consistently high at gestational day 15.5 (GD15.5) as well as primary adipocytes of 6-week-old arsenic-exposed male offspring. Along with TNF-α, downstream p-JNK1/2 levels were also increased, which led to inhibitory phosphorylation of IRS1and reduced GLUT4 translocation upon insulin stimulation in adipocytes. Insulin response and downstream signaling were restored upon TNF-α inhibition, confirming its central role. The persistent overexpression of TNF-α in adipocytes of arsenic-exposed mice resulted from diminished EZH2 occupancy and reduced H3K27me3 (gene silencing histone marks) at the TNF-α promoter. This further led to chromatin relaxation, recruitment of c-Jun and CBP/p300, formation of an enhanceosome complex, and TNF-α expression. Our findings show how prenatal arsenic exposure can epigenetically modulate TNF-α expression to promote adipocyte dysfunction and insulin resistance which contributes to the early onset of MetS in offspring.

Animals↗
PubMed1979

Embryotoxicity of arsenic acid: light and electron microscopy of its effect on neurulation-stage rat embryo.

To clarify the light and electron microscopic changes accompanying embryonic death from a lethal dose of arsenic acid, MP 1 pregnant rats were injected i.p. with 30 mg/kg arsenic acid at 1:30 p.m. on day 9 of gestation (the neurulation stage). At 4 hours after treatment, some cell necrosis occurred in the neuroectoderm and the mesoderm of the embryo. At six hours later, cell necrosis increased in the neuroectoderm and the mesoderm, whereas those in the surface ectoderm and the endoderm were very few. In the embryo 12 hours after treatment, abnormal mitotic cells exhibiting vesiculation of the endoplasmic reticula, and abnormal interphase cells characterized by the ring-shaped nucleoli in the nucleus and the enlargement of cisternae of the endoplasmic reticula and the nuclear envelope, were observed in the neuroectoderm and the mesoderm. Debris from cell necrosis and the said abnormal mitotic and interphase cells were ejected from the neuroectoderm into the amniotic coele. In the embryo 24 hours later, neurulation was stopped and the V-shaped neural fold remained. The somite formation was retarded. The surviving cells in the embryo sometimes contained phagocytic vesicles in the cytoplasm, but no other anomalies were encountered. It was considered that a variety of metabolic reactions may be disturbed by arsenic acid, resulting in numerous cell necrosis and abnormal mitotic and interphase cells in the neuroectoderm and the mesoderm of the rat embryo.

Animals↗
PubMed2026

Deficient arsenic methylation and global proteomic reprogramming in human keratinocytes during arsenic-induced skin carcinogenesis.

Chronic inorganic arsenic (iAs) exposure affects > 220 million people worldwide and skin cancer is a hallmark of long-term iAs exposure. Limited information exists regarding arsenic methylation by human keratinocytes and how methylation influences skin carcinogenesis. Inorganic arsenite (iAsIII) and its methylated metabolites disrupt diverse zinc finger proteins, leading to differential toxicity patterns. We examined arsenic methylation capacity in non-malignant human keratinocytes and interrogated proteomic remodeling across three stages of iAsIII induced malignant transformation using the well-established preclinical HaCaT model. Arsenic methylation was assessed by hydride generation cryotrapping inductively coupled-mass spectrometry and global proteomic changes were analyzed by tandem-mass tagging liquid chromatography-tandem mass spectrometry. Primary, hTERT-immortalized and HaCaT human keratinocytes exhibited negligible arsenic methylation, with iAsIII comprising at least 98.5% of total intracellular arsenic, attributable to minimal expression of arsenite methyltransferase. Proteomic profiling identified over 275 differentially expressed proteins at each stage of transformation, including multiple zinc finger proteins implicated in cell cycle control, RNA metabolism, and genome stability. Ingenuity® Pathway Analysis revealed progressive, coordinated disruption of cancer-associated pathways and regulatory networks over the transformation timeline, including zinc-coordinating upstream regulators that may explain widespread pathway dysregulation. Collectively, our findings suggest that iAsIII promotes skin carcinogenesis by disrupting C3H1- and C4-type zinc finger protein-centered regulatory networks that coordinate cancer-associated signaling and metabolic pathways in human keratinocytes, highlighting key candidates for future mechanistic studies.

Arsenic↗
PubMedDate not supplied

A suicide by ingestion of a mixture of copper, chromium and arsenic compounds.

A suicide resulting from the ingestion of copper, chromium and arsenic is reported. Death was delayed for 36 hours, during which time copper was rapidly eliminated from the body but chromium and arsenic remained in substantial quantities. The different metabolism of these elements is discussed and the tissue levels discovered are compared with the normal levels.

Arsenic↗
PubMedDate not supplied

The mitochondrial activation of sulfate and arsenate and their role in carcinogenesis.

Sulfate substitutes for phosphate in the transitory uncoupling of rat liver mitochondria induced by hydrazine when beta-hydroxybutyrate is the substrate. A high level of sulfate in the absence of added phosphate induces a pseudo state three of the mitochondria. Uncoupling is inhibited by rutamycin. Thus sulfate is activated by the mechanism usually utilized by phosphate, and the target for hydrazine is the bond holding electrophilic sulfate. ATP, ADP, PPi, and Mg++ protect against hydrazine, presumably by causing a conformational change of the phosphorylating enzymes which participate in oxidative phosphorylation. Arsenate also could substitute for phosphate in the transitory uncoupling induced by hydrazine. Uncoupling is again inhibited by rutamycin; thus arsenate is also activated by the enzymic mechanism usually utilized by phosphate. Since sulfate is known to enhance the carcinogenicity of certain carcinogens, these results expand the experimental confluence between oxidative phosphorylation and chemical carcinogenesis and also serve to explain at least in part the "toxic" effects of sulfate. Because of the analogous results with arsenate and sulfate, it is suggested that arsenate, like sulfate, may enhance the carcinogenicity of other carcinogens. The data are compatible with epidemiological studies which implicate some role in carcinogenesis for sulfate (often measured as a sulfur dioxide equivalent) and arsenate.

Animals↗
PubMed1975

Accumulation of arsenate, phosphate, and aspartate by Sreptococcus faecalis.

Uptake of arsenate and phosphate by Streptococcus faecalis 9790 is strictly dependent on concurrent energy metabolism and essentially unidirectional. targinine supports uptake only in presence of glycerol or related substances; glycerol is not directly involved in transport but depletes the cellular orthophosphate pool and thus relieves feedback inhibition of transport. Uptake of phosphate and arsenate is stimulated by K+ and by other permeant cations. The results suggest that electroneutrality is preserved by compensatory movement of either H+ or OH minus. Ionophores and N,N'-dicyclohexylcarbodiimide, which prevent establishment of a proton motive force, block the accumulation of thiomethylgalactoside and of threonine but not that of arsenate or phosphate. We conclude that arsenate accumulation requires adenosine 5'-triphosphate but is not driven by the proton-motive force. However, conditions and reagents that lower the cytoplasmic pH do inhibit accumulation of arsenate and phosphate, suggesting that uptake depends on the capacity of the cells to maintain a neutral or alkaline cytoplasm. We therefore propose that phosphate accumulation is an electroneutral exchange for OH driven by adenosine 5'-triphosphate or by a metabolite thereof. Accumulation of aspartate and glutamate also requires adenosine 5'-triphosphate but not the proton-motive force and may involve a similar mechanism.

Adenosine Triphosphate↗
PubMed2025

Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling.

PURPOSE: Type I interferonopathy encompasses disorders marked by systemic inflammation and neurological involvement, arising from genetic mutations that result in the upregulation of type I IFN signaling through various mechanisms. Currently, therapeutic options are limited, and no standard therapy exists. This study aims to develop a strategy for identifying new therapeutic targets for type I interferonopathy using induced pluripotent stem cells (iPSCs). METHODS: The IFIH1 R779H variant was introduced into iPSCs through genome editing. RNA sequencing of iPSC-derived dendritic cells (DCs) was performed, and differentially expressed genes (DEGs) were identified. IFN-α secretion, reactive oxygen species (ROS), and mitochondrial oxygen consumption rate (OCR) were analyzed in iPSC-derived DCs. An in silico prediction of compounds binding to the OAS-like domain was conducted. Candidate compounds were evaluated for their ability to inhibit IFN secretion from IFIH1 R779H-mutated iPSC-derived DCs. RESULTS: Transcriptome analysis indicated upregulation of the IFN-related and metabolic pathways. IFIH1 R779H-mutated iPSC-derived DCs exhibited increased OCR and ROS generation, and blocking mitochondrial metabolism significantly reduced excessive IFN-α secretion. Among the DEGs, PML was upregulated, and targeting this gene with arsenic trioxide (ATO), a PML antagonist, suppressed IFN-α secretion from IFIH1 R779H-mutated iPSC-derived DCs. Additionally, bisantrene, phthalylsulfathiazole and ganaplacide were predicted to bind to the RNA binding groove of OAS-like domain of human OASL in silico, effectively inhibiting IFN-α secretion from IFIH1 R779H-mutated DCs. CONCLUSION: Our iPSC-based disease modeling and drug investigation approach provides a robust platform for validating the efficacy and toxicity of candidate therapeutic agents for rare and intractable human diseases such as type I interferonopathy.

Humans↗
PubMed1977

Some characteristics of soluble fatty acid synthesis in germinating pea seeds.

Soluble fractions from germinating pea synthesize palmitic acid de novo and stearic acid by elongation. Malonyl CoA, acyl carrier protein and NADPH are required for both reactions. In contrast to some other plant systems, no requirement was found for divalent cations. On the other hand, the formation of both stearate and palmitate was inhibited by sulphydryl reagents and palmitate elongation was sensitive to arsenite. The products of the reactions were examined and found to be principally acyl-acyl carrier proteins and unesterified fatty acids. Unlike the pea microsomal fractions, the soluble enzymes are stimulated only slightly by the addition of exogenous lipids. The substrate for palmitate elongation is palmitoylacyl carrier protein, which is quantitatively elongated to stearate. Comparisons are made with membrane-localised fatty acid synthesis from the same tissue.

Arsenic↗
PubMed1979

The 'dying back' process. A common denominator in many naturally occurring and toxic neuropathies.

The "dying back" process can be defined as a pathological changes affecting certain neurons in a number of systematized degenerative conditions. Examples exist to illustrate the nature of this process, which is unique to nervous tissue, and there is an association of this process with certain chronic vitamin-deficiency syndromes and some important neurotoxic chemicals. Albeit largely speculative, one can attempt to group the conditions showing the dying back process in terms of putative metabolic lesions. Although this attempt is admittedly only a first approximation, it enables us to look ahead to a future understanding of the metabolic problems of long neurons and how their selective degeneration comes about.

Acrylamides↗
PubMed1979

Chemical exposure and intestinal function.

The particular substances that are ingested by individuals are the consequence of their environmental, residential, and occupational exposures. The possible effects of these exposures on intestinal functions can be examined by the evaluation of in vivo or in vitro exposure followed by an in vivo and/or in vitro monitoring of effects. Several examples of the in vivo exposure and in vitro monitoring approach are presented to demonstrate the consequences of oral exposure to either a heavy metal (arsenic), or a herbicide contaminant (2,3,7,8-tetrachlorodibenzo-p-dioxin) or a jet fuel propellant (hydrazine) and the subsequent measurement of either a particular metabolic pathway, or a cell-specific enzyme induction or the development of brush border enzymes are presented.

Animals↗