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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.


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.



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.



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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