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14 pages, 26824 KiB

Open AccessArticle

Mercury Chloride but Not Lead Acetate Causes Apoptotic Cell Death in Human Lung Fibroblast MRC5 Cells via Regulation of Cell Cycle Progression

by Ji-Young Kim, Mi-Jin An, Geun-Seup Shin, Hyun-Min Lee, Mi Jin Kim, Chul-Hong Kim and Jung-Woong Kim

Int. J. Mol. Sci. 2021, 22(5), 2494; https://doi.org/10.3390/ijms22052494 - 02 Mar 2021

Cited by 2 | Viewed by 2088

Abstract

Heavy metals are important for various biological systems, but, in excess, they pose a serious risk to human health. Heavy metals are commonly used in consumer and industrial products. Despite the increasing evidence on the adverse effects of heavy metals, the detailed mechanisms [...] Read more.

Heavy metals are important for various biological systems, but, in excess, they pose a serious risk to human health. Heavy metals are commonly used in consumer and industrial products. Despite the increasing evidence on the adverse effects of heavy metals, the detailed mechanisms underlying their action on lung cancer progression are still poorly understood. In the present study, we investigated whether heavy metals (mercury chloride and lead acetate) affect cell viability, cell cycle, and apoptotic cell death in human lung fibroblast MRC5 cells. The results showed that mercury chloride arrested the sub-G₁ and G₂/M phases by inducing cyclin B1 expression. In addition, the exposure to mercury chloride increased apoptosis through the activation of caspase-3. However, lead had no cytotoxic effects on human lung fibroblast MRC5 cells at low concentration. These findings demonstrated that mercury chloride affects the cytotoxicity of MRC5 cells by increasing cell cycle progression and apoptotic cell death. Full article

(This article belongs to the Special Issue Heavy Metal Toxicity in Humans)

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13 pages, 3186 KiB

Open AccessArticle

Transcriptome Analysis Reveals HgCl₂ Induces Apoptotic Cell Death in Human Lung Carcinoma H1299 Cells through Caspase-3-Independent Pathway

by Mi Jin Kim, Jinhong Park, Jinho Kim, Ji-Young Kim, Mi-Jin An, Geun-Seup Shin, Hyun-Min Lee, Chul-Hong Kim and Jung-Woong Kim

Int. J. Mol. Sci. 2021, 22(4), 2006; https://doi.org/10.3390/ijms22042006 - 18 Feb 2021

Cited by 4 | Viewed by 2301

Abstract

Mercury is one of the detrimental toxicants that can be found in the environment and exists naturally in different forms; inorganic and organic. Human exposure to inorganic mercury, such as mercury chloride, occurs through air pollution, absorption of food or water, and personal [...] Read more.

Mercury is one of the detrimental toxicants that can be found in the environment and exists naturally in different forms; inorganic and organic. Human exposure to inorganic mercury, such as mercury chloride, occurs through air pollution, absorption of food or water, and personal care products. This study aimed to investigate the effect of HgCl₂ on cell viability, cell cycle, apoptotic pathway, and alters of the transcriptome profiles in human non-small cell lung cancer cells, H1299. Our data show that HgCl₂ treatment causes inhibition of cell growth via cell cycle arrest at G₀/G₁- and S-phase. In addition, HgCl₂ induces apoptotic cell death through the caspase-3-independent pathway. Comprehensive transcriptome analysis using RNA-seq indicated that cellular nitrogen compound metabolic process, cellular metabolism, and translation for biological processes-related gene sets were significantly up- and downregulated by HgCl₂ treatment. Interestingly, comparative gene expression patterns by RNA-seq indicated that mitochondrial ribosomal proteins were markedly altered by low-dose of HgCl₂ treatment. Altogether, these data show that HgCl₂ induces apoptotic cell death through the dysfunction of mitochondria. Full article

(This article belongs to the Special Issue Heavy Metal Toxicity in Humans)

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15 pages, 1308 KiB

Open AccessArticle

The Effect of Cadmium on GFR Is Clarified by Normalization of Excretion Rates to Creatinine Clearance

by Soisungwan Satarug, David A. Vesey, Muneko Nishijo, Werawan Ruangyuttikarn, Glenda C. Gobe and Kenneth R. Phelps

Int. J. Mol. Sci. 2021, 22(4), 1762; https://doi.org/10.3390/ijms22041762 - 10 Feb 2021

Cited by 10 | Viewed by 2573

Abstract

Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-β-D-glucosaminidase concentrations ([Cd]_uand [NAG]_u) to the urine creatinine concentration ([cr]_u). In theory, the sources of these errors are nullified by normalization of excretion rates (E_Cd and [...] Read more.

Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-β-D-glucosaminidase concentrations ([Cd]_uand [NAG]_u) to the urine creatinine concentration ([cr]_u). In theory, the sources of these errors are nullified by normalization of excretion rates (E_Cd and E_NAG) to creatinine clearance (C_cr). We hypothesized that this alternate approach would clarify the contribution of Cd-induced tubular injury to nephron loss. We studied 931 Thai subjects with a wide range of environmental Cd exposure. For x = Cd or NAG, E_x/E_cr and E_x/C_cr were calculated as [x]_u/[cr]_u and [x]_u[cr]_p/[cr]_u, respectively. Glomerular filtration rate (GFR) was estimated according to the Chronic Kidney Disease (CKD) Epidemiology Collaboration (eGFR), and CKD was defined as eGFR < 60 mL/min/1.73m². In multivariable logistic regression analyses, prevalence odds ratios (PORs) for CKD were higher for log(E_Cd/C_cr) and log(E_NAG/C_cr) than for log(E_Cd/E_cr) and log(E_NAG/E_cr). Doubling of E_Cd/C_cr and E_NAG/C_cr increased POR by 132% and 168%; doubling of E_Cd/E_cr and E_NAG/E_cr increased POR by 64% and 54%. As log(E_Cd/C_cr) rose, associations of eGFR with log(E_Cd/C_cr) and log(E_NAG/C_cr) became stronger, while associations of eGFR with log(E_Cd/E_cr) and log(E_NAG/E_cr) became insignificant. In univariate regressions of eGFR on each of these logarithmic variables, R² was consistently higher with normalization to C_cr. Our tabular and graphic analyses uniformly indicate that normalization to C_crclarified relationships of E_Cdand E_NAG to eGFR. Full article

(This article belongs to the Special Issue Heavy Metal Toxicity in Humans)

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16 pages, 2959 KiB

Open AccessArticle

Pancreatic Islets Accumulate Cadmium in a Rodent Model of Cadmium-Induced Hyperglycemia

by Ryan Fitzgerald, Andrew Olsen, Jessica Nguyen, Winifred Wong, Malek El Muayed and Joshua Edwards

Int. J. Mol. Sci. 2021, 22(1), 360; https://doi.org/10.3390/ijms22010360 - 31 Dec 2020

Cited by 21 | Viewed by 2076

Abstract

Cadmium (Cd) is an anthropogenic as well as a naturally occurring toxicant associated with prediabetes and T2DM in humans and experimental models of Cd exposure. However, relatively few studies have examined the mechanism(s) of Cd-induced hyperglycemia. The purpose of this study was to [...] Read more.

Cadmium (Cd) is an anthropogenic as well as a naturally occurring toxicant associated with prediabetes and T2DM in humans and experimental models of Cd exposure. However, relatively few studies have examined the mechanism(s) of Cd-induced hyperglycemia. The purpose of this study was to examine the role of pancreatic islets in Cd-induced hyperglycemia. Male Sprague–Dawley rats were given daily subcutaneous doses of Cd at 0.6 mg/kg over 12 weeks. There was a resulting time-dependent increase in fasting blood glucose and altered insulin release in vitro. Islets isolated from control (saline-treated) and Cd-treated animals were incubated in low (0.5 mg/mL) or high (3 mg/mL) glucose conditions. Islets from 12 week Cd-treated animals had significantly less glucose-stimulated insulin release compared to islets from saline-treated control animals. The actual Cd content of isolated islets was 5 fold higher than the whole pancreas (endocrine + exocrine) and roughly 70% of that present in the renal cortex. Interestingly, islets isolated from Cd-treated animals and incubated in high glucose conditions contained significantly less Cd and zinc than those incubated in low glucose. These results show that within whole pancreatic tissue, Cd selectively accumulates in pancreatic islets and causes altered islet function that likely contributes to dysglycemia. Full article

(This article belongs to the Special Issue Heavy Metal Toxicity in Humans)

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27 pages, 6880 KiB

Open AccessArticle

A Clearance Period after Soluble Lead Nanoparticle Inhalation Did Not Ameliorate the Negative Effects on Target Tissues Due to Decreased Immune Response

by Jana Dumková, Tereza Smutná, Lucie Vrlíková, Bohumil Dočekal, Daniela Kristeková, Zbyněk Večeřa, Zuzana Husáková, Veronika Jakešová, Adriena Jedličková, Pavel Mikuška, Lukáš Alexa, Pavel Coufalík, Michaela Tvrdoňová, Kamil Křůmal, Tomáš Vaculovič, Viktor Kanický, Aleš Hampl and Marcela Buchtová

Int. J. Mol. Sci. 2020, 21(22), 8738; https://doi.org/10.3390/ijms21228738 - 19 Nov 2020

Cited by 8 | Viewed by 2751

Abstract

The inhalation of metal (including lead) nanoparticles poses a real health issue to people and animals living in polluted and/or industrial areas. In this study, we exposed mice to lead(II) nitrate nanoparticles [Pb(NO₃)₂ NPs], which represent a highly soluble form [...] Read more.

The inhalation of metal (including lead) nanoparticles poses a real health issue to people and animals living in polluted and/or industrial areas. In this study, we exposed mice to lead(II) nitrate nanoparticles [Pb(NO₃)₂ NPs], which represent a highly soluble form of lead, by inhalation. We aimed to uncover the effects of their exposure on individual target organs and to reveal potential variability in the lead clearance. We examined (i) lead biodistribution in target organs using laser ablation and inductively coupled plasma mass spectrometry (LA-ICP-MS) and atomic absorption spectrometry (AAS), (ii) lead effect on histopathological changes and immune cells response in secondary target organs and (iii) the clearance ability of target organs. In the lungs and liver, Pb(NO₃)₂ NP inhalation induced serious structural changes and their damage was present even after a 5-week clearance period despite the lead having been almost completely eliminated from the tissues. The numbers of macrophages significantly decreased after 11-week Pb(NO₃)₂ NP inhalation; conversely, abundance of alpha-smooth muscle actin (α-SMA)-positive cells, which are responsible for augmented collagen production, increased in both tissues. Moreover, the expression of nuclear factor κB (NF-κB) and selected cytokines, such as tumor necrosis factor alpha (TNFα), transforming growth factor beta 1 (TGFβ1), interleukin 6(IL-6), IL-1α and IL-1β , displayed a tissue-specific response to lead exposure. In summary, diminished inflammatory response in tissues after Pb(NO₃)₂ NPs inhalation was associated with prolonged negative effect of lead on tissues, as demonstrated by sustained pathological changes in target organs, even after long clearance period. Full article

(This article belongs to the Special Issue Heavy Metal Toxicity in Humans)

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19 pages, 4701 KiB

Open AccessArticle

Cadmium-Induced Cell Homeostasis Impairment is Suppressed by the Tor1 Deficiency in Fission Yeast

by Miroslava Požgajová, Alica Navrátilová, Eva Šebová, Marek Kovár and Miroslava Kačániová

Int. J. Mol. Sci. 2020, 21(21), 7847; https://doi.org/10.3390/ijms21217847 - 22 Oct 2020

Cited by 8 | Viewed by 2234

Abstract

Cadmium has no known physiological function in the body; however, its adverse effects are associated with cancer and many types of organ system damage. Although much has been shown about Cd toxicity, the underlying mechanisms of its responses to the organism remain unclear. [...] Read more.

Cadmium has no known physiological function in the body; however, its adverse effects are associated with cancer and many types of organ system damage. Although much has been shown about Cd toxicity, the underlying mechanisms of its responses to the organism remain unclear. In this study, the role of Tor1, a catalytic subunit of the target of rapamycin complex 2 (TORC2), in Cd-mediated effects on cell proliferation, the antioxidant system, morphology, and ionome balance was investigated in the eukaryotic model organism Schizosaccharomyces pombe. Surprisingly, spectrophotometric and biochemical analyses revealed that the growth rate conditions and antioxidant defense mechanisms are considerably better in cells lacking the Tor1 signaling. The malondialdehyde (MDA) content of Tor1-deficient cells upon Cd treatment represents approximately half of the wild-type content. The microscopic determination of the cell morphological parameters indicates the role for Tor1 in cell shape maintenance. The ion content, determined by inductively coupled plasma optical emission spectroscopy (ICP-OES), showed that the Cd uptake potency was markedly lower in Tor1-depleted compared to wild-type cells. Conclusively, we show that the cadmium-mediated cell impairments in the fission yeast significantly depend on the Tor1 signaling. Additionally, the data presented here suggest the yet-undefined role of Tor1 in the transport of ions. Full article

(This article belongs to the Special Issue Heavy Metal Toxicity in Humans)

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13 pages, 2311 KiB

Open AccessArticle

Metformin Mitigates Nickel-Elicited Angiopoietin-Like Protein 4 Expression via HIF-1α for Lung Tumorigenesis

by Yu-Ting Kang, Wen-Cheng Hsu, Chu-Chyn Ou, Hui-Chun Tai, Hui-Ting Hsu, Kun-Tu Yeh and Jiunn-Liang Ko

Int. J. Mol. Sci. 2020, 21(2), 619; https://doi.org/10.3390/ijms21020619 - 17 Jan 2020

Cited by 11 | Viewed by 2966

Abstract

Nickel (Ni), which is a carcinogenic workplace hazard, increases the risk of lung cancer. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine that is involved in both angiogenesis and metastasis, but its role in lung cancer is still not clear. In this study, [...] Read more.

Nickel (Ni), which is a carcinogenic workplace hazard, increases the risk of lung cancer. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine that is involved in both angiogenesis and metastasis, but its role in lung cancer is still not clear. In this study, we assessed the role of ANGPTL4 in lung carcinogenesis under nickel exposure and investigated the effects of the antidiabetic drug metformin on ANGPTL4 expression and lung cancer chemoprevention. Our results showed that ANGPTL4 is increased in NiCl₂-treated lung cells in a dose- and time-course manner. The expression of ANGPTL4 and HIF-1α induced by NiCl₂ were significantly repressed after metformin treatment. The downregulation of HIF-1α expression by ROS savenger and HIF-1α inhibitor or knockdown by lentiviral shRNA infection diminished NiCl₂-activated ANGPTL4 expression. Chromatin immunoprecipitation and the luciferase assay revealed that NiCl₂-induced HIF-1α hypoxia response element interactions activate ANGPTL4 expression, which is then inhibited by metformin. In conclusion, the increased presence of ANGPTL4 due to HIF-1α accumulation that is caused by nickel in lung cells may be one mechanism by which nickel exposure contributes to lung cancer progression. Additionally, metformin has the ability to prevent NiCl₂-induced ANGPTL4 through inhibiting HIF-1α expression and its binding activity. These results provide evidence that metformin in oncology therapeutics could be a beneficial chemopreventive agent. Full article

(This article belongs to the Special Issue Heavy Metal Toxicity in Humans)

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Review

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18 pages, 1624 KiB

Open AccessReview

Erythrocytes as a Model for Heavy Metal-Related Vascular Dysfunction: The Protective Effect of Dietary Components

by Rosaria Notariale, Rosmara Infantino, Enza Palazzo and Caterina Manna

Int. J. Mol. Sci. 2021, 22(12), 6604; https://doi.org/10.3390/ijms22126604 - 20 Jun 2021

Cited by 14 | Viewed by 2493

Abstract

Heavy metals are toxic environmental pollutants associated with severe ecological and human health risks. Among them is mercury (Hg), widespread in air, soil, and water, due to its peculiar geo-biochemical cycle. The clinical consequences of Hg exposure include neurotoxicity and nephrotoxicity. Furthermore, increased [...] Read more.

Heavy metals are toxic environmental pollutants associated with severe ecological and human health risks. Among them is mercury (Hg), widespread in air, soil, and water, due to its peculiar geo-biochemical cycle. The clinical consequences of Hg exposure include neurotoxicity and nephrotoxicity. Furthermore, increased risk for cardiovascular diseases is also reported due to a direct effect on cardiovascular tissues, including endothelial cells, recently identified as important targets for the harmful action of heavy metals. In this review, we will discuss the rationale for the potential use of erythrocytes as a surrogate model to study Hg-related toxicity on the cardiovascular system. The toxic effects of Hg on erythrocytes have been amply investigated in the last few years. Among the observed alterations, phosphatidylserine exposure has been proposed as an underlying mechanism responsible for Hg-induced increased proatherogenic and prothrombotic activity of these cells. Furthermore, following Hg-exposure, a decrease in NOS activity has also been reported, with consequent lowering of NO bioavailability, thus impairing endothelial function. An additional mechanism that may induce a decrease in NO availability is the generation of an oxidative microenvironment. Finally, considering that chronic Hg exposure mainly occurs through contaminated foods, the protective effect of dietary components is also discussed. Full article

(This article belongs to the Special Issue Heavy Metal Toxicity in Humans)

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