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02 Epigallocatechin-3-gallate Mo nanoparticles (EGM NPs) efficiently treat liver injury by strongly reducing oxidative stress, inflammation and endoplasmic reticulum stress

Drug-induced liver injury (DILI) is a serious clinical disease associated with reactive oxygen species (ROS) burst and subsequent inflammatory responses. However, traditional treatments were limited by low efficacy and serious side effects due to the special liver structure. Here, we developed a molybdenum (Mo)-based nanoparticles, EGM NPs, after overall consideration of the pathophysiology of DILI and the advantages of nanodrugs. It demonstrated that EGM NPs treated acetaminophen (APAP)-induced DILI by scavenging ROS and inhibiting inflammation. EGM NPs effectively scavenged various ROS and reduced cell apoptosis at the cellular level. More importantly, EGM NPs can treat APAP-induced DILI in vivo, reducing the levels of liver function indicators in mice with liver injury, scaling down the area of hepatocyte necrosis and successfully inhibiting endoplasmic reticulum (ER) stress in the liver. EGM NPs also showed a certain anti-inflammatory effect by reducing infiltration of macrophages, decreasing pro-inflammatory factors and inhibiting the expression levels of inducible nitric oxide synthase (NOS2) and myeloperoxidase (MPO). Collectively, our findings suggest that EGM NPs-based nanotherapeutic is a novel strategy for the treatment of DILI.

  1. R. Yang, M. Liu, T. J. Zhao, Q. H. Chen, Y. Q. Yang, S. Y. Wang, J. P. Zhang, G. M. Deng, K. W. Sun, Y. Y. Nan, K. Cao, K. L. Ai, and Q. Huang,Epigallocatechin-3-gallate Mo nanoparticles (EGM NPs) efficiently treat liver injury by strongly reducing oxidative stress, inflammation and endoplasmic reticulum stress, Frontiers in Pharmacology, 2022, 13.

 

02 Aluminum, Arsenic, Beryllium, Cadmium, Chromium, Cobalt, Copper, Iron, Lead, Mercury, Molybdenum, Nickel, Platinum, Thallium, Titanium, Vanadium, and Zinc: Molecular Aspects in Experimental Liver Injury

Experimental liver injury with hepatocelluar necrosis and abnormal liver tests is caused by exposure to heavy metals (HMs) like aluminum, arsenic, beryllium, cadmium, chromium, cobalt, copper, iron, lead, mercury, molybdenum, nickel, platinum, thallium, titanium, vanadium, and zinc. As pollutants, HMs disturb the ecosystem, and as these substances are toxic, they may affect the health of humans and animals. HMs are not biodegradable and may be deposited preferentially in the liver. The use of animal models can help identify molecular and mechanistic steps leading to the injury. HMs commonly initiate hepatocellular overproduction of ROS (reactive oxygen species) due to oxidative stress, resulting in covalent binding of radicals to macromolecular proteins or lipids existing in membranes of subcellular organelles. Liver injury is facilitated by iron via the Fenton reaction, providing ROS, and is triggered if protective antioxidant systems are exhausted. Ferroptosis syn pyroptosis was recently introduced as mechanistic concept in explanations of nickel (Ni) liver injury. NiCl2 causes increased iron deposition in the liver, upregulation of cyclooxygenase 2 (COX-2) protein and mRNA expression levels, downregulation of glutathione eroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), nuclear receptor coactivator 4 (NCOA4) protein, and mRNA expression levels. Nickel may cause hepatic injury through mitochondrial damage and ferroptosis, defined as mechanism of iron-dependent cell death, similar to glutamate-induced excitotoxicity but likely distinct from apoptosis, necrosis, and autophagy. Under discussion were additional mechanistic concepts of hepatocellular uptake and biliary excretion of mercury in exposed animals. For instance, the organic anion transporter 3 (Oat3) and the multidrug resistance-associated protein 2 (Mrp2) were involved in the hepatic handling of mercury. Mercury treatment modified the expression of Mrp2 and Oat3 as assessed by immunoblotting, partially explaining its impaired biliary excretion. Concomitantly, a decrease in Oat3 abundance in the hepatocyte plasma membranes was observed that limits the hepatic uptake of mercury ions. Most importantly and shown for the first time in liver injury caused by HMs, titanium changed the diversity of gut microbiota and modified their metabolic functions, leading to increased generation of lipopolysaccharides (LPS). As endotoxins, LPS may trigger and perpetuate the liver injury at the level of gut-liver. In sum, mechanistic and molecular steps of experimental liver injury due to HM administration are complex, with ROS as the key promotional compound. However, additional concepts such as iron used in the Fenton reaction, ferroptosis, modification of transporter systems, and endotoxins derived from diversity of intestinal bacteria at the gut-liver level merit further consideration.

  1. Teschke,Aluminum, Arsenic, Beryllium, Cadmium, Chromium, Cobalt, Copper, Iron, Lead, Mercury, Molybdenum, Nickel, Platinum, Thallium, Titanium, Vanadium, and Zinc: Molecular Aspects in Experimental Liver Injury, Int J Mol Sci, 2022, 23.

           

02 What adverse health effects will environmental heavy metal co-exposure bring us: based on a biological monitoring study of sanitation workers

To investigate the relationship between health effect profile and co-exposure to heavy metal, 254 sanitation workers from Guangzhou, China, were recruited. Ten urinary metals were determined by inductively coupled plasma mass spectrometry. Parameters of physical examination, including blood lipid metabolism, renal function, blood pressure, and lung function, were tested for each participant. The hazard quotients (HQs) of eight heavy metals were evaluated. Cobalt, copper (Cu), molybdenum (Mo), nickel (Ni), and tin (Sn) demonstrated the top five associations with human health with the ∑(19)β as 2.220, 1.351, 1.234, 0.957, and 0.930, respectively. Most physical examination parameters of workers were under the normal ranges, except the levels of forced mid expiratory flow rate (MMEF(75/25)), the maximum expiratory flow rate at 25% vital capacity (MEF(25)) and apolipoprotein B in the first quartile, and the level of uric acid in the third quartile of sanitation works. Moreover, Cu was significantly associated with diastolic pressure, pulse, and high density lipid (p < 0.05). Each unit increase in Mo level was related to a 120% increase odd ratio (OR) of abnormal of systolic pressure, but was significantly and negatively correlated with high density lipoprotein and apolipoprotein A, suggesting that Mo exposure may be a risk factor of cardiovascular disease. Each unit increase in Ni and Sn levels was associated with an increased OR of abnormal rate of MMEF(75/25) and MEF(25) (p < 0.001), suggesting the increasing risks of respiratory diseases. Sanitation workers exposed to Ni and Pb alone had no carcinogenic risks (HQ < 1). However, 23.8%, 34.6%, and 87.3% of sanitation workers confronted non-carcinogenic risks when exposed to Cu, Mo alone (HQ > 1), or co-exposed to the four heavy metals (HI > 1). Our study preliminarily revealed the potential sensitive health indicators of heavy metal co-exposure, which will provide beneficial health protection suggestions for the occupational populations.

  1. Li, H. Kuang, L. Li, M. Wu, Z. Liao, K. Zeng, Y. Ye, and R. Fan,What adverse health effects will environmental heavy metal co-exposure bring us: based on a biological monitoring study of sanitation workers, Environ Sci Pollut Res Int, 2022.

           

02 Sex-specific and dose-response relationships of urinary cobalt and molybdenum levels with glucose levels and insulin resistance in U.S. adults

Growing studies have linked metal exposure to diabetes risk. However, these studies had inconsistent results. We used a multiple linear regression model to investigate the sex-specific and dose-response associations between urinary metals (cobalt (Co) and molybdenum (Mo)) and diabetes-related indicators (fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homeostasis model assessment for insulin resistance (HOMA-IR), and insulin) in a cross-sectional study based on the United States National Health and Nutrition Examination Survey. The urinary metal concentrations of 1423 eligible individuals were stratified on the basis of the quartile distribution. Our results showed that the urinary Co level in males at the fourth quartile (Q4) was strongly correlated with increased FPG (β = 0.61, 95% CI: 0.17-1.04), HbA1c (β = 0.31, 95% CI: 0.09-0.54), insulin (β = 8.18, 95% CI: 2.84-13.52), and HOMA-IR (β = 3.42, 95% CI: 1.40-5.44) when compared with first quartile (Q1). High urinary Mo levels (Q4 vs. Q1) were associated with elevated FPG (β = 0.46, 95% CI: 0.17-0.75) and HbA1c (β = 0.27, 95% CI: 0.11-0.42) in the overall population. Positive linear dose-response associations were observed between urinary Co and insulin (P(nonlinear) = 0.513) and HOMA-IR (P(nonlinear) = 0.736) in males, as well as a positive linear dose-response relationship between urinary Mo and FPG (P(nonlinear) = 0.826) and HbA1c (P(nonlinear) = 0.376) in the overall population. Significant sex-specific and dose-response relationships were observed between urinary metals (Co and Mo) and diabetes-related indicators, and the potential mechanisms should be further investigated.

  1. Yang, Y. Lu, Y. Bai, and Z. Cheng,Sex-specific and dose-response relationships of urinary cobalt and molybdenum levels with glucose levels and insulin resistance in U.S. adults, J Environ Sci (China), 2023, 124, 42-49.

           

02 Molybdenum as a Potential Biocompatible and Resorbable Material for Osteosynthesis in Craniomaxillofacial Surgery-An In Vitro Study

Titanium and stainless steel are commonly known as osteosynthesis materials with high strength and good biocompatibility. However, they have the big disadvantage that a second operation for hardware removal is necessary. Although resorbable systems made of polymers or magnesium are increasingly used, they show some severe adverse foreign body reactions or unsatisfying degradation behavior. Therefore, we started to investigate molybdenum as a potential new biodegradable material for osteosynthesis in craniomaxillofacial surgery. To characterize molybdenum as a biocompatible material, we performed in vitro assays in accordance with ISO Norm 10993-5. In four different experimental setups, we showed that pure molybdenum and molybdenum rhenium alloys do not lead to cytotoxicity in human and mouse fibroblasts. We also examined the degradation behavior of molybdenum by carrying out long-term immersion tests (up to 6 months) with molybdenum sheet metal. We showed that molybdenum has sufficient mechanical stability over at least 6 months for implants on the one hand and is subject to very uniform degradation on the other. The results of our experiments are very promising for the development of new resorbable osteosynthesis materials for craniomaxillofacial surgery based on molybdenum.

  1. Toschka, G. Pöhle, P. Quadbeck, C. V. Suschek, A. Strauß, C. Redlich, and M. Rana,Molybdenum as a Potential Biocompatible and Resorbable Material for Osteosynthesis in Craniomaxillofacial Surgery-An In Vitro Study, Int J Mol Sci, 2022, 23.

02 Metal hypersensitivity and pro-inflammatory cytokine production in patients with failed orthopedic implants: A case-control study

Orthopedic implants heal well without complications in most patients but fail for unclear reasons in some in-dividuals. This study determined the relevance of metal hypersensitivity in patients with failed orthopedic im-plants and those requiring orthopedic implant surgery. The study included 35 patients with failed orthopedic implants and 15 subjects scheduled for orthopedic implant surgery. The production of selected pro-inflammatory cytokines was measured in patients with failed orthopedic implants. Metal hypersensitivity was measured in all subjects using the MELISA (R) test. Of common metals in orthopedic alloys, the patients with failed orthopedic implants responded most frequently to nickel, chromium, titanium, iron, and molybdenum. Hypersensitivity to metals found in implants was measured in 40% of patients with failed implants. The study also showed that titanium exposure in patients with titanium hypersensitivity might lead to implant failure. Metal hypersensitivity testing should be offered to patients before surgery to minimize the risk of implant failure.

  1. Podzimek, L. Himmlova, T. Janatova, G. Bjorklund, R. Vrbova, M. Janovska, M. Peana, C. T. Chasapis, A. Vinsu, J. Prochazkova, and J. Duskova,Metal hypersensitivity and pro-inflammatory cytokine production in patients with failed orthopedic implants: A case-control study, Clinical Immunology, 2022, 245.

 

           

02 Metal exposure and breast cancer among Northern Mexican women: assessment of genetic susceptibility

This study aims to assess breast cancer (BC) association with metals and whether polymorphisms in CYP1A1, CYP1B1, GSTM1 and GSTT1 act as confounders or as modifiers of those relationships. We performed a secondary analysis of 499 histologically confirmed BC cases and the same number of age-matched population controls. We measured urinary concentrations of 18 metals with mass spectrometry. We determined the genetic variants of interest by allelic discrimination and multiplex PCR. After adjusting for covariates, we found BC negatively associated with arsenic, barium, cobalt, copper, magnesium, molybdenum and vanadium concentrations and positively with those of caesium, manganese, tin and thallium. Most associations remained after stratifying by the genetic variants. We identified that polymorphisms in CYP1B1, CYP1A1 and GSTM1 genes interacted with some metals on BC: interaction p-values CYP1B1 G119T × antimony= 0.036, CYP1B1 G119T × cobalt <0.001, CYP1B1 G119T × tin= 0.032, CYP1A1 A4889G × aluminium= 0.018, CYP1A1 A4889G × arsenic= 0.031, CYP1A1 A4889G × nickel= 0.036, CYP1A1 A4889G × vanadium= 0.031 and GSTM1 deletion × barium= 0.035. Exposure to various individual metals, along with genetic characteristics may contribute to BC development. Further studies are warranted to confirm our results.

  1. Gamboa-Loira, Á. Mérida-Ortega, S. J. Rothenberg, M. E. Cebrián, and L. López-Carrillo,Metal exposure and breast cancer among Northern Mexican women: assessment of genetic susceptibility, Environ Sci Pollut Res Int, 2022, 29, 89002-89013.

           

02 Long-term impact of the Tyrnyauz tungsten-molybdenum mining and processing factory waste on environmental pollution and children's population

We studied the consequences of the long-term impact of remediated tailing ponds from the Tyrnyauz tungsten-molybdenum mining and processing factory on the environmental pollution and children living in the area. For more than 60 years, the factory has been engaged in the development of tungsten-molybdenum deposits by open-pit and mine methods and the enrichment of the extracted ore. More than 252,771 thousand tons of waste accumulated in its dumps and tailings ponds. This 170-hectare tailing pond contains more than 125 million tons of waste with arsenic, tungsten, molybdenum and other metals. To examine the possible accumulation of potentially toxic elements in children's bodies, we determined the content of heavy metals in drinking water and in the hair of children. An exfoliated buccal micronucleus test was used to determine the cytogenetic status of children. We did not find significant differences in the content of heavy metals inherent of a tailing pond in children's hair from polluted area compared to the control zone. In buccal cells of children living in the vicinity of the tailings pond, the total number of cytogenetic abnormalities was increased by 4.1 times, the total index of proliferation by 1.5 times, early destruction of the nucleus by 2 times and apoptosis by 1.2 times compared to the clean zone. Thus, we identified a genotoxic and cytotoxic effect on children living in the vicinity of the tailing ponds, which led to an increase in the number of children belonging to the medium- and high-risk groups. No correlations were found between the content of heavy metals in children's hair and the frequency of cells with cytogenetic abnormalities. Weak positive correlation was found between the content of manganese, zinc and copper in children's hair and the indicators of buccal epithelial cell proliferation.

  1. V. Reutova, T. V. Reutova, F. R. Dreeva, and A. A. Shevchenko,Long-term impact of the Tyrnyauz tungsten-molybdenum mining and processing factory waste on environmental pollution and children's population, Environ Geochem Health, 2022, 44, 4557-4568.

           

02 Extracellular and Intracellular Concentrations of Molybdenum and Zinc in Soccer Players: Sex Differences

Molybdenum (Mo) and zinc (Zn) play important roles in the process of adaptation to physical training. The aims of the present study were: (i) to analyze the differences in extracellular (plasma and urine) and intracellular (erythrocytes and platelets) Mo and Zn concentrations between sexes and (ii) to relate extracellular Zn concentrations with biomarkers of muscle damage and muscle mass. The present study involved 138 semi-professional soccer players divided according to sex: male (n = 68) and female (n = 70). Mo and Zn concentrations were determined by inductively coupled plasma mass spectrometry. Erythrocytes, platelets, creatine kinase (CK), and lactate dehydrogenase (LDH) values were also determined by automatic cell counter and spectrophotometric techniques. There were no sex differences in Mo and Zn intake. Male soccer players obtained higher values of erythrocytes, CK, and LDH (p &lt; 0.05), and showed higher plasma and urinary concentrations of Mo and Zn (p &lt; 0.05). Female soccer players showed relatively higher Zn concentrations in erythrocytes (p &lt; 0.05). Finally, positive correlations were observed between extracellular Zn concentrations with CK, LDH and muscle mass. Extracellular concentrations of Mo and Zn were higher in male soccer players. However, the relative concentrations of Zn in relation to the number of erythrocytes were higher in female soccer players.

  1. Toro-Román, M. C. Robles-Gil, D. Muñoz, I. Bartolomé, J. Siquier-Coll, and M. Maynar-Mariño,Extracellular and Intracellular Concentrations of Molybdenum and Zinc in Soccer Players: Sex Differences, Biology (Basel), 2022, 11.

           

           

02 Environmental and dietary determinants of metal exposure in four-year-old children from a cohort located in an industrial area (Asturias, Northern Spain)

Urine samples from four-year-old children located in a heavily industrialized zone in Asturias (Spain) were collected between 2009 and 2012 (n = 334). Vanadium (V; median 54 mu g/g creatinine), cobalt (Co; 1.0 mu g/g c.), nickel (Ni; 3.8 mu g/g c.), copper (Cu; 22 mu g/g c.), zinc (Zn; 590 mu g/g c.), arsenic (As; 64 mu g/g c.), selenium (Se; 49 mu g/g c.), molybdenum (Mo; 110 mu g/g c.), cadmium (Cd; 0.27 mu g/g c.), antimony (Sb; 1.0 mu g/g c.), cesium (Cs; 14 mu g/g c.), barium (Ba; 2.6 mu g/g c.), thallium (Tl; 0.55 mu g/g c.) and lead (Pb; 1.9 mu g/g c.) were analysed. Com-parison with children from other sites showed that this Asturias cohort was characterized by high levels of V, As, Sb, Cs and Tl. The concentrations of Co, Ni, Zn, Cu, Mo, Se, Cd, Ba and Pb were within the range of other cohorts. Terrestrial dietary items were most strongly related to increased urinary concentrations of metals in children, e.g., red meat with Ba and Ni, pasta/cereal with Ni and Zn, sweets with Zn, Co, and Cu, eggs with Mo, Cd, and Cs, and dairy products with Co and Sb. Seafood was the second group of dietary items significantly related to increased metals, e.g., shellfish with Ba, Cs, Pb, and V, fatty fish with As, and lean fish with As and Se. In contrast, higher fruit intake was significantly associated with decreased Cu and Sb, and higher legume intake with decreased Cu, Se and Cs. Higher intakes of other dietary items also led to significant decreases in some metals, such as vegetables and lower concentrations of Se and Mo, and dairy products with decreases in Cu and As. These negative correlations implied very low concentrations of the mentioned metals in these foods. Higher exposure to traffic was associated with higher concentrations of Ba, present in brake components. Children living outside urban areas had higher concentrations of Se. No association of metals with smoking in the family was found.

  1. Junque, A. Tardon, A. Fernandez-Somoano, and J. O. Grimalt,Environmental and dietary determinants of metal exposure in four-year-old children from a cohort located in an industrial area (Asturias, Northern Spain), Environmental Research, 2022, 214.

02 Effect of umbilical cord essential and toxic elements, thyroid levels, and Vitamin D on childhood development

INTRODUCTION: The in-utero environment has dramatic effects on childhood development. We hypothesized prenatal levels of inorganic agents, thyroid levels, and Vitamin D effect childhood development. METHODS: Umbilical cord blood was collected from April 3, 2013 to January 30, 2014 and analyzed for 20 different elements, thyroid and Vitamin D. A retrospective review (n = 60) was performed of well-child examinations from birth to 5 years old (y.o.). RESULTS: There were associations with calcium and 4 month BMI (p = <0.01), 12 month language (p = 0.03); Magnesium and 6 month language (p = 0.04) and gross motor skills at 5 years old (y.o.) (p = 0.03); Copper and 12 month fine motor (p = 0.02); Zinc with fine motor (p = <0.01) and language (p = 0.03) at 2 y.o.; Manganese was associated with language development at 2 y.o. (p = 0.02); Molybdenum and fine motor at 12 months of age (p = 0.02); Selenium with gross motor (p = 0.04) and BMI (p = 0.02) at 5 y.o.; Lead with cognitive function at 4 months (p = 0.04) and 2 y.o. (p = 0.01); Mercury with gross motor at 4 months (p = 0.04) and language at 2 y.o. (p = 0.02). Platinum at 12 months of age (p = <.01) as well as multiple associations at 5 y.o. (p = <.01). Thyroid function tests for free T3 were associated with multiple cognitive and physical milestones. T3 Uptake was associated with 5 y.o. gross motor skills (p = 0.02). Total and Free T4 was associated with cognitive development (p = <.01) and fine motor development, respectively. Vitamin D was associated with a delay of fine motor development (p<0.01). CONCLUSION: There were multiple associations between umbilical cord essential and toxic elements, thyroid levels, and Vitamin D on childhood development.

  1. Cottrell, C. Nelson, C. Waldron, M. Bergeron, A. Samson, and M. Valentovic,Effect of umbilical cord essential and toxic elements, thyroid levels, and Vitamin D on childhood development, Biomed Pharmacother, 2022, 158, 114085.

           

           

02 Combined exposure to multiple metals on cardiovascular disease in NHANES under five statistical models

BACKGROUND: It is well-documented that heavy metals are associated with cardiovascular disease (CVD). However, there is few studies exploring effect of metal mixture on CVD. Therefore, the primary objective of present study was to investigate the joint effect of heavy metals on CVD and to identify the most influential metals in the mixture. METHODS: Original data for study subjects were obtained from the National Health and Nutrition Examination Survey. In this study, adults with complete data on 12 kinds of urinary metals (antimony, arsenic, barium, cadmium, cobalt, cesium, molybdenum, mercury, lead, thallium, tungsten, and uranium), cardiovascular disease, and core covariates were enrolled. We applied five different statistical strategies to examine the CVD risk with metal exposure, including multivariate logistic regression, adaptive elastic net combined with Environmental Risk Score, Quantile g-computation, Weighted Quantile Sum regression, and Bayesian kernel machine regression. RESULTS: Higher levels of cadmium, tungsten, cobalt, and antimony were significantly associated with Increased risk of CVD when covariates were adjusted for multivariate logistic regression. The results from multi-pollutant strategies all indicated that metal mixture was positively associated with the risk of CVD. Based on the results of multiple statistical strategies, it was determined that cadmium, tungsten, cobalt, and antimony exhibited the strongest positive correlations, whereas barium, lead, molybdenum, and thallium were most associated with negative correlations. CONCLUSION: Overall, our study demonstrates that exposure to heavy metal mixture is linked to a higher risk of CVD. Meanwhile, this association may be driven primarily by cadmium, tungsten, cobalt, and antimony. Further prospective studies are warranted to validate or refute our primary findings as well as to identify other important heavy metals linked with CVD.

  1. Guo, N. Li, H. Wang, W. Su, Q. Song, Q. Liang, M. Liang, C. Sun, Y. Li, S. Lowe, R. Bentley, E. J. Song, Q. Zhou, X. Ding, and Y. Sun,Combined exposure to multiple metals on cardiovascular disease in NHANES under five statistical models, Environ Res, 2022, 215, 114435.

                       

02 Association Between Essential and Non-essential Metals, Body Composition, and Metabolic Syndrome in Adults

Growing evidence indicates that metal exposure is associated with metabolic syndrome [a combination of diabetes, high blood pressure (hypertension) and obesity] (MetS); however, mixed results have been reported. The aim of this study was to clarify associations of exposure to essential and non-essential metals with body composition and risks of obesity and MetS. Anthropometry and blood biochemistry of metabolic parameters were obtained from 150 middle-aged Taiwanese adults. Plasma metals were assessed using inductively coupled plasma mass spectrometry, and body compositions were measured by a bioelectrical impedance analysis (BIA). The essential metals of copper (Cu), manganese (Mn), and chromium (Cr) were positively correlated with the body fat mass but inversely correlated with the skeletal muscle mass (all p < 0.05). An adjusted logistic regression showed that Mn [odds ratio (OR) = 1.624 (95% confidence interval 1.072, 2.462), p = 0.02] and, to a lesser extent, Cu [OR = 1.501 (0.985, 2.292), p = 0.059] predicted abdominal obesity, while plasma Cu [OR = 2.211 (1.146, 4.266), p = 0.02] and zinc (Zn) [OR = 2.228 (1.048, 4.736) p = 0.04] predicted MetS. Significant correlations [odds ratio OR, 95% confidence interval] between dyslipidemia  [imbalance of lipids such as cholesterol, low-density lipoprotein cholesterol, (LDL-C), triglycerides, and high-density lipoprotein (HDL)] and lithium [OR = 1.716 (1.080, 2.726)], Cu [OR = 2.210 (1.415, 3.454)], Mn [OR = 2.200 (1.320, 3.666)], molybdenum [OR = 1.853 (1.160, 2.958)], and Zn [OR = 1.993 (1.186, 3.349)], and between boron [OR = 2.583 (1.137, 5.868)] and hyperglycemia were observed (all p < 0.05). Exposure to essential metals may affect the body composition and metabolic profiles, exacerbating the risk of MetS.

  1. J. Ngu, A. V. Skalny, A. A. Tinkov, C. S. Tsai, C. C. Chang, Y. K. Chuang, V. N. Nikolenko, D. A. Zotkin, C. F. Chiu, and J. S. Chang,Association Between Essential and Non-essential Metals, Body Composition, and Metabolic Syndrome in Adults, Biol Trace Elem Res, 2022, 200, 4903-4915.

[“An odds ratio (OR) is a statistic that quantifies the strength of the association between two events, A and B. The odds ratio is defined as the ratio of the odds of A in the presence of B and the odds of A in the absence of B, or equivalently (due to symmetry), the ratio of the odds of B in the presence of A and the odds of B in the absence of A. Two events are independent if and only if the OR equals 1, i.e., the odds of one event are the same in either the presence or absence of the other event. If the OR is greater than 1, then A and B are associated (correlated) in the sense that, compared to the absence of B, the presence of B raises the odds of A, and symmetrically the presence of A raises the odds of B. Conversely, if the OR is less than 1, then A and B are negatively correlated, and the presence of one event reduces the odds of the other event.

Note that the odds ratio is symmetric in the two events, and there is no causal direction implied (correlation does not imply causation): an OR greater than 1 does not establish that B causes A, or that A causes B.[1]”] https://en.wikipedia.org/wiki/Odds_ratio

           

 

01 Dioxidomolybdenum(VI) complexes of azo-hydrazones: Structural investigation, DNA binding and cytotoxicity studies

The synthesis of three new dioxidomolybdenum(VI) complexes [MoO2L1-3(X)] (1-3) {where X = EtOH for 1 and 3 and DMSO for 2} of aroylhydrazone ligands (H2L1-3) containing azobenzene moiety have been reported. H2L1-3 has been synthesized from the condensation of 5-(arylazo) salicylaldehyde derivatives with corresponding aroyl hydrazides. The azobenzene functionality was incorporated in the aroylhydrazone systems containing benzoyl, naphthyl and furyl moieties in order to explore their influence if any, on the biological properties of the corresponding molybdenum complexes. All the synthesized ligands and metal complexes were successfully characterized by elemental analysis, IR, UV-vis, NMR spectroscopy and HRMS. Redox properties of the complexes were studied by cyclic voltammetry. Molecular structures of 1-3 have been determined by X-ray crystallography. The electronic spectra of the complexes have been further analysed using time dependent density functional theory (TDDFT). DNA binding studies reveal that the complexes interact with calf-thymus DNA (CT-DNA) with binding constants in the range 10(4) M-1. The cytotoxicity activity of the complexes against A549 and HCT-15 cell lines has also been explored.

  1. Dinda, S. Majumder, M. Mohanty, D. Mohapatra, S. A. Patra, R. Parida, S. Giri, H. Reuter, C. Kausar, and S. K. Patra,Dioxidomolybdenum(VI) complexes of azo-hydrazones: Structural investigation, DNA binding and cytotoxicity studies, Polyhedron, 2022, 227.

ECOTOXICITY

The toxicity of molybdate to freshwater and marine organisms. III. Generating additional chronic toxicity data for the refinement of safe environmental exposure concentrations in the US and Europe

The freshwater and marine long-term ecotoxicity datasets used in the European REACH registration dossiers for molybdenum and molybdenum compounds resulted in the derivation of a HC5,50%,freshwater (38.2mgMo/L) and HC5,50%,marine (5.70mgMo/L) by means of the statistical extrapolation method. Both datasets, however, did not meet the US-EPA information requirements for deriving Final Chronic Values (FCV) that were based on chronic data. US-EPA compliance was achieved by generating chronic no-effect data for the freshwater benthic amphipod Hyalella azteca and the marine inland silverside fish Menidia beryllina, using sodium molybdate dihydrate as test substance. A 42d-EC10 of 44.6mgMo/L for reproduction was determined in a water-only exposure with H. azteca. For M. beryllina, a 37d-NOEC of 139mg mMo/L for standard length and blotted wet weight was found. Other endpoints (e.g., survival, hatching success) proved to be less sensitive. Data were added to the existing chronic toxicity datasets, together with new long-term no-effect values that were identified in open literature for brown trout Salmo trutta, the marine alga Isochrysis galbana, the marine snail Nassarius dorsatus and the marine barnacle Amphibalanus amphitrite. The updated data sets resulted in a freshwater and marine HC5,50% of 35.7 and 6.85mgMo/L, respectively. The same data sets were also used for the determination of US-EPA FCVs, where the FVCfreshwater was 36.1mg/L, and the FCVmarine was 3.85mgMo/L. As the Final Plant Values for both aquatic environments were higher than their respective FCVs, the Criterion Continuous Concentration (CCC) for molybdenum is equal to the FCV.

D. G. Heijerick, and S. Carey,The toxicity of molybdate to freshwater and marine organisms. III. Generating additional chronic toxicity data for the refinement of safe environmental exposure concentrations in the US and Europe, The Science of the total environment, 2017, 609, 420-428.

Exploring the Nanotoxicology of MoS2: A Study on the Interaction of MoS2 Nanoflakes and K+ Channels

Molybdenum disulfide (MoS2) nanomaterial has recently found various applications in the biomedical field mainly due to its outstanding physicochemical properties. However, little is known about its interactions with biological systems at the atomic level, which intimately relates to the biocompatibility of the material. To provide insights into the effects of MoS2 in biological entities, we investigated the interactions of MoS2 with proteins from a functionally important membrane family, the ubiquitous potassium (K(+)) channels. Here, we study four representative K(+) channels-KcsA, Kir3.2, the Kv1.2 paddle chimera, and K2P2-to investigate their interactions with a triangular MoS2 nanoflake using Molecular Dynamics (MD) simulations combined with electrophysiology experiments. These particular K(+) channels were selected based on the diversity in their structure; that is, although these K(+) channels display similar structural motifs, they also contain significant differences related to their particular function. Our results indicate that the MoS2 nanoflake is able to stably bind to three out of the four channels, albeit through distinct binding modes. The binding mode between each channel and MoS2 underlies the specific deleterious influence on the channel's basic physiological function: For KcsA, MoS2 binds on the extracellular loops, which indirectly destroys the delicate structure of the selectivity filter causing a strong leak of K(+) ions. In the binding mode with Kir3.2, the MoS2 nanoflake completely covers the entrance to the channel pore affecting the normal ion conduction. For the Kv1.2 chimera, the MoS2 nanoflake prefers to bind into a crevice located at the extracellular side of the Voltage Sensor Domain (VSD). Interestingly, the crevice involves the N-terminal segment of S4, a crucial transmembrane helix which directly controls the gating process of the Kv1.2 chimera channel by electromechanical coupling the VSD to the transmembrane electric field. MoS2 in contact with S4 from the Kv1.2 chimera, potentially influences the channel's gating process from open to closed states. In all three systems, the van der Waals contribution to the total energy dominates the binding interactions; also, hydrophobic residues contribute the most contact points, which agrees with the strong hydrophobic character of the MoS2 nanomaterial. Electrophysiology recordings using two-electrode voltage-clamp show that currents of Kir3.2 and Kv1.2 are both blocked by the MoS2 nanoflakes in a concentration-dependent way. While the background K(+) channel, K2P2 (TREK-1), identified as a negative control, is not blocked by the MoS2 nanoflakes. The large and rigid extracellular domain of K2P2 appears to protect the channel from disturbance by the nanoflakes. Intrinsic chemical properties of MoS2, together with the specific features of the channels, such as the electrostatic character and complex surface architecture, determine the critical details of the binding events. These findings might shed light on the potential nanotoxicology of MoS2 nanomaterials and help us to understand the underlying molecular mechanism.

Z. Gu, L. D. Plant, X. Y. Meng, J. M. Perez-Aguilar, Z. Wang, M. Dong, D. E. Logothetis, and R. Zhou,Exploring the Nanotoxicology of MoS2: A Study on the Interaction of MoS2 Nanoflakes and K(+) Channels, .ACS Nano, 2018, 12, 705–717.

 

Reproductive and developmental toxicology

Sodium molybdate added to the feed of rats from the time of weaning (80 or 140 ppm during 8 weeks) resulted in fewer litters and impaired growth of pups [Jeter and Davis,1954]. The effect of Dietary molybdenum had effects upon the hemoglobin, growth, reproduction and lactation of rats [Jeter and Davis, 1954; Schroeder and Mitchener, 1971]. Sodium molybdate did not induce embryonic toxicity when injected into the yolk sacs of 4- and 8-day-old chick embryos [Ridgway and Karnofsky, 1952]. Radioactive 99Mo administered orally to pregnant sows was not present in the fetus. However, demyelination of the cerebral nervous system was observed in the newborn lambs from pregnant ewes were fed a diet high in molybdate [Mills and Fell, 1960].

Jeter, M. A. and Davis, G. K., J. Nutr., 1954, 54, 215.
Schroeder, H. A., Mitchener, M. and Nason, A. P., J. Nutr., 1971, 101, 247.
Schroeder, H. A. and Mitchener, M., Arch. Environ. Health, 1971, 23, 102.
Ridgway, L. P. and Karnofsky, D. A., Ann. N.Y. Acad. Sci., 1952, 55, 203.
Mills, C. F. and Fell, B. F., Nature, 1960, 185, 20.

The effect of molybdenum on estrous activity and reproductive hormones: LH, FSH and estradiol in Wistar weanling female rats whose diet was supplemented, inter alia, with 500 ppm Na2MoO4. High dietary Mo prolonged the length of the estrous cycle and altered the cytological characteristics of the different phases of the cycle. Peak values of FSH were significantly lower in molybdenotic animals and Serum E(2) was lower [Igarza et al.,1996].

Igarza, L., Agostini, M., Becuvillalobos, D., Auza, N., Effects Of Molybdenosis On Luteinizing-Hormone, Follicle-Stimulating And Estradiol Hormones In Rats, Archivos De Medicina Veterinaria , 1996, 28, 101-106.

CYTOTOXICITY

Interactions between chromium(III) and iron(III), molybdenum(III) [MoO3] or nickel(II): Cytotoxicity, genotoxicity and mutagenicity studies

The aim of this study was to examine the effect of chromium(III) and iron(111) and molybdenum(111) and nickel(11) and their combinations on cyto-, genotoxicity and mutagenicity in BALB/3T3 and HepG2 cells. The results obtained from cytotoxicity assays indicate that there are differences between BALB/3T3 and HepG2 cell lines in their sensitivity to chromium chloride, iron chloride, molybdenum trioxide and nickel chloride. The statistically significant increase of DNA damage of all used microelements in both cell lines was observed. The micronucleus assay performed with the use of all concentrations shows statistically significant induction of chromosomal aberrations in all tested microelements in both cell lines. Moreover, treated cells display characteristic apoptosis in comparison to control cells. In all tested microelements, the increase of number of reverse mutations was observed with and without metabolic activation. Additions of Cr(III) at 200 mu M plus Fe(111) at 1000 mu M showed synergistic effect in decrease of cell viability and increase of comets, micronuclei and number of revertants in both cell lines. In case of Cr(111) at 200 mu M plus Mo(III) at 1000 mu M, a protective effect of chromium against molybdenum at 1000 mu M toxicity in both cell lines (assessed by MIT, LDH and NRU, comet, micronucleus and Ames assays) was observed. The protective effect of Cr(111) in decrease of cell viability was observed in pair of Cr(III) at 200 mu M and Ni(II) at 1000 mu M in BALB/3T3 and HepG2 cell lines assessed by mu, LDH and NRU, comet, micronucleus and Ames assays. (C) 2018 Elsevier Ltd. All rights reserved.

S. Terpilowska, and A. K. Siwicki,Interactions between chromium(III) and iron(III), molybdenum(III) or nickel(II): Cytotoxicity, genotoxicity and mutagenicity studies, Chemosphere, 2018, 201, 780-789.

 

Cytotoxicity

Industrial grade 2D molybdenum disulfide (MoS2): an in vitro exploration of the impact on cellular uptake, cytotoxicity, and inflammation

The recent surge in graphene research, since its liquid phase monolayer isolation and characterization in 2004, has led to advancements which are accelerating the exploration of alternative 2D materials such as molybdenum disulphide (MoS2), whose unique physico-chemical properties can be exploited in applications ranging from cutting edge electronic devices to nanomedicine. However, to assess any potential impact on human health and the environment, the need to understand the bio-interaction of MoS2 at a cellular and sub-cellular level is critical. Notably, it is important to assess such potential impacts of materials which are produced by large scale production techniques, rather than research grade materials.
The aim of this study was to explore cytotoxicity, cellular uptake and inflammatory responses in established cell-lines that mimic different potential exposure routes (inhalation, A549; ingestion, AGS; monocyte, THP-1) following incubation with MoS2 flakes of varying sizes (50 nm, 117 nm and 177 nm), produced by liquid phase exfoliation.
Using high content screening (HCS) and Live/Dead assays, it was established that 1 mu g ml-1 (for the three different MoS2 sizes) did not induce toxic effects on any of the cell-lines.
Confocal microscopy images revealed a normal cellular morphology in all cases.
Transmission electron microscopy (TEM) confirmed the uptake of all MoS2 nanomaterials in all the cell-lines, the MoS2 ultimately locating in single membrane vesicles.
At such sub-lethal doses, inflammatory responses are observed, however, associated, at least partially, with the presence of lipopolysaccharide endotoxin in nanomaterial suspensions and surfactant samples. Therefore, the inflammatory response of the cells to the MoS2 or endotoxin contamination was interrogated using a 10-plex ELISA which illustrates cytokine production. The experiments carried out using wild-type and endotoxin hyporesponsive bone marrow derived dendritic cells confirmed that the inflammatory responses result from a combination of endotoxin contamination, the MoS2 nanomaterials themselves, and the stabilizing surfactant.


Moore, C., Movia, D., Smith, R. J., Hanlon, D., Lebre, F., Lavelle, E. C., Byrne, H. J., Coleman, J. N., Volkov, Y., and McIntyre, J.,Industrial grade 2D molybdenum disulphide (MoS2): an in vitro exploration of the impact on cellular uptake, cytotoxicity, and inflammation, 2d Materials, 2017, 4.

 

CYTOTOXICITY

Molybdenum nanoparticles-induced cytotoxicity, oxidative stress, G2/M arrest, and DNA damage in mouse skin fibroblast cells (L929)

The present investigation was aimed to study the cytotoxicity, oxidative stress, and genotoxicity induced by molybdenum nanoparticles (Mo-NPs) in mouse skin fibroblast cells (L929). Cells were exposed to different concentrations (1-100 mug/ml) of Mo-NPs (size 40 nm) for 24 and 48 h. After the exposure, different cytotoxicity assays (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide, MTT; neutral red uptake, NRU; and cellular morphology) and oxidative stress markers (lipid peroxidation, LPO; glutathione, GSH; and catalase) were studied. Further, Mo-NPs-induced intracellular reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), cell cycle arrest, and DNA damage were also studied. L929 cells treated with Mo-NPs showed a concentration- and time-dependent decrease in cell viability and a loss of the normal cell morphology. The percentage cell viability was recorded as 25%, 42%, and 58% by MTT assay and 24%, 46%, and 56% by NRU assay at 25, 50, and 100 mug/ml of Mo-NPs, respectively after 48 h exposure. Furthermore, the cells showed a significant induction of oxidative stress. This was confirmed by the increase in LPO and ROS generation, as well as the decrease in the GSH and catalase levels. The decrease in MMP also confirms the impaired mitochondrial membrane. The cell cycle analysis and comet assay data revealed that Mo-NPs induced G2/M arrest and DNA damage in a concentration-dependent manner. Our results demonstrated, for the first time, Mo-NPs induced cytotoxicity, oxidative stress and genotoxicity in L929 cells. Thus, data suggest the potential hazardous nature of Mo-NPs.

M. A. Siddiqui, Q. Saquib, M. Ahamed, N. N. Farshori, J. Ahmad, R. Wahab, S. T. Khan, H. A. Alhadlaq, J. Musarrat, A. A. Al-Khedhairy, and A. B. Pant,Molybdenum nanoparticles-induced cytotoxicity, oxidative stress, G2/M arrest, and DNA damage in mouse skin fibroblast cells (L929), Colloids and surfaces. B, Biointerfaces, 2015, 125, 73-81.

 Effects of Molybdenum on Reproduction and Molybdenum/Copper Enzyme Activity in the Female Rat

According to Wei et al molybdenum (Mo) inhibits mammary tumors. Analogies have been drawn between carcinogenesis and embryogenesis. The effect of Mo on non-ruminant reproduction has not been extensively investigated. The main objective of this study was to investigate the effect of dietary levels of Mo on the estrus cycle, fertility, and reproduction and some molybdenum and Copper (Cu) enzyme activity in the female rat.

T. V. Fungwe, F. Buddingh, M. T. Yang, S. P. Yang,  Effects of Molybdenum on Reproduction and Molybdenum/Copper Enzyme Activity in the Female Rat, Trace Elements in Man and Animals, 6 1988, pp 619-620.

Hepatic, placental, and fetal trace elements following molybdenum supplementation during gestation

The effect of dietary Mo (Na2MoO42H2O) added to drinking water at levels of 0, 5, 10, 50, or 100 mg on hepatic (gestating dams), placental, and fetal Mo, Cu, Zn, and Fe contents of Sprague-Dawley rats was studied. These elements were determined by a polarographic catalytic procedure for Mo and by atomic absorption spectrophotometry for Cu, Fe, and Zn. Hepatic Mo increased two to sixfold (5–100 mg Mo). There was a 1.5-fold increase in hepatic Cu, significant only at the 50 to 100 mg Mo/L treatment levels. Although the hepatic Fe content of the gestating rats significantly increased with Mo supplementation, the extent of the increase appeared to be influenced by the litter size, fetal weights, and the degree of fetal resorption. Zinc values did not differ at any of the treatment levels. Placental Mo increased 3–76-fold, Cu one to threefold. No differences were observed in placenta Fe or Zn. Fetal Mo increased two to six-fold (10–100 mg/L) and Cu increased one to fivefold. There were no differences in the Fe and Zn content although both of these elements appeared to decline as the level of supplemental Mo increased. Significant correlations were also observed between hepatic, placental, and fetal Mo, Cu, Fe, and Zn. These results suggest that changes in trace mineral status in gestation, owing to high Mo intake, do occur and such occurrences are also reflected in the fetus

Fungwe,Thomas V., Fred Buddingh, Meiling T. Yang, Shiang P. Yang, Hepatic, placental, and fetal trace elements following molybdenum supplementation during gestation, Biological Trace Element Research, 1989, 22, 189-199.

The role of dietary molybdenum on estrous activity, fertility, reproduction and molybdenum and copper enzyme activities of female rats

In this study, we investigated the effect of supplemental molybdenum (Mo) on estrous activity, fertility and reproduction, hepatic xanthine dehydrogenase/oxidase (XDH/OX), sulfite oxidase (SOX) and plasma ceruloplasmin (Cp) in female SD rats. Weanling female rats were assigned to five dietary treatment groups and fed an AIN-76A diet. They were given deionized water containing either no Mo or Mo at 5, 10, 50 and 100 mg/l. Mo significantly prolonged the estrous cycle when fed 10 mg/l or higher. Gestational weight gain was higher for the controls and the 5 mg/l, than for the 10–100 mg/l treatments. Histological data suggested that Mo supplemented at 10 mg/l or higher delayed fetal esophageal development, transfer of fetal hemopoiesis to bone marrow and myelination in the spinal cord. Intrauterine deaths were few, but the rate of fetal resorption increased with supplementation at 10 mg/l or higher. Mean hepatic XDH/XO, SOX and plasma Cu-Cp activity increased with Mo supplementation. This study suggests that supplemental Mo may influence estrous activity and embryogenesis. Hepatic XDH/OX, SOX and plasma ceruloplasmin may be affected differently in gestating and nongestating animals.

Fungwe, Thomas V., Fred Buddingh, Diane S. Demick,  Charles D. Lox, Meiling T. Yang, Shiang P. Yang, The role of dietary molybdenum on estrous activity, fertility, reproduction and molybdenum and copper enzyme activities of female rats, Nutrition Research, 1990, 10, 515–524.

90-Day subchronic toxicity study of sodium molybdate dihydrate in rats

This study investigated the subchronic toxicity of molybdenum (Mo) in Sprague-Dawley rats given sodium molybdate dihydrate in the diet for 90 days at dose levels of 0, 5, 17 or 60 mg Mo/kg(bw)/day. The study complied with OECD Test Guideline (TG) 408, with additional examination of estrus cycles and sperm count, motility, and morphology from OECD TG 416.

The overall no-observed-adverse-effect level was 17 mg Mo/kgbw/day, based on effects on body weight, body weight gain, food conversion efficiency and renal histopathology (females only) at 60 mg Mo/kg(bw)/day.

No treatment-related adverse effects on reproductive organ weights or histopathology, estrus cycles or sperm parameters were observed at any dose level.

No adverse effects were observed in the high dose animals after the 60-day recovery period, with the exception that male rats did not fully recover from reduced body weight.

Serum blood, liver and kidney samples were analyzed for molybdenum, copper, zinc, manganese, iron, cobalt and selenium; high levels of molybdenum and copper were found in the serum, blood, liver and kidneys of rats treated with 60 mg Mo/kg(bw)/day.

In conclusion, the LOAEL and NOAEL for molybdenum were determined to be 60 and 17 mg Mo/kg(bw)/day, respectively. (C) 2013 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-SA license

Murray, F. J., Sullivan, F. M., Tiwary, A. K., and Carey, S., 90-Day subchronic toxicity study of sodium molybdate dihydrate in rats, Regulatory Toxicology and Pharmacology, 2014, 70, 579-588

Developmental toxicity study of sodium molybdate dihydrate administered in the diet to Sprague Dawley rats

Molybdenum is an essential nutrient for humans and animals and is a constituent of several important oxidase enzymes.

It is normally absorbed from the diet and to a lesser extent from drinking water and the typical human intake is around 2 mu g/kg bodyweight per day.

No developmental toxicity studies to contemporary standards have been published and regulatory decisions have been based primarily on older studies where the nature of the test material, or the actual dose levels consumed is uncertain.

In the current study the developmental toxicity of sodium molybdate dihydrate as a representative of a broad class of soluble molybdenum(VI) compounds, was given in the diet to Sprague Dawley rats in accordance with OECD Test Guideline 414. Dose levels of 0, 3, 10, 20 and 40 mg Mo/kg bw/day were administered from GD6 to GD20.

No adverse effects were observed at any dose level on the dams, or on embryofetal survival, fetal bodyweight, or development, with no increase in malformations or variations.

Significant increases in serum and tissue copper levels were observed but no toxicity related to these was observed.

The NOAEL observed in this study was 40 mg Mo/kg bw/day, the highest dose tested. (C) The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/)

Murray, F. J., Tyl, R. W., Sullivan, F. M., Tiwary, A. K., and Carey, S., Developmental toxicity study of sodium molybdate dihydrate administered in the diet to Sprague Dawley rats, Reproductive Toxicology, 2014, 49, 202-208.

 

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