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Article ; Online: Metal-induced autoimmunity in neurological disorders: A review of current understanding and future directions.

Bjørklund, Geir / Đorđević, Aleksandra Buha / Hamdan, Halla / Wallace, David R / Peana, Massimiliano

2023 Volume 23, Issue 3, Page(s) 103509

Abstract: Autoimmunity is a multifaceted disorder influenced by both genetic and environmental factors, and metal exposure has been implicated as a potential catalyst, especially in autoimmune diseases affecting the central nervous system. Notably, metals like ... ...

Abstract	Autoimmunity is a multifaceted disorder influenced by both genetic and environmental factors, and metal exposure has been implicated as a potential catalyst, especially in autoimmune diseases affecting the central nervous system. Notably, metals like mercury, lead, and aluminum exhibit well-established neurotoxic effects, yet the precise mechanisms by which they elicit autoimmune responses in susceptible individuals remain unclear. Recent studies propose that metal-induced autoimmunity may arise from direct toxic effects on immune cells and tissues, coupled with indirect impacts on the gut microbiome and the blood-brain barrier. These effects can activate self-reactive T cells, prompting the production of autoantibodies, inflammatory responses, and tissue damage. Diagnosing metal-induced autoimmunity proves challenging due to nonspecific symptoms and a lack of reliable biomarkers. Treatment typically involves chelation therapy to eliminate excess metals and immunomodulatory agents to suppress autoimmune responses. Prevention strategies include lifestyle adjustments to reduce metal exposure and avoiding occupational and environmental risks. Prognosis is generally favorable with proper treatment; however, untreated cases may lead to autoimmune disorder progression and irreversible organ damage, particularly in the brain. Future research aims to identify genetic and environmental risk factors, enhance diagnostic precision, and explore novel treatment approaches for improved prevention and management of this intricate and debilitating disease.
MeSH term(s)	Humans ; Autoimmunity/drug effects ; Autoimmunity/immunology ; Metals/adverse effects ; Metals/immunology ; Nervous System Diseases/immunology ; Animals ; Autoimmune Diseases/immunology
Chemical Substances	Metals
Language	English
Publishing date	2023-12-28
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2144145-5
ISSN	1873-0183 ; 1568-9972
ISSN (online)	1873-0183
ISSN	1568-9972
DOI	10.1016/j.autrev.2023.103509
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Article ; Online: The Validity of Benchmark Dose Limit Analysis for Estimating Permissible Accumulation of Cadmium.

Satarug, Soisungwan / Vesey, David A / Gobe, Glenda C / Đorđević, Aleksandra Buha

International journal of environmental research and public health

2022 Volume 19, Issue 23

Abstract: Cadmium (Cd) is a toxic metal pollutant that accumulates, especially in the proximal tubular epithelial cells of kidneys, where it causes tubular cell injury, cell death and a reduction in glomerular filtration rate (GFR). Diet is the main Cd exposure ... ...

Abstract	Cadmium (Cd) is a toxic metal pollutant that accumulates, especially in the proximal tubular epithelial cells of kidneys, where it causes tubular cell injury, cell death and a reduction in glomerular filtration rate (GFR). Diet is the main Cd exposure source in non-occupationally exposed and non-smoking populations. The present study aimed to evaluate the reliability of a tolerable Cd intake of 0.83 μg/kg body weight/day, and its corresponding toxicity threshold level of 5.24 μg/g creatinine. The PROAST software was used to calculate the lower 95% confidence bound of the benchmark dose (BMDL) values of Cd excretion (E
MeSH term(s)	Male ; Female ; Humans ; Middle Aged ; Cadmium/analysis ; Acetylglucosaminidase ; beta 2-Microglobulin ; Reproducibility of Results ; Environmental Exposure/analysis ; Creatinine ; Biomarkers
Chemical Substances	Cadmium (00BH33GNGH) ; Acetylglucosaminidase (EC 3.2.1.52) ; beta 2-Microglobulin ; Creatinine (AYI8EX34EU) ; Biomarkers
Language	English
Publishing date	2022-11-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph192315697
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Article ; Online: The Validity of Benchmark Dose Limit Analysis for Estimating Permissible Accumulation of Cadmium

Soisungwan Satarug / David A. Vesey / Glenda C. Gobe / Aleksandra Buha Đorđević

International Journal of Environmental Research and Public Health, Vol 19, Iss 15697, p

2022 Volume 15697

Abstract	Cadmium (Cd) is a toxic metal pollutant that accumulates, especially in the proximal tubular epithelial cells of kidneys, where it causes tubular cell injury, cell death and a reduction in glomerular filtration rate (GFR). Diet is the main Cd exposure source in non-occupationally exposed and non-smoking populations. The present study aimed to evaluate the reliability of a tolerable Cd intake of 0.83 μg/kg body weight/day, and its corresponding toxicity threshold level of 5.24 μg/g creatinine. The PROAST software was used to calculate the lower 95% confidence bound of the benchmark dose (BMDL) values of Cd excretion (E Cd ) associated with injury to kidney tubular cells, a defective tubular reabsorption of filtered proteins, and a reduction in the estimated GFR (eGFR). Data were from 289 males and 445 females, mean age of 48.1 years of which 42.8% were smokers, while 31.7% had hypertension, and 9% had chronic kidney disease (CKD). The BMDL value of E Cd associated with kidney tubular cell injury was 0.67 ng/L of filtrate in both men and women. Therefore, an environmental Cd exposure producing E Cd of 0.67 ng/L filtrate could be considered as Cd accumulation levels below which renal effects are likely to be negligible. A reduction in eGFR and CKD may follow when E Cd rises from 0.67 to 1 ng/L of filtrate. These adverse health effects occur at the body burdens lower than those associated with E Cd of 5.24 µg/g creatinine, thereby arguing that current health-guiding values do not provide a sufficient health protection.
Keywords	benchmark dose ; BMD lower confidence limit ; BMDL ; BMD upper confidence limit ; BMDU ; cadmium ; Medicine ; R
Subject code	616
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Xenobiotics, Trace Metals and Genetics in the Pathogenesis of Tauopathies

Jan Aaseth / Aleksandra Buha / David R. Wallace / Geir Bjørklund

International Journal of Environmental Research and Public Health, Vol 17, Iss 4, p

2020 Volume 1269

Abstract: Tauopathies are a disease group characterized by either pathological accumulation or release of fragments of hyperphosphorylated tau proteins originating from the central nervous system. The tau hypotheses of Parkinson’s and Alzheimer’s diseases contain ... ...

Abstract	Tauopathies are a disease group characterized by either pathological accumulation or release of fragments of hyperphosphorylated tau proteins originating from the central nervous system. The tau hypotheses of Parkinson’s and Alzheimer’s diseases contain a clinically diverse spectrum of tauopathies. Studies of case records of various tauopathies may reveal clinical phenotype characteristics of the disease. In addition, improved understanding of different tauopathies would disclose environmental factors, such as xenobiotics and trace metals, that can precipitate or modify the progression of the disorder. Important for diagnostics and monitoring of these disorders is a further development of adequate biomarkers, including refined neuroimaging, or proteomics. Our goal is to provide an in-depth review of the current literature regarding the pathophysiological roles of tau proteins and the pathogenic factors leading to various tauopathies, with the perspective of future advances in potential therapeutic strategies.
Keywords	xenobiotics ; metals ; pathogenesis ; tauopathies ; Medicine ; R
Subject code	610
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: The NOAEL Equivalent of Environmental Cadmium Exposure Associated with GFR Reduction and Chronic Kidney Disease.

Satarug, Soisungwan / Đorđević, Aleksandra Buha / Yimthiang, Supabhorn / Vesey, David A / Gobe, Glenda C

Toxics

2022 Volume 10, Issue 10

Abstract: Cadmium (Cd) is a highly toxic metal pollutant present in virtually all food types. Health guidance values were established to safeguard against excessive dietary Cd exposure. The derivation of such health guidance figures has been shifted from the no- ... ...

Abstract	Cadmium (Cd) is a highly toxic metal pollutant present in virtually all food types. Health guidance values were established to safeguard against excessive dietary Cd exposure. The derivation of such health guidance figures has been shifted from the no-observed-adverse-effect level (NOAEL) to the lower 95% confidence bound of the benchmark dose (BMD), termed BMDL. Here, we used the PROAST software to calculate the BMDL figures for Cd excretion (E
Language	English
Publishing date	2022-10-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2733883-6
ISSN	2305-6304 ; 2305-6304
ISSN (online)	2305-6304
ISSN	2305-6304
DOI	10.3390/toxics10100614
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Article ; Online: Conducting bioinformatics analysis to predict sulforaphane-triggered adverse outcome pathways in healthy human cells.

Bozic, Dragica / Živančević, Katarina / Baralić, Katarina / Miljaković, Evica Antonijević / Djordjević, Aleksandra Buha / Ćurčić, Marijana / Bulat, Zorica / Antonijević, Biljana / Đukić-Ćosić, Danijela

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2023 Volume 160, Page(s) 114316

Abstract: Sulforaphane (SFN) is a naturally occurring molecule present in plants from Brassica family. It becomes bioactive after hydrolytic reaction mediated by myrosinase or human gastrointestinal microbiota. Sulforaphane gained scientific popularity due to its ... ...

Abstract	Sulforaphane (SFN) is a naturally occurring molecule present in plants from Brassica family. It becomes bioactive after hydrolytic reaction mediated by myrosinase or human gastrointestinal microbiota. Sulforaphane gained scientific popularity due to its antioxidant and anti-cancer properties. However, its toxicity profile and potential to cause adverse effects remain largely unidentified. Thus, this study aimed to generate SFN-triggered adverse outcome pathway (AOP) by looking at the relationship between SFN-chemical structure and its toxicity, as well as SFN-gene interactions. Quantitative structure-activity relationship (QSAR) analysis identified 2 toxophores (Derek Nexus software) that have the potential to cause chromosomal damage and skin sensitization in mammals or mutagenicity in bacteria. Data extracted from Comparative Toxicogenomics Database (CTD) linked SFN with previously proposed outcomes via gene interactions. The total of 11 and 146 genes connected SFN with chromosomal damage and skin diseases, respectively. However, network analysis (NetworkAnalyst tool) revealed that these genes function in wider networks containing 490 and 1986 nodes, respectively. The over-representation analysis (ExpressAnalyst tool) pointed out crucial biological pathways regulated by SFN-interfering genes. These pathways are uploaded to AOP-helpFinder tool which found the 2321 connections between 19 enriched pathways and SFN which were further considered as key events. Two major, interconnected AOPs were generated: first starting from disruption of biological pathways involved in cell cycle and cell proliferation leading to increased apoptosis, and the second one connecting activated immune system signaling pathways to inflammation and apoptosis. In both cases, chromosomal damage and/or skin diseases such as dermatitis or psoriasis appear as adverse outcomes.
MeSH term(s)	Animals ; Humans ; Adverse Outcome Pathways ; Isothiocyanates/pharmacology ; Sulfoxides ; Signal Transduction ; Apoptosis ; Mammals
Chemical Substances	sulforaphane (GA49J4310U) ; Isothiocyanates ; Sulfoxides
Language	English
Publishing date	2023-02-01
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2023.114316
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Article ; Online: In vivo and in silico approach in revealing the influence of lead (Pb) on thyroid gland function.

Vukelić, Dragana / Djordjevic, Aleksandra Buha / Anđelković, Milena / Baralić, Katarina / Ćurčić, Marijana / Đukić-Ćosić, Danijela / Antonijević, Biljana / Bulat, Zorica

Environmental research

2023 Volume 237, Issue Pt 2, Page(s) 117035

Abstract: The purpose of this study was to examine the impact of low doses of lead (Pb) on levels of thyroid hormones (T3, T4, FT3, and FT4) and thyroid-related antibodies (anti-Tg and anti-TPO) in the rat model, as well as genes that are related to Pb and thyroid ...

Abstract	The purpose of this study was to examine the impact of low doses of lead (Pb) on levels of thyroid hormones (T3, T4, FT3, and FT4) and thyroid-related antibodies (anti-Tg and anti-TPO) in the rat model, as well as genes that are related to Pb and thyroid function, relationships between genes, biological processes, molecular processes, and pathways using an in silico approach. Male rats were randomized into seven groups (n = 42), one control group and six groups that received a range of Pb doses: 0.1, 0.5, 1, 3, 7, and 15 mg Pb/kg body weight (b.w.). Dose-response modelling was performed by PROAST software using model averaging method. The Comparative Toxicogenomics Database, GeneMANIA server, and ToppGene Suite portal were used as the main bioinformatic tools in this analysis. The results of our study have shown that low Pb doses induced elevation of thyroid hormones (T4, FT4, and TSH) in rats after subacute exposure, while had no impact on T3, FT3, anti-TPO, and anti-Tg, indicating hyperthyroidism. Dose-dependent effects were increases in T4 and FT4, with the lowest benchmark dose derived for FT4 levels. In silico toxicogenomic data analysis showed that the main molecular pathways/process related to Pb-induced hyperthyroidism are connected with 14 genes involved in antioxidant defense and Se-dependent processes. The results presented here may be useful in further investigation of the health impacts of low-level Pb exposure on thyroid function and endocrine disruption effects.
Language	English
Publishing date	2023-08-31
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	205699-9
ISSN	1096-0953 ; 0013-9351
ISSN (online)	1096-0953
ISSN	0013-9351
DOI	10.1016/j.envres.2023.117035
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Article ; Online: Hepato-renal toxicity of low dose metal(oid)s mixture in real-life risk simulation in rats: Effects on Nrf2/HO-1 signalling and redox status.

Vukelić, Dragana / Baralić, Katarina / Marić, Đurđica / Đukic-Ćosić, Danijela / Bulat, Zorica / Panieri, Emiliano / Saso, Luciano / Djordjevic, Aleksandra Buha

The Science of the total environment

2023 Volume 908, Page(s) 168352

Abstract: The understanding that humans are exposed to a low level of toxic metals and metalloids in their lifetime has resulted in a shift in scientific and regulatory perspectives from the traditional evaluation of single metal toxicity to complex mixtures, ... ...

Abstract	The understanding that humans are exposed to a low level of toxic metals and metalloids in their lifetime has resulted in a shift in scientific and regulatory perspectives from the traditional evaluation of single metal toxicity to complex mixtures, relevant to real-life exposure. Therefore, the aim of this study was to examine the impact of real-life, 90-days exposure to mixture of toxic metal(oid)s, Cd, Pb, Ni, Cr, As and Hg, on the nuclear factor erythroid 2-related factor 2 and hemoxygenase-1 (Nrf2/HO-1) signalling and redox status by assessing total sulfhydryl groups (SH), glutathione (GSH), superoxide dismutase activity (SOD), malondialdehyde (MDA), and ischemia modified albumin (IMA) in the liver and kidney of Wistar rats. Animals (20 males and 20 females) were randomized in 2 control and 6 treated groups that received by oral gavage mixture of metal(oid)s solutions in doses that reflect blood metal(oid) levels determined in previous human biomonitoring study as benchmark dose (F/M _BMD), median (F/M _MED), and 95th percentile (F/M _95). Our results have shown that metal(oid)s mixture impaired the activation of the Nrf2/HO-1 pathway in the kidney and liver of male rats and kidney of female rats, followed by depletion of GSH levels in males. Additionally, in males elevated levels of IMA in the liver were observed, while in both genders increased MDA levels were observed in the kidney. Interestingly, the effects were more pronounced in male than in female rats. This study is among the first that examined hepato-renal toxic mechanisms of real-life metal mixture exposure, while our results might be of immense importance for assessing the risk of exposure to mixtures of toxic substances.
MeSH term(s)	Humans ; Rats ; Female ; Male ; Animals ; NF-E2-Related Factor 2/metabolism ; Rats, Wistar ; Biomarkers/metabolism ; Serum Albumin/metabolism ; Serum Albumin/pharmacology ; Liver/metabolism ; Metals/metabolism ; Glutathione/metabolism ; Oxidation-Reduction ; Oxidative Stress
Chemical Substances	NF-E2-Related Factor 2 ; Biomarkers ; Serum Albumin ; Metals ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2023-11-10
Publishing country	Netherlands
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	121506-1
ISSN	1879-1026 ; 0048-9697
ISSN (online)	1879-1026
ISSN	0048-9697
DOI	10.1016/j.scitotenv.2023.168352
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Zs.A 949: Show issues

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Article ; Online: Cadmium and lead implication in testis cancer; is there a connection?

Anđelković, Milena / Djordjevic, Aleksandra Buha / Vukelić, Dragana / Đukić-Ćosić, Danijela / Aćimović, Miodrag / Bojanić, Nebojša / Bartolović, Daniela / Bulat, Petar / Antonijević, Biljana / Bulat, Zorica

Chemosphere. 2023 July, v. 330 p.138698-

2023

Abstract: Testis cancer (TC) is the most common malignancy of young men. Current evidence from studies, alongside genetics and hormonal status, suggests a significant role of toxic metals, cadmium (Cd) and lead (Pb), in the origin and development of TC. Besides ... ...

Abstract	Testis cancer (TC) is the most common malignancy of young men. Current evidence from studies, alongside genetics and hormonal status, suggests a significant role of toxic metals, cadmium (Cd) and lead (Pb), in the origin and development of TC. Besides oxidative stress and endocrine disruption, interaction with bioelements is one of the critical mechanisms of Cd and Pb toxicity and malign transformation. This study aimed to investigate metal levels in blood, healthy, and tumor testis tissue and to reveal hormone, oxidative status, and bioelements levels in patients with TC. The study enrolled 52 patients with TC and 61 healthy volunteers. Toxic metals and bioelements levels were analyzed by atomic absorption spectrophotometry (AAS) while electrochemiluminescence immunoassay (ECLIA) and spectrophotometry methods were used for hormone and oxidative parameters evaluation. Significantly higher blood Cd levels were depicted in TC cohort. Furthermore, blood Cd elevation was associated with a 1.98 higher probability of TC developing. However, a metal concentration between healthy and tumor testis tissue did not differ significantly. Lower levels of estradiol and testosterone, established in a cohort of TC patients, followed the significant role of hormones in TC development. At the same time, ischemia-modified albumin (IMA) has been recognized as a parameter with very good accuracy as a potential diagnostic marker for TC. The study revealed different distribution patterns of copper (Cu) and zinc (Zn) in the three compartments of the patients, as well significant correlation between essential metals Cu/Zn and toxic metals Cd/Pb indicating metal-metal interactions as pivotal mechanisms of metals toxicity.
Keywords	albumins ; atomic absorption spectrometry ; blood ; cadmium ; copper ; electrochemiluminescence ; estradiol ; genetics ; immunoassays ; lead ; neoplasms ; oxidative stress ; probability ; testes ; testosterone ; toxicity ; zinc ; Testis cancer ; Oxidative status ; Bioelements
Language	English
Dates of publication	2023-07
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2023.138698
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Increased oxidative stress in shoe industry workers with low-level exposure to a mixture of volatile organic compounds.

Umićević, Nina / Kotur-Stevuljević, Jelena / Baralić, Katarina / Đukić-Ćosić, Danijela / Miljaković, Evica Antonijević / Đorđević, Aleksandra Buha / Ćurčić, Marijana / Bulat, Zorica / Antonijević, Biljana

Arhiv za higijenu rada i toksikologiju

2024 Volume 75, Issue 1, Page(s) 51–60

Abstract: This study aimed to assess the redox status and trace metal levels in 49 shoe industry workers (11 men and 38 women) occupationally exposed to a mixture of volatile organic compounds (VOCs), which includes aliphatic hydrocarbons, aromatic hydrocarbons, ... ...

Abstract	This study aimed to assess the redox status and trace metal levels in 49 shoe industry workers (11 men and 38 women) occupationally exposed to a mixture of volatile organic compounds (VOCs), which includes aliphatic hydrocarbons, aromatic hydrocarbons, ketones, esters, ethers, and carboxylic acids. All measured VOCs were below the permitted occupational exposure limits. The control group included 50 unexposed participants (25 men and 25 women). The following plasma parameters were analysed: superoxide anion (O
MeSH term(s)	Male ; Humans ; Female ; Antioxidants/pharmacology ; Copper/toxicity ; Volatile Organic Compounds/toxicity ; Shoes ; Oxidative Stress ; Oxidation-Reduction ; Trace Elements ; Aryldialkylphosphatase/metabolism ; Aryldialkylphosphatase/pharmacology
Chemical Substances	Antioxidants ; Copper (789U1901C5) ; Volatile Organic Compounds ; Trace Elements ; PON1 protein, human (EC 3.1.8.1) ; Aryldialkylphosphatase (EC 3.1.8.1)
Language	English
Publishing date	2024-03-29
Publishing country	Croatia
Document type	Journal Article
ZDB-ID	127289-5
ISSN	1848-6312 ; 0004-1254
ISSN (online)	1848-6312
ISSN	0004-1254
DOI	10.2478/aiht-2024-75-3804
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