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MOUSE MICE

Effects of environmental metals on mitochondrial bioenergetics of the CD-1 mice pancreatic beta-cells

Environmental metals are believed to have diabetogenic effects without any clear underlying mechanisms. The study investigated the effects of metals, lead (Pb), mercury (Hg), cadmium (Cd), and molybdenum (Mo), on the bioenergetics of isolated pancreatic β-cells from CD-1 mice via different functional and structural techniques. The tested metals caused significant decrease in ATP production in concentration and exposure duration-dependent pattern; Cd was the most potent cytotoxic metal. In ATP assay estimated effective concentration 50 (EC50) (25, 40, 20, and 100 μM for Pb, Hg, Cd, and Mo, respectively), the metals also significantly inhibited the glucose-stimulated insulin secretion (GSIS), mitochondrial complexes activity, mitochondrial membranes potential, and oxygen consumption rates of the treated cells with parallel increases in their lactate production and in the mitochondrial swelling and permeation of their inner mitochondrial membranes to potassium (K(+)) and hydrogen (H(+)) ions. In addition, Cd, Pb, and Hg produced significant increases in mitochondrial membrane fluidity (MMF) with significant decreases in saturated/unsaturated fatty acid ratios. In 10 μM concentration, away from Mo, the three metals showed inhibitory effects on the mitochondrial functions to variable degrees. Only Cd showed significant effect on MMF and fatty acid ratios at a concentration of 10 μM. In conclusion, the tested metals significantly affected the bioenergetics of the pancreatic β-cells with significant effect on GSIS. Cd showed the most significant functional and structural effects on their mitochondria followed by Pb, then Hg, while Mo was almost safe up to 10 μM concentration. Hence, bioenergetic mitochondrial disruption can be considered as an underlying mechanism of the diabetogenic effects of the tested metals.

E. Elmorsy, A. Al-Ghafari, H. Al Doghaither, and J. Ghulam,Effects of environmental metals on mitochondrial bioenergetics of the CD-1 mice pancreatic beta-cells, Toxicol In Vitro, 2021, 70, 105015.

             

RATS

 Assessment of acute toxicological effects of molybdenum(IV) disulfide nano- and microparticles after single intratracheal administration in rats

Despite growing applications of molybdenum(IV) sulfide (MoS2) nano- and microparticles in their capacity as lubricants, data available on their safety are scarce. In this study the effect of MoS2 nano- and microparticles after single intratracheal instillation in rats has been analyzed. MoS2suspensions were administered at the dose of 1.5 or 5 mg MoS2/kg body weight. The analysis after 24 h and 7 days included: blood biochemical parameters, hematological parameters, bronchoalveolar lavage fluid (BALF) parameters with selected cytokines, a comet assay and histopathological examination. In the BALF cells isolated from animals exposed to both forms, numerous macrophages loaded with particles were observed. The hematological and biochemical parameters analyzed 24 h or 7 days after the exposure to both forms did not show any biologically meaningful changes. Comet assay results showed no genotoxic effect. The histopathological analysis of the lungs revealed inflammatory changes in the respiratory system of the treated animals, slightly stronger for the microsized form. The deposits of particles observed in the lung tissue up to 7 days after the instillation indicate their easy penetration through the epithelium and prolonged clearance. Concluding, no meaningful acute systemic effects were observed, however some pathological changes were noted in the lung tissue.

Z. Sobańska, K. Sitarek, J. Gromadzińska, R. Świercz, M. Szparaga, K. Domeradzka-Gajda, K. Kowalczyk, L. Zapór, W. Wąsowicz, J. Grobelny, K. Ranoszek-Soliwoda, E. Tomaszewska, G. Celichowski, J. Roszak, and M. Stępnik,Assessment of acute toxicological effects of molybdenum(IV) disulfide nano- and microparticles after single intratracheal administration in rats, The Science of the total environment, 2020, 742, 140545.

             

 Effect of sodium molybdate on cadmium-related testicular damage in adult male Wistar rats

BACKGROUND: Molybdenum, as a trace element, has various pharmacological effects, including antioxidant, antiviral, anti-allergic, anti-osteoporosis, anti-tumor, anti-inflammatory, anti-diabetic, anti-obesity, and free radical-scavenging activities. This study aimed at investigating the sodium molybdate impacts on cadmium chloride (CdCl2)-induced testicular toxicity in adult Wistar rats. METHODS: The impacts of oral administration of sodium molybdate (0.05, 0.1, 0.2, and 0.4 mg/kg) was evaluated in healthy and infertile animals. Animals were randomly assigned to nine groups, including healthy control, sodium molybdate alone, infertile control (3 mg/kg of CdCl2), and sodium molybdate plus CdCl2. Following 30 days of administration, animals were sacrificed for biochemical and histopathological assays. RESULTS: The results indicated that administration of sodium molybdate to infertile rats significantly mitigated the cadmium impacts on sperm appearance, concentration, and motility parameters. Also, sodium molybdate reduced the production of malondialdehyde (MDA) and enhanced antioxidant enzymes activities in the testicular homogenates in rats; these findings were supported by histopathological examinations. Treatment with sodium molybdate significantly increased aquaporin-9 (AQP9) expression in the testicular tissues of infertile rats. CONCLUSIONS: The current findings suggested that sodium molybdate performs as a strong protective agent from CdCl2-related testicular toxicity in rats.

H. Khorami, A. Eidi, P. Mortazavi, and M. Modaresi,Effect of sodium molybdate on cadmium-related testicular damage in adult male Wistar rats, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 2020, 62, 126621.

DUCK

Inhibition of autophagy aggravates molybdenum-induced mitochondrial dysfunction by aggravating oxidative stress in duck renal tubular epithelial cells
Excessive molybdenum (Mo) has adverse effects on animals. To elucidate the effects of autophagy on Mo-induced nephrotoxicity, the duck renal tubular epithelial cells were cultured in medium in absence and presence of (NH4)6Mo7O24.4H2O (0, 480, 720, 960 μM Mo), 3-Methyladenine (3-MA) (2.5 μM), and the combination of Mo and 3-MA for 12 h. After 12 h exposure, the MDC staining, morphologic observation, LC3 puncta, cell viability, autophagy-related genes mRNA and proteins levels, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) level, antioxidant indices, mitochondrial membrane potential (MMP), mitochondrial mass, mitochondrial respiratory control ratio (RCR) and oxidative phosphorylation rate (OPR) were determined. The results showed that excessive Mo exposure significantly elevated the number of autophagosome and LC3 puncta, upregulated Beclin-1, Atg5, LC3A and LC3B mRNA levels, and LC3II/LC3I and Beclin-1 protein levels, decreased mTOR, p62 and Dynein mRNA levels and p62 protein level. Besides, co-treatment with Mo and 3-MA dramatically increased LDH release, ROS level, hydrogen peroxide H2O2 and malondialdehyde (MDA) contents as well as cell dam age, reduced cell viability, the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), MMP, mitochondrial mass, mitochondrial RCR and OPR compared to treatment with Mo alone. Taken together, these results suggest that excessive Mo exposure can induce autophagy in duck renal tubular epithelial cells, inhibition of autophagy aggravates Mo-induced mitochondrial dysfunction by regulating oxidative stress.
J. Zhuang, G. Nie, R. Hu, C. Wang, C. Xing, G. Li, G. Hu, F. Yang, and C. Zhang,Inhibition of autophagy aggravates molybdenum-induced mitochondrial dysfunction by aggravating oxidative stress in duck renal tubular epithelial cells, Ecotoxicol Environ Saf, 2020, 209, 111771.

RAT MoS2

Assessment of acute toxicological effects of molybdenum(IV) disulfide nano- and microparticles after single intratracheal administration in rats

Despite growing applications of molybdenum(IV) sulfide (MoS2) nano- and microparticles in their capacity as lubricants, data available on their safety are scarce. In this study the effect of MoS2 nano- and microparticles after single intratracheal instillation in rats has been analyzed. MoS2 suspensions were administered at the dose of 1.5 or 5 mg MoS2/kg body weight. The analysis after 24 h and 7 days included: blood biochemical parameters, hematological parameters, bronchoalveolar lavage fluid (BALF) parameters with selected cytokines, a comet assay and histopathological examination. In the BALF cells isolated from animals exposed to both forms, numerous macrophages loaded with particles were observed. The hematological and biochemical parameters analyzed 24 h or 7 clays after the exposure to both forms did not show any biologically meaningful changes. Comet assay results showed no genotoxic effect. The histopathological analysis of the lungs revealed inflammatory changes in the respiratory system of the treated animals, slightly stronger for the microsized form. The deposits of particles observed in the lung tissue up to 7 clays after the instillation indicate their easy penetration through the epithelium and prolonged clearance. Concluding, no meaningful acute systemic effects were observed, however some pathological changes were noted in the lung tissue. (C) 2020 Elsevier B.V. All rights reserved.

Z. Sobanska, K. Sitarek, J. Gromadzinska, R. Swiercz, M. Szparaga, K. Domeradzka-Gajda, K. Kowalczyk, L. Zapor, W. Wasowicz, J. Grobelny, K. Ranoszek-Soliwoda, E. Tomaszewska, G. Celichowski, J. Roszak, and M. Stepnik,Assessment of acute toxicological effects of molybdenum(IV) disulfide nano- and microparticles after single intratracheal administration in rats, Science of the Total Environment, 2020, 742.

 

GOAT

Molybdenum Induces Mitochondrial Oxidative Damage in Kidney of Goats

The purpose of this study was to evaluate the effects of excessive molybdenum (Mo) on renal function and oxidative stress in goats. Twenty-seven healthy goats were randomly allotted in three groups and were fed deionized water to which sodium ammonium molybdate [(NH4)6)Mo7O24.·4H2O] was added at different doses of 0, 15, and 45 mg Mo/(kg·BW) for 50 days, respectively.

The results indicated that white blood cell (WBC) counts were significantly increased (P < 0.05), while red blood cell (RBC) counts, hemoglobin (HGB), and mean corpuscular hemoglobin concentration (MCH) were tended to decrease with the increasing of the experimental period in high-Mo group compared with the control group.

Besides, blood urea nitrogen (BUN) and creatinine (CREA) contents in serum were increased (P < 0.05) in both groups supplemented with molybdenum.

Meanwhile, contents of copper (Cu) from the both experimental groups were significantly decreased (P < 0.05), while contents of zinc (Zn) and iron (Fe) were increased (P < 0.05) in serum.

The contents of Cu were significantly increased (P < 0.05), while the contents of zinc (Zn) and iron (Fe) did not obviously change (P > 0.05) in the kidney.

In addition, the activities of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and catalase (CAT) significantly decreased (P < 0.05) in the mitochondria, whereas malondialdehyde (MDA) and nitric oxide synthase (NOS) expression significantly increased (P < 0.05).

Collectively, these results indicated that excess Mo exposure could induce secondary Cu deficiency and oxidative stress in the kidney, which finally undermine the renal function of goats.

J. Feng, J. Chen, C. Xing, A. Huang, Y. Zhuang, F. Yang, C. Zhang, G. Hu, Y. Mao, and H. Cao,Molybdenum Induces Mitochondrial Oxidative Damage in Kidney of Goats, Biological trace element research, 2020, 197, 167-174.

‘ammonium’ in the text.

CHICKEN

Toxicity assessment of two-dimensional nanomaterials molybdenum disulfide in Gallus gallus domesticus [chicken]

Recently two-dimensional nanomaterials, such as graphene and molybdenum disulfide (MoS2), have received much attention as adsorbent materials for the effective removal of organic contaminants. MoS2 is attracting attention, not only for its chemical-physical properties, but also for its wide availability in nature as a constituent of molybdenite. The aim of this investigation was to assess the effects of different MoS2 concentrations 5 × 10-1, 5 × 10-2 and 5 × 10-3  mg/ml) on the embryonated eggs of Gallus gallus domesticus, according to Beck method. We evaluated the toxic effect of the MoS2 powder purchased at Sigma-Aldrich indicated as "received" and MoS2 powder treated via mechanical milling indicated as "ball mille". Subsequently, the embryos were sacrificed at different times of embryonic development (11th, 15(th) and 19(th) day after incubation) in order to evaluate their embryotoxic and teratogenic effects. The alterations of the embryonic development were studied by morphological and immunohistochemical analysis of the tissues. The results obtained have shown the toxicity of both powders of MoS2 with a high percentage of deaths and growth delays. Moreover, the immunohistochemical analysis performed on several tissue sections showed a strong positivity to the anti-metallothionein1 antibody only for the erythrocytes.

E. M. Scalisi, A. Salvaggio, F. Antoci, A. Messina, R. Pecoraro, M. Cantarella, G. Gorrasi, G. Impellizzeri, and M. V. Brundo,Toxicity assessment of two-dimensional nanomaterials molybdenum disulfide in Gallus gallus domesticus, Ecotoxicology and environmental safety, 2020, 200, 110772.

             

DUCK

Molybdenum and cadmium co-induce oxidative stress and apoptosis through mitochondria-mediated pathway in duck renal tubular epithelial cells

High doses of molybdenum (Mo) and cadmium (Cd) cause adverse reactions on animals, but the joint toxic effects of Mo and Cd on duck renal tubular epithelial cells are not fully illustrated. To investigate the combined effects of Mo and Cd on oxidative stress and mitochondrial apoptosis in primary duck renal tubular epithelial cells, the cells were either treated with (NH4)6Mo7O24 4H2O (480, 960 mu M Mo), 3CdSO4 8H2O (2.5, 5.0 mu M Cd) or combination of Mo and Cd for 12 h, and then the joint cytotoxicity was evaluated. The results demonstrated that Mo or/and Cd exposure could induce release of intracellular lactate dehydrogenase, reactive oxygen species generation, acidification, increase levels of malondialdehyde and [Ca2+](i), decrease levels of glutathione, glutathione peroxidase, catalase, superoxide dismutase, total antioxidant capacity, Na+/K+-ATPase, Ca2+-ATPase, and mitochondria' membrane potential; upregulate mRNA levels of Caspase-3, Bak-1, Bax, and cytochrome C, inhibit Bcl-2 mRNA level, and induce cell apoptosis in a dose-dependent manner. Furthermore, the changes of these indicators in co-treated groups were more remarkable. The results indicated that exposure to Mo or/and Cd could induce oxidative stress and apoptosis via the mitochondrial pathway in duck renal tubular epithelial cells and the two metals may have a synergistic effect.

C. Wang, G. H. Nie, F. Yang, J. Chen, Y. Zhuang, X. Y. Dai, Z. Y. Liao, Z. Yang, H. B. Cao, C. H. Xing, G. L. Hu, and C. Y. Zhang,Molybdenum and cadmium co-induce oxidative stress and apoptosis through mitochondria-mediated pathway in duck renal tubular epithelial cells, Journal of Hazardous Materials, 2020, 383.

HENS

Alteration of the Antioxidant Capacity and Gut Microbiota under High Levels of Molybdenum and Green Tea Polyphenols in Laying Hens

High dietary levels of molybdenum (Mo) can negatively affect productive performances and health status of laying hens, while tea polyphenol (TP) can mitigate the negative impact of high Mo exposure. However, our understanding of the changes induced by TP on Mo challenged layers performances and oxidative status, and on the microbiota, remains limited. The aim of the present study was to better understand host (performances and redox balance) and microbiota responses in Mo-challenged layers with dietary TP. In this study, 200 Lohmann laying hens (65-week-old) were randomly allocated in a 2 x 2 factorial design to receive a diet with or without Mo (0 or 100 mg/kg)[as Na2MoO4.2H2O], and supplemented with either 0 or 600 mg/kg TP. The results indicate that 100 mg/kg Mo decreased egg production (p = 0.03), while dietary TP increased egg production in Mo challenged layers (p < 0.01). Egg yolk color was decreased by high Mo (p < 0.01), while dietary TP had no effect on yolk color (p > 0.05). Serum alanine transaminase (ALT), aspartate aminotransferase (AST), and malonaldehyde (MDA) [and LDH] concentration were increased by high Mo, while total antioxidant capacity (T-AOC), xanthine oxidase (XOD) activity, glutathione s-transferase (GSH-ST), and glutathione concentration in serum were decreased (p < 0.05). Dietary TP was able to reverse the increasing effect of Mo on ALT and AST (p < 0.05). High Mo resulted in higher Mo levels in serum, liver, kidney, and egg, but it decreased Cu and Se content in serum, liver, and egg (p < 0.05). The Fe concentration in liver, kidney, and eggs was significantly lower in Mo supplementation groups (p < 0.05). High Mo levels in the diet led to lower Firmicutes and higher Proteobacteria abundance, whereas dietary TP alone and/or in high Mo treatment increased the Firmicutes abundance and the Firmicutes/Bacteroidetes ratio at phylum level. High Mo increased the abundance of Proteobacteria (phylum), Deltaproteobacteria (class), Mytococcales (order), and Nanocystaceae (family), whereas dietary TP promoted the enrichment of Lactobacillus agilis (species). Dietary TP also enhanced the enrichment of Bacilli (class), Lactobacillates (order), Lactobacillus (family), and Lactobacillus gasseri (species). Microbiota analysis revealed differentially enriched microbial compositions in the cecum caused by Mo and TP, which might be responsible for the protective effect of dietary TP during a Mo challenge.

J. P. Wang, Z. Q. Yang, P. Celi, L. Yan, X. M. Ding, S. P. Bai, Q. F. Zeng, X. B. Mao, B. Feng, S. Y. Xu, and K. Y. Zhang,Alteration of the Antioxidant Capacity and Gut Microbiota under High Levels of Molybdenum and Green Tea Polyphenols in Laying Hens, Antioxidants, 2019, 8(10), 503.

 

Sodium molybdate attenuates lipid accumulation in the livers of mice fed a diet deficient in methionine and choline

Both lipid accumulation and oxidative stress are major pathologic contributors to the development of hepatic steatosis. Treatment with molybdate reduces hepatic levels of lipids in diabetic rats. Potential activities of molybdate as an antioxidant have also been demonstrated in various animal models. In the present study, we evaluated the effects of sodium molybdate dihydrate (SM) on hepatic steatosis and associated disturbances in a widely used mouse model of the metabolic disease. Male C57Bl/6 mice at 10 weeks of age were fed a diet deficient in methionine and choline (MCD) and bottled water containing SM for four weeks. The SM treatment markedly attenuated MCD-induced accumulation of lipids, mainly triglycerides, in the liver. Lipid catabolic autophagic pathways were activated by SM in the MCD-fed mouse livers, as evidenced by a decreased level of p62 expression. MCD-induced oxidative damage, such as lipid and protein oxidation, was also alleviated by SM in the liver. However, the level of MCD-induced hepatocellular damage was not affected by SM. Taken together, these findings suggest that molybdate can be used in the treatment and prevention of hepatic steatosis without inducing adverse effects in the liver. To the best of our knowledge, this is the first experimental study to investigate the effects of molybdate in non-alcoholic fatty liver disease, and also the first that demonstrates molybdate-induced autophagy.

D. Y. R. Ryu, and S. Lee,Sodium molybdate attenuates lipid accumulation in the livers of mice fed a diet deficient in methionine and choline, Toxicology Letters, 2018, 295, S197-S197.

Hepatic steatosis is an accumulation of fat in the liver

Autophagy (“self-eating”) is a detox process your body undergoes to clean out damaged cells and regenerate new ones. A protein called p62 activates to induce autophagy and is the key to an improved human lifespan over time.

The p62 protein, also called sequestosome 1 (SQSTM1), is a ubiquitin-binding scaffold protein that colocalizes with ubiquitinated protein aggregates in many neurodegenerative diseases and proteinopathies of the liver.

               

Sodium molybdate attenuates lipid accumulation in the livers of mice fed a diet deficient in methionine and choline

Both lipid accumulation and oxidative stress are major pathologic contributors to the development of hepatic steatosis. Treatment with molybdate reduces hepatic levels of lipids in diabetic rats. Potential activities of molybdate as an antioxidant have also been demonstrated in various animal models. In the present study, we evaluated the effects of sodium molybdate dihydrate (SM) on hepatic steatosis and associated disturbances in a widely used mouse model of the metabolic disease. Male C57Bl/6 mice at 10 weeks of age were fed a diet deficient in methionine and choline (MCD) and bottled water containing SM for four weeks. The SM treatment markedly attenuated MCD-induced accumulation of lipids, mainly triglycerides, in the liver. Lipid catabolic autophagic pathways were activated by SM in the MCD-fed mouse livers, as evidenced by a decreased level of p62 expression. MCD-induced oxidative damage, such as lipid and protein oxidation, was also alleviated by SM in the liver. However, the level of MCD-induced hepatocellular damage was not affected by SM. Taken together, these findings suggest that molybdate can be used in the treatment and prevention of hepatic steatosis without inducing adverse effects in the liver. To the best of our knowledge, this is the first experimental study to investigate the effects of molybdate in non-alcoholic fatty liver disease, and also the first that demonstrates molybdate-induced autophagy.

D. Y. R. Ryu, and S. Lee,Sodium molybdate attenuates lipid accumulation in the livers of mice fed a diet deficient in methionine and choline, Toxicology Letters, 2018, 295, S197-S197.

Hepatic steatosis is an accumulation of fat in the liver

Autophagy (“self-eating”) is a detox process your body undergoes to clean out damaged cells and regenerate new ones. A protein called p62 activates to induce autophagy and is the key to an improved human lifespan over time.

The p62 protein, also called sequestosome 1 (SQSTM1), is a ubiquitin-binding scaffold protein that colocalizes with ubiquitinated protein aggregates in many neurodegenerative diseases and proteinopathies of the liver.

               

OSTRICH

Mineral profiling of ostrich (Struthio camelus) seminal plasma and its relationship with semen traits and collection day

Successful assisted reproduction techniques, with specific focus on in vitro semen storage for artificial insemination, are dependent on certain key elements which includes the biochemical profiling of semen. The objective of this study was to complete an ostrich seminal plasma (SP) evaluation by inductively coupled plasma mass spectrometry (ICP-MS) among seven males at different daily intervals (day 1, 3, 7, 11, 15, 19, 21, 23, 25, 26, 27, 28) for a period of 28 days during spring (August to September) for mineral profiling. The effect of collection day and male on sperm concentration, semen volume and seminal plasma volume, was explored as well as the relationships amongst these specific sperm traits and SP minerals. Variation amongst SP mineral concentrations, accounted for by the fixed effects of sperm concentration, semen volume, seminal plasma volume, collection day and male, ranged from 18% to 77%. Male had the largest effect on variation in SP minerals, namely: phosphorus (P), potassium (K), calcium (Ca), sodium (Na), boron (B), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), molybdenum (Mo), barium (Ba), arsenic (As) and selenium (Se). Sperm concentration instigated fluctuations of P, magnesium (Mg), B, zinc (Zn), Fe, aluminium (Al), Se, manganese (Mn) and lead (Pb). Semen volume had an effect on Na, K, B, Pb and Ba while seminal plasma volume only influenced variation in Na. There were fluctuations among collection days of specific micro minerals, Ni and Mo, with initial Ni concentrations being relatively greater and Mo at lesser concentrations. Semen volume, seminal plasma volume and sperm concentration varied amongst males. Sperm concentrations during the initial collection days, 1 and 3, were less than that for days 7 to 28. Significant variation of SP minerals and sperm characteristics among ejaculates and males suggest an association of these specific elements with sperm function and are, therefore, considered to be of potential importance to success of assisted reproduction technology for the ostrich. The relationship amongst sperm concentration and collection day confirms the need to conduct an initial period of collection to stabilise a greater sperm concentration to optimise sperm numbers for artificial insemination purposes.

A. M. J. Smith, M. Bonato, K. Dzama, I. A. Malecki, and S. W. P. Cloete,Mineral profiling of ostrich (Struthio camelus) seminal plasma and its relationship with semen traits and collection day, Animal reproduction science, 2018, 193, 98-106.

Ruminants

Risk assessment of high concentrations of molybdenum in forage

Molybdenum is toxic to ruminants when present in high levels in forage, causing physiological copper deficiency. A critical level for ruminants is 3-10 mg Mo kg(-1) dry matter. The average Mo level varies considerably between different arable soils, depending mainly on soil parent material. This study investigated the possibility of using various existing sources of geospatial information (geophysical, biogeochemical and soil chemical) to develop a geography-based risk assessment system. Forage samples (n = 173) were collected in 2006-2007. Three types of national geoscientific datasets were tested: (1) SEPA topsoil, comprising data from arable land within the Swedish environmental monitoring programme; (2) SGU biogeochemical, containing data from aquatic plant root material collected in small streams; and (3) SGU geophysical, consisting of data from airborne gamma-ray scanning. The digital postcode area map was used for geocoding, with Mo concentrations in forage assigned to arable parts of the corresponding postcode area. By combining this with the three national geoscientific databases, it was possible to construct a risk map using fuzzy classification depicting High-risk, Intermediate-risk, Low-risk and Very-low-risk areas. The map was validated using 42 randomly selected samples. All samples but one with Mo > 3 mg kg(-1) were found in postcode areas designated High risk. Thus, the risk map developed seems to be useful as a decision support system on where standard forage analyses need to be supplemented with Mo analyses.

U. Axelson, M. Soderstrom, and A. Jonsson,Risk assessment of high concentrations of molybdenum in forage, Environmental geochemistry and health, 2018.

 

RAT

Effect of sodium molybdate on cadmium-related testicular damage in adult male Wistar rats

BACKGROUND: Molybdenum, as a trace element, has various pharmacological effects, including antioxidant, antiviral, anti-allergic, anti-osteoporosis, anti-tumor, anti-inflammatory, anti-diabetic, anti-obesity, and free radical-scavenging activities. This study aimed at investigating the sodium molybdate impacts on cadmium chloride (CdCl2)-induced testicular toxicity in adult Wistar rats. METHODS: The impacts of oral administration of sodium molybdate (0.05, 0.1, 0.2, and 0.4 mg/kg) was evaluated in healthy and infertile animals. Animals were randomly assigned to nine groups, including healthy control, sodium molybdate alone, infertile control (3 mg/kg of CdCl2), and sodium molybdate plus CdCl2. Following 30 days of administration, animals were sacrificed for biochemical and histopathological assays. RESULTS: The results indicated that administration of sodium molybdate to infertile rats significantly mitigated the cadmium impacts on sperm appearance, concentration, and motility parameters. Also, sodium molybdate reduced the production of malondialdehyde (MDA) and enhanced antioxidant enzymes activities in the testicular homogenates in rats; these findings were supported by histopathological examinations. Treatment with sodium molybdate significantly increased aquaporin-9 (AQP9) expression in the testicular tissues of infertile rats. CONCLUSIONS: The current findings suggested that sodium molybdate performs as a strong protective agent from CdCl2-related testicular toxicity in rats.

H. Khorami, A. Eidi, P. Mortazavi, and M. Modaresi,Effect of sodium molybdate on cadmium-related testicular damage in adult male Wistar rats, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 2020, 62, 126621.

             

Molybdenum bupropion combined neurotoxicity in rats

Heavy metal toxicity is a common foodborne problem in Egypt, especially in combination. Molybdenum toxicity has been studied as a model of the heavy metal toxicity. Molybdenum could promote toxicity via oxidative-inflammatory mechanisms. Bupropion is a well-known antidepressant that has anti-oxidant mechanisms. It exerts a cytoprotective action against molybdenum induced metal toxicity. The aim of the study is to evaluate the effects of combined bupropion and molybdenum in a toxic animal model. The results showed that the combination of bupropion and high doses of molybdenum was extremely toxic with an evident animal fatality. Bupropion showed a clear anti-oxidant/anti-inflammatory profile detected by the ELISA assay of malondialdehyde (MDA), reduced glutathione, and interleukin -6 (IL-6), and real-time gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and tumor necrosis factor-alpha (TNF-alpha). The immunohistochemistry of nuclear factor Kappa Beta (NF-kappaB) showed that bupropion reduced the inflammatory response induced by the molybdenum neurotoxicity. Despite the improved laboratory profile, the animals were extremely intoxicated with recorded fatalities raising the question about other pathways and mechanisms explaining the drug metal interaction. Furthermore, Bupropion even in normal doses was toxic to the animals. Choroid plexus hyperplasia was reported in the histological examination of the animal brain loaded with bupropion, and choroid plexus papilloma was recorded in the combined drug metal group. More wide-scale studies are needed to verify the safety of the current antidepressant medications for the long-term therapy. It is important to focus on drug metal interaction as a possible cause of neuropathology.

A. M. Helaly, N. Mokhtar, A. E. L. Firgany, N. M. Hazem, E. El Morsi, and D. Ghorab, Molybdenum bupropion combined neurotoxicity in rats, Regul Toxicol Pharmacol, 2018, 98, 224-230.

Rat

The effect of ingested sulfite on active avoidance in normal and sulfite oxidase-deficient aged rats

The aim of this study was to investigate the possible toxic effects of sulfite on neurons by measuring active avoidance learning in normal and sulfite oxidase (SOX)-deficient aged rats. Twenty-four months of age Wistar rats were divided into four groups: control (C), sulfite-treated group (S), SOX-deficient group (D) and SOX-deficient+sulfite-treated group (DS). SOX deficiency was established by feeding rats with a low molybdenum (Mo) diet and adding 200ppm tungsten (W) to their drinking water. Sulfite in the form of sodium metabisulfite (25mg/kg) was given by gavage for six weeks. Active avoidance responses were determined by using an automated shuttle box. Hepatic SOX activity was measured to confirm SOX deficiency. The hippocampus was used for determining the activity of cyclooxygenase (COX) and caspase-3 enzymes and the level of prostaglandin E2 (PGE2) and nitrate/nitrite. SOX-deficient rats had an approximately 10-fold decrease in hepatic SOX activity compared with normal rats. Sulfite did not induce impairment of active avoidance learning in SOX-deficient rats and in normal rats compared with their control groups. Sulfite had no effect on the activity of COX and caspase-3 in the hippocampus. Treatment with sulfite did not significantly increase the level of PGE2 and nitrate/nitrite in the hippocampus.


Ozsoy, O., Aras, S., Ozkan, A., Parlak, H., Gemici, B., Uysal, N., Aslan, M., Yargicoglu, P., and Agar, A.,The effect of ingested sulfite on active avoidance in normal and sulfite oxidase-deficient aged rats, Toxicology Mechanisms and Methods, 2017, 27, 81-87.

 

Rat

Effect of Molybdenum Nanoparticles on Blood Cells, Liver Enzymes, and Sexual Hormones in MALE RATS

Despite an increasing surge in application of nanoparticles in industries, there is a serious lack of information concerning their impact on human health and the environment. The present study investigated effects of molybdenum nanoparticles (Mo NPs) injected intraperitoneally into Sprague-Dawley rats at different doses of Mo NPs (5, 10, and 15 mg/kg BW per day) during a period of 28 days. Hematological and biochemical parameters as well as sexual hormones and histopathological examinations of the liver and testis were assessed and compared with control group.

The results showed that the serum levels of testosterone decreased significantly in both groups of 10 and 15 mg (Mo NPs)/kg BW in comparison with the control group (p < 0.05). However, there were insignificant differences observed in luteinizing hormone (LH) levels and hematological parameters when compared with the control group (p > 0.05). The results of liver enzymes showed that serum levels of aspartate aminotransferase (AST) decreased significantly in both dosage groups of 5 and 10 mg/kg BW (Mo NPs) when compared with the control group (p < 0.05), and significant decrease obtained in lactate dehydrogenase (LDH) levels at dose of 5 mg/kg BW in comparison with the control group (p < 0.05). The histopathological examination of testis showed a decrease in number of Leydig cells. Also, the number of chronic inflammatory cells increased in portal triad and parenchyma in liver tissue of rats exposed to Mo NPs.

Asadi, F., Mohseni, M., Dadashi Noshahr, K., Soleymani, F. H., Jalilvand, A., and Heidari, A.,Effect of Molybdenum Nanoparticles on Blood Cells, Liver Enzymes, and Sexual Hormones in Male Rats, Biological trace element research, 2017, 175, 50-56.

Cattle

A frameshift mutation in MOCOS is associated with familial renal syndrome (xanthinuria) in TYROLEAN GREY CATTLE

Background: Renal syndromes are occasionally reported in domestic animals. Two identical twin Tyrolean Grey calves exhibited weight loss, skeletal abnormalities and delayed development associated with kidney abnormalities and formation of uroliths. These signs resembled inherited renal tubular dysplasia found in Japanese Black cattle which is associated with mutations in the claudin 16 gene. Despite demonstrating striking phenotypic similarities, no obvious presence of pathogenic variants of this candidate gene were found. Therefore further analysis was required to decipher the genetic etiology of the condition.

Results: The family history of the cases suggested the possibility of an autosomal recessive inheritance. Homozygosity mapping combined with sequencing of the whole genome of one case detected two associated non-synonymous private coding variants: A homozygous missense variant in the uncharacterized KIAA2026 gene (g.39038055C > G; c. 926C > G), located in a 15 Mb sized region of homozygosity on BTA 8; and a homozygous 1 bp deletion in the molybdenum cofactor sulfurase (MOCOS) gene (g.21222030delC; c.1881delG and c.1782delG), located in an 11 Mb region of homozygosity on BTA 24. Pathogenic variants in MOCOS have previously been associated with inherited metabolic syndromes and xanthinuria in different species including Japanese Black cattle. Genotyping of two additional clinically suspicious cases confirmed the association with the MOCOS variant, as both animals had a homozygous mutant genotype and did not show the variant KIAA2026 allele. The identified genomic deletion is predicted to be highly disruptive, creating a frameshift and premature termination of translation, resulting in severely truncated MOCOS proteins that lack two functionally essential domains. The variant MOCOS allele was absent from cattle of other breeds and approximately 4% carriers were detected among more than 1200 genotyped Tyrolean Grey cattle. Biochemical urolith analysis of one case revealed the presence of approximately 95% xanthine.

Conclusions: The identified MOCOS loss of function variant is highly likely to cause the renal syndrome in the affected animals. The results suggest that the phenotypic features of the renal syndrome were related to an early onset form of xanthinuria, which is highly likely to lead to the progressive defects. The identification of the candidate causative mutation thus enables selection against this pathogenic variant in Tyrolean Grey cattle.

Murgiano, L., Jagannathan, V., Piffer, C., Diez-Prieto, I., Bolcato, M., Gentile, A., and Drogemuller, C.,A frameshift mutation in MOCOS is associated with familial renal syndrome (xanthinuria) in Tyrolean Grey cattle, Bmc Veterinary Research, 2016, 12.

 

DUCK

Molybdenum and cadmium co-induce oxidative stress and apoptosis through mitochondria-mediated pathway in duck renal tubular epithelial cells

High doses of molybdenum (Mo) and cadmium (Cd) cause adverse reactions on animals, but the joint toxic effects of Mo and Cd on duck renal tubular epithelial cells are not fully illustrated. To investigate the combined effects of Mo and Cd on oxidative stress and mitochondrial apoptosis in primary duck renal tubular epithelial cells, the cells were either treated with (NH4)6Mo7O24.4H2O (480, 960muM Mo), 3CdSO4.8H2O (2.5, 5.0muM Cd) or combination of Mo and Cd for 12h, and then the joint cytotoxicity was evaluated. The results demonstrated that Mo or/and Cd exposure could induce release of intracellular lactate dehydrogenase, reactive oxygen species generation, acidification, increase levels of malondialdehyde and [Ca(2+)]i, decrease levels of glutathione, glutathione peroxidase, catalase, superoxide dismutase, total antioxidant capacity, Na(+)/K(+)-ATPase, Ca(2+)-ATPase, and mitochondrial membrane potential; upregulate mRNA levels of Caspase-3, Bak-1, Bax, and cytochrome C, inhibit Bcl-2 mRNA level, and induce cell apoptosis in a dose-dependent manner. Furthermore, the changes of these indicators in co-treated groups were more remarkable. The results indicated that exposure to Mo or/and Cd could induce oxidative stress and apoptosis via the mitochondrial pathway in duck renal tubular epithelial cells and the two metals may have a synergistic effect.

C. Wang, G. Nie, F. Yang, J. Chen, Y. Zhuang, X. Dai, Z. Liao, Z. Yang, H. Cao, C. Xing, G. Hu, and C. Zhang,Molybdenum and cadmium co-induce oxidative stress and apoptosis through mitochondria-mediated pathway in duck renal tubular epithelial cells, Journal of hazardous materials, 2020, 383, 121157.

Alterations of mitochondrial antioxidant indexes and apoptosis in duck livers caused by Molybdenum or/and cadmium

Cadmium (Cd) and high Molybdenum (Mo) can lead to adverse reactions on animals, but the co-induced toxicity of Mo and Cd to liver in ducks was not well understood. To investigate the co-induced toxic effects of Mo combined with Cd on mitochondrial oxidative stress and apoptosis in duck livers. 240 healthy 11-day-old ducks were randomly divided into 6 groups (control, LMo group, HMo group, Cd group, LMoCd group and HMoCd group). After being treated for 30, 60, 90 and 120 days, liver mitochondrial antioxidant indexes, ceruloplasmin (CP), metallothionein (MT), Bak-1 and Caspase-3 genes mRNA expression levels, and ultrastructural changes were evaluated. The results showed that total antioxidative capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD) and xanthine oxidase (XOD) activities in experimental groups were decreased, whereas malondialdehyde (MDA) content and nitric oxide synthase (NOS) activity were increased compared with control group, and these changes of co-treated groups were more obvious in the later period of the experiment. The mRNA expression levels of CP, Bak-1 and Caspase-3 were up-regulated in experimental groups compared with control group and showed significant difference between co-treated groups and single treated groups. The mRNA expression level of MT in Cd group was higher than that in co-treated groups. Additionally, ultrastructural changes showed karyopyknosis, mitochondrial swelling, vacuolation and disruption of mitochondrial cristae in co-treated groups. Taken together, it was suggested that dietary Mo and Cd might lead to mitochondrial oxidative stress and apoptosis in duck livers, and it showed a possible synergistic relationship between the two elements.

X. Dai, C. Xing, H. Cao, J. Luo, T. Wang, P. Liu, X. Guo, G. Hu, and C. Zhang,Alterations of mitochondrial antioxidant indexes and apoptosis in duck livers caused by Molybdenum or/and cadmium, Chemosphere, 2018, 193, 574-580.

Effects of molybdenum and cadmium on the oxidative damage and kidney apoptosis in Duck

Molybdenum (Mo) is an essential element for human beings and animals; however, high dietary intake of Mo can lead to adverse reactions. Cadmium (Cd) is one of the major transitional metals which has toxic effects in animals. To investigate the co-induced toxic effects of Mo and Cd on oxidative damage and kidney apoptosis in duck, 120 ducks were randomly divided into control group and 5 treatment groups which were treated with a commercial diet containing different dosages of Mo and Cd. Kidney samples were collected on the 60th and 120th days to determine the mRNA expression levels of ceruloplasmin (CP), metallothionein (MT), Bak-1, and Caspase-3 by quantitative RT-PCR. Additionally, we also determined the antioxidant activity indexes and contents of Mo, Cd, copper (Cu), iron (Fe), zinc (Zn), and selenium (Se) in serum. Meanwhile, ultrastructural changes of the kidney were observed. The results showed that glutathione reductase (GR) activity and CP level in serum were decreased in combination groups. In addition, the antioxidant indexes were decreased in co-treated groups compared with single treated groups. The mRNA expression levels of Bak-1 and Caspase-3 increased in co-treated groups. The mRNA expression level of CP in high-dose combination group was downregulated, while the mRNA expression of MT was upregulated except for low-dose Mo group. Additionally, in the later period the content of Cu in serum decreased in joint groups while the contents of Mo and Cd increased. In addition, ultrastructural changes showed mitochondrial crest fracture, swelling, deformed nuclei, and karyopyknosis in co-treated groups. Taken together, it was suggested that dietary Mo and Cd might lead to oxidative stress, kidney apoptosis and disturb homeostasis of trace elements in duck, and it showed a possible synergistic relationship between the two elements.

Shi, L. L., Cao, H. B., Luo, J. R., Liu, P., Wang, T. C., Hu, G. L., and Zhang, C. Y.,Effects of molybdenum and cadmium on the oxidative damage and kidney apoptosis in Duck, Ecotoxicology and Environmental Safety, 2017, 145, 24-31.

Duck

Changes in Trace Element Contents and Morphology in Bones of DUCK exposed to Molybdenum or/and Cadmium

Cadmium (Cd) and high molybdenum (Mo) can lead to adverse reactions on animals, but the coinduced toxicity of Mo and Cd to bone in ducks was not well understood. The objective of this study was to investigate the changes in trace elements' contents and morphology in bones of duck exposed to Mo or/and Cd. One hundred twenty healthy 11-day-old male ducks were randomly divided into six groups and treated with commercial diet containing Cd or/and Mo. On the 60th and 120th days, the blood, excretion, and metatarsals were collected to determine alkaline phosphatase (ALP) activity and the contents of Mo, Cd, calcium (Ca), phosphorus (P), copper (Cu), iron (Fe), zine (Zn), and selenium (Se). In addition, metatarsals were subjected to histopathological analysis with the optical microscope and radiography. The results indicated that Mo and Cd contents significantly increased while Ca, P, Cu, and Se contents remarkably decreased in metatarsals in coexposure groups (P < 0.01). Contents of Fe and Zn in metatarsals had no significant difference among groups (P > 0.05). Ca content in serum had no significant difference among experimental groups (P > 0.05), but P content was significantly decreased in HMo and HMo + Cd groups (P < 0.05). Contents of Ca and P in excretion and ALP activity were significantly increased in coinduced groups (P < 0.05). Furthermore, osteoporotic lesions, less and thinner trabecular bone were observed in combination groups. The findings suggested that dietary of Cd or/and Mo could lead to bone damages in ducks via disturbing the balance of Ca and P in body and homeostasis of Cu, Fe, Zn, and Se in bones; moreover, the two elements showed a possible synergistic relationship.

Liao, Y., Cao, H., Xia, B., Xiao, Q., Liu, P., Hu, G., and Zhang, C.,Changes in Trace Element Contents and Morphology in Bones of Duck Exposed to Molybdenum or/and Cadmium, Biological trace element research, 2017, 175, 449-457.

DUCK

The co-induced effects of molybdenum and cadmium on the mRNA expression of inflammatory cytokines and trace element contents in duck kidneys

The aims of this study were determining the co-induced effects of dietary Cadmium (Cd) and high intake of Molybdenum (Mo) on renal toxicity in ducks.

240 healthy 11-day-old ducks were randomly divided into 6 groups, which were treated with Mo or/and Cd at different doses added to the basal diet for 120 days. Ducks of control group were fed with basal diet, LMo and HMo groups were fed with 15mg/kg Mo and 100mg/kg Mo respectively; ducks of Cd group were provided with 4mg/kg Cd which was added into basal diet. Two combination groups were treated with 15mg/kg Mo+4mg/kg Cd and 100mg/kg Mo+4mg/kg Cd respectively. On days 30, 60, 90 and 120, the mRNA expression levels of inflammatory cytokines and contents of trace elements were detected. In addition, transmission electron microscopic examination was used for ultrastructural studies.

The results indicated that the mRNA expression levels of tumor necrosis factor-alpha (TNF-alpha), nuclear factor-kappa B (NF-kappaB), and cyclooxygenase-2 (COX-2) showed an upward tendency in treatment groups in comparison with control group, and in the later period of the experiment it showed a significant rise in joint groups compared with the Mo and Cd group (P<0.01); the contents of copper (Cu) and iron (Fe) decreased in joint groups in the later period (P<0.05) while the contents of Mo and Cd significantly increased (P<0.01); zinc (Zn) and selenium (Se) concentration had a slight downtrend in treated groups, but showed no significant difference (P>0.05). The ultrastructural analysis showed that kidney tissues were severely injured in joint groups on day 120.

These results suggested that the combination of Mo and Cd could aggravate damages to the kidney. In addition, dietary of Mo or/and Cd caused the decrease of Cu, Fe, Zn, and Se contents, inflammatory response and pathological lesions whose mechanism is somehow linked with Mo and Cd deposition in kidney.

Cao, H., Gao, F., Xia, B., Xiao, Q., Guo, X., Hu, G., and Zhang, C.,The co-induced effects of molybdenum and cadmium on the mRNA expression of inflammatory cytokines and trace element contents in duck kidneys, Ecotoxicology and environmental safety, 2016, 133, 157-63.

               

GOATS LIVER OXIDATIVE STRESS  

Oxidative Stress and Cell Apoptosis in Caprine Liver Induced by Molybdenum and Cadmium in Combination

To investigate the effects of co-exposure to molybdenum (Mo) and cadmium (Cd) on oxidative stress and cell apoptosis in caprine livers, 36 Boer goats were randomly divided into four groups with nine goats in each group. Three groups were randomly assigned with one of three oral treatments of CdCl2 (0.5 mg Cd kg(-1).BW) and [(NH4)6Mo7O24.4H2O] (15 mg Mo kg(-1).BW, 30 mg Mo kg(-1).BW, 45 mg Mo kg(-1).BW), while the control group received deionized water. Liver tissues on days 0, 25, and 50 were subjected to determine antioxidant activity indexes and the messenger RNA (mRNA) expression levels of ceruloplasmin (CP), cysteinyl aspartate-specific proteinase-3 (caspase-3), second mitochondria-derived activator of caspases (Smac), and cytochrome-C (Cyt-C) genes. The results showed that significant reductions were observed in total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) activities (P < 0.05), while activities or contents of malondialdehyde (MDA), nitric oxide (NO), and nitric oxide synthase (NOS) were increased (P < 0.05). The mRNA expression levels of CP, caspase-3, Smac, and Cyt-C genes were upregulated (P < 0.05). In addition, histopathological lesions showed different degrees of vacuolar degeneration and edematous and mitochondrial swelling. The results suggest that co-exposure to Mo and Cd could induce oxidative stress and cell apoptosis possibly associated with mitochondrial intrinsic pathway in goat liver and show possible synergistic effects between the two elements.

Yang, F., Zhang, C., Zhuang, Y., Gu, X., Xiao, Q., Guo, X., Hu, G., and Cao, H.,Oxidative Stress and Cell Apoptosis in Caprine Liver Induced by Molybdenum and Cadmium in Combination, Biol Trace Elem Res, 2016, 173, 79-86.

 

Experimental animal studies

Dietary toxicity of soluble and insoluble molybdenum to northern bobwhite QUAIL (Colinus virginianus)

Limited data are available on the effects of molybdenum (Mo) on avian wildlife, which impairs evaluation of ecological exposure and risk. While Mo is an essential trace nutrient in birds, little is known of its toxicity to birds exposed to molybdenum disulfide (MoS2), the predominant form found in molybdenite ore.

The chemical form and bioavailability of Mo is important in determining its toxicity. Avian toxicity tests typically involve a soluble form of Mo, such as sodium molybdate dihydrate (SMD, Na2MoO4.2H2O); however MoS2 is generally insoluble, with low bioaccessibility under most environmental conditions.

The current study monitored survival and general health (body weight and food consumption) of 9-day old northern bobwhite exposed to soluble Mo (SMD) and ore-related Mo (MoS2) in their diet for 30 days.

Toxicity and bioavailability (e.g. tissue distribution) of the two Mo forms were compared. Histopathology evaluations and serum, kidney, liver, and bone tissue sample analyses were conducted.

Copper, a nutrient integrally associated with Mo toxicity, was also measured in the diet and tissue.

No treatment-related mortality occurred and no treatment-related lesions were recorded for either Mo form.

Tissue analyses detected increased Mo concentrations in serum, kidney, liver, and bone tissues following exposure to SMD, with decreasing concentrations following a post-exposure period.

For the soluble form, a No-Observed-Adverse-Effect Concentration (NOAEC) of 1200 mg Mo as SMD/kg feed (134 mg SMD/kg body weight/day) was identified based on body weight and food consumption.

No adverse effects were observed in birds exposed to MoS2 at the maximum dose of 5000 mg MoS2/kg feed (545 mg MoS2/kg body weight/day).

These results show that effects associated with MoS2, the more environmentally prevalent and less bioavailable Mo form, are much less than those observed for SMD. These data should support more realistic representations of exposure and risks to avian receptors from environmental Mo.

Stafford, J. M., Lambert, C. E., Zyskowski, J. A., Engfehr, C. L., Fletcher, O. J., Clark, S. L., Tiwary, A., Gulde, C. M., and Sample, B. E.,Dietary toxicity of soluble and insoluble molybdenum to northern bobwhite quail (Colinus virginianus), Ecotoxicology (London, England), 2016, 25, 291-301.

Mitochondrial oxidative stress-induced hepatocyte apoptosis reflects increased molybdenum intake in caprine [GOATS]

Molybdenum (Mo) is an essential trace element for animals and humans. However, the high dietary intake of Mo leads to disease conditions in heavy metal pollution areas. To the best of our knowledge, the effect of high levels of Mo on the apoptosis of hepatocyte in goats has not been investigated. Therefore, the aim of the present in vivo study was to investigate the impact of Mo on mitochondrial oxidative stress and apoptosis genes in the liver using real-time quantitative polymerase chain reaction (RT-qPCR) and transmission electron microscopy, respectively.

Thirty-six healthy goats were randomly divided into three groups: two groups treated with ammonium molybdate [(NH4)6.Mo7O24.H2O] at 15 and 45 mg Mo kg-1 BW, respectively, and a control group without treatment. Liver samples were collected from individual goats at different time intervals.

The levels of oxidative stress in the mitochondrial membrane and expression of liver-related apoptosis genes, including Bcl-2, Cyt c, caspase-3, and Smac, were examined.

The results demonstrated that the levels of superoxide dismutase (SOD) and catalase (CAT) expression were significantly down-regulated in liver cells, whereas malondialdehyde (MDA), nitric oxide (NO), and total nitric oxide synthase (T-NOS) expression was up-regulated (P < 0.01). The expression of Smac, Cyt c, and caspase-3 was significantly up-regulated, whereas Bcl-2 expression was down-regulated in liver cells (P < 0.01).

In addition, histopathological examination revealed varying degrees of vacuolization, irregularity, nuclear fission, and mitochondrial swelling and high-density electrons in the cytoplasm of hepatocytes in groups treated with 15 and 45 mg Mo kg(-1) BW.

Thus, these results suggested that high molybdenum induced hepatocyte apoptosis and might involve a mitochondrial pathway.

Zhuang, Y., Liu, P., Wang, L., Luo, J., Zhang, C., Guo, X., Hu, G., and Cao, H.,Mitochondrial oxidative stress-induced hepatocyte apoptosis reflects increased molybdenum intake in caprine, Biological trace element research, 2016, 170, 106-14.

Aquatic acute toxicity assessments of molybdenum (+VI) to DAPHNIA MAGNA

Generally, molybdenum (Mo) metals in the environment are very rare, but wastewater discharges from industrial processes may contain high concentrations of Mo, which has the potential to contaminate water or soil if not handled properly.

In this study, the impact of three common compounds of hexavalent Mo (sodium molybdate (Na2MoO42H2O), ammonium molybdate ((NH4)6Mo7O244H2O) and molybdenum trioxide (MoO3)) in an aquatic system were assessed based on 48-h exposure acute toxicity to Daphnia magna (D. magna). The LC50 toxicities for associated conjugate ions including Na+, Cl-, SO42-, and NH4(+) were determined.

Furthermore, the LC50 values for the three forms of hexavalent Mo were determined, and the acute toxicities of the Mo forms were found to follow the order: (NH4)6Mo7O244H2O > MoO3 > Na2MoO42H2O in solution. (NH4)6Mo7O244H2O exhibited the lowest LC50 of 43.3 mg L-1 (corresponding to 23.5 mg Mo L-1) among the three molybdenum salts.

The research confirmed that the toxicity of molybdenum in the aquatic system is highly dependent on the form of molybdenum salts used, and is also associated with the influence of the background water quality.

Wang, C. W., Liang, C., and Yeh, H. J.,Aquatic acute toxicity assessments of molybdenum (+VI) to Daphnia magna, Chemosphere, 2016, 147, 82-7.

Molybdenum induces pancreatic beta-cell dysfunction and apoptosis via interdependent of JNK and AMPK activation-regulated mitochondria-dependent and ER stress-triggered pathways [MOUSE]

Molybdenum (Mo), a well-known toxic environmental and industrial pollutant, causes adverse health effects and diseases in humans and has received attention as a potential risk factor for DM [diabetes]. However, the roles of Mo in the mechanisms of the toxicological effects in pancreatic beta-cells are mostly unclear.

In this study, the results revealed dysfunction of insulin secretion and apoptosis in the pancreatic beta-cell-derived RIN-m5F cells and the isolated mouse islets in response to Mo.

These effects were accompanied by a mitochondria-dependent apoptotic signals including a decreased in the MMP, an increase in cytochrome c release, and the activation of caspase cascades and PARP.

In addition, ER stress was triggered as indicated by several key molecules of the UPR.

Furthermore, exposure to Mo induced the activation of ERK1/2, JNK, AMPKalpha, and GSK3-alpha/beta.

Pretreatment with specific pharmacological inhibitors (in RIN-m5F cells and isolated mouse islets) of JNK (SP600125) and AMPK (Compound C) or transfection with si-RNAs (in RIN-m5F cells) specific to JNK and AMPKalpha effectively prevented the Mo-induced apoptosis and related signals, but inhibitors of ERK1/2 and GSK3-alpha/beta (PD98059 and LiCl, respectively) did not reverse the Mo-induced effects.

Additionally, both the inhibitors and specific si-RNAs could suppress the Mo-induced phosphorylation of JNK and AMPKalpha each other.

Taken together, these results suggest that Mo exerts its cytotoxicity on pancreatic beta-cells by inducing dysfunction and apoptosis via interdependent JNK and AMPK activation downstream-regulated mitochondrial-dependent and ER stress-triggered apoptosis pathways.

Yang, T. Y., Yen, C. C., Lee, K. I., Su, C. C., Yang, C. Y., Wu, C. C., Hsieh, S. S., Ueng, K. C., and Huang, C. F.,Molybdenum induces pancreatic beta-cell dysfunction and apoptosis via interdependent of JNK and AMPK activation-regulated mitochondria-dependent and ER stress-triggered pathways, Toxicology and applied pharmacology, 2016, 294, 54-64.

NOTE The authors’ names are on the paper as

Tsung-Yuan Yang, Cheng-Chieh Yen, Kuan-I Lee, Chin-Chuan Su, Ching-Yao Yang, Chin-Ching Wu, Shang-Shu Hsieh, Kwo-Chang Ueng, Chun-Fa Huang

Accumulation, storage and distribution of molybdenum in animals

In experimental animals given lethal or near lethal doses, however administered, of molybdenum trioxide, calcium molybdate or ammonium heptamolybdate the rate of excretion of molybdenum was less than the rate of absorption [Underwood, 1962; Kolomiitseva et al., 1968; Schroeder et al., 1970]. The amount accumulating in the tissues increased with increasing size and number of doses. After administration of molybdenum had ceased the molybdenum content of the tissues dropped quite rapidly. For example, in guinea pigs exposed to molybdenum trioxide for eight days total molybdenum had dropped to the control value four days after the dose had ceased. [Fairhall et al., 1945] The percentage drop for bone was least so it appears that there is some preferential storage of molybdenum in bone. In general absorption and excretion of molybdenum are rapid and a high proportion (ca 95%) of molybdenum added to the diet is excreted and rather little molybdenum is stored in the tissues. Additional studies involving rats gave the following breakdown of absorbing organs; 3.6% stomach, 9.5% duodenum and 8.2 % in the ileum [van Campen and Mitchell, 1965]. However, as stated, many other groups have found that the process of absorption and retention is dependent on dose, mode of administration and the age of the experimental animal.

Underwood, E. J.,Trace Elements in Human and Animal Nutrition, Academic Press, London, 2nd Ed., 1962, 100.
Kolomiitseva, M. G., Polonskaya, M. N. and Osipov, G. K.,Mikroelem. Sel. Khoz. Med., 1968, 4, 183
Schroeder, H. A., Balassa, J. J.and Tipton,I. H., J. Chronic Diseases, 1970, 23, 481.
Fairhall, L. T., Dunn, R. C., Sharpless, N. E. and Pritchard, E. A., U. S. Public Health Bull., 1945, 293, 1.
Van Campen, D. R., Mitchell, E. A. (1965), J. Nutr., 86, 120-124.

In lactating goats,99MoO3 , administered orally was found in skeleton, liver, skin, muscles, blood, kidney, ovary and hair 4 days later. Molybdenum was also detected in the milk of goats fed molybdenum trioxide [Anke et al., 1971].

The concentration of molybdenum in cows' milk increased after daily feeding of 500 mg ammonium molybdate [Mills and Davis, 1987].

Fairhall, L. T., Dunn, R. C., Sharpless, N. E. and Pritchard, E. A., U. S. Public Health Bull., 1945, 293, 1.
Venugopal, B. and Luckey, T. D., Metal Toxicity in Mammals, 1978, Vol. 2, Chemical Toxicity of Metals and Metalloids, Plenum Press, New York.
Anke, M., Hennig, A., Dieltrich, M., Hoffmann, G., Wicke, G. and Pflug, D.,Arch. Tierernaehr., 1971, 21, 205.
Mills, C. F. and Davis, G. K., in :Trace elements in Human and Animal Nutritution, Metrz, W., ed., 1987, 429, Academic Press, New York.

Fischer rats given subcutaneous injections of N-methyl-N-benzylnitrosamine and fed dietary sodium molybdate (2 ppm) had increased molybdenum concentrations in the esophagus, forestomach, blood serum, and liver. Xanthine oxidase activities were also increased in the esophagus and forestomach, but not in the liver [Komada et al., 1990]. Radioactivity was detected in the liver, bone, heart, lungs, blood, and kidneys 2.5 hours after rats were fed a single dose (13.34 mg) of99Mo. The concentrations of radioactivity were higher in the intestine, kidney, and bone than in other tissues 51 hours after dosing. It was estimated that 35% of the administered dose was absorbed [Neilands et al., 1948].

Komada, H., Kise, Y., Nakagawa, M., Yamamura, M., Hioki, K. and Yamamoto, M., Cancer Res., 1990, 50, 2418.
Neilands, J. B., Strong, F. M. and Elvehjem, C. A., J. Biol. Chem., 1948, 172, 431.

In dogs receiving99Mo by injection, molybdenum was selectively concentrated in the liver, kidneys and endocrine glands (pancreas, pituitary, adrenal and thyroid). The brain, bone marrow and fat contained neglible amounts of the injected molybdenum [Clayton and Clayton, 1981].

Clayton, G. D. and Clayton, F. E., eds, Patty's Industrial Hygiene and Toxicology, 3rd Ed., 1981, 2A, 1493. John Wiley and Sons, New York.

The absorption, tissue distribution and excretion patterns of molybdenum in rabbits are similar to those found for other species as described above. Increased molybdenum intake by experimental animals has been shown to increase tissue levels of xanthine oxidase; liver, intestine and kidney; [Luo et al., 1983].

Luo, X. -M., Wei, H. -J. and Yang, S. P., J. Nat. Cancer Inst.,1983, 71, 75.

Exposure to molybdenum trioxide dust (30 mg/m3 ) for 5.5 months increased serum and urinary ascorbic acid levels in rabbits but no similar effects occurred in rats [Lukashev and Shishkova, 1971].

Lukashev, A. A. and Shishkova, Tr. Nauch.-Issled. Inst. Kraev. Patol. Alma Ata, 1971, 22, 152, 175, 191.

Absorption of molybdenum experimental animals

In animals (guinea pigs, rabbits, rats, sheep) water-soluble molybdenum compounds and also molybdenum trioxide and calcium molybdate, but not molybdenum disulfide, are readily absorbed from the intestinal tract and lungs. Concentrations of molybdenum in the tissues, bones, and blood rise rapidly after administration of molybdenum compounds [Rosoff and Spencer, 1964].

Rosoff, B. and Spencer, H., Nature, 1964, 202, 410.

Excretion of molybdenum in animals

With animals the concentration of molybdenum in the urine and faeces rises rapidly after administration of molybdenum trioxide and molybdates. Molybdenum is excreted mainly in the urine probably as the molybdate anion. With human subjects injected intravenously with a single tracer dose of 99Mo, after five days 16.6-27.2% of the99Mo had been excreted in the urine and only 1-6.8% in the faeces [Rosoff and Spencer, 1964]. It has been estimated that the average excretion of molybdenum by humans is about 50-70 microg per day [Friberg and Lener, 1986]. The amount of molybdenum excreted and the route are affected by sulfate (added to, or as part of, the diet). For cattle, sheep and rats the total amount of molybdenum excreted and the proportion in the urine increases with increasing sulfate in the diet [Dick, 1969]. A study using radiomolybdenum to trace the excretion process in cattle found that the biological half-life of molybdenum was 19.9 ± 1.4 h [Robinson et al., 1968].

Rosoff, B. and Spencer, H., Nature, 1964, 202, 410.
Friberg, L. and Lener, J., in: Handbook of Toxicology of Metals, Friberg L. et al. (eds.), 2nd Ed., 1986, II, 446. Elsevier Science Publishers, Amsterdam.
Dick, A. T., Outlook Agr., 1969, 6, 14.
Robinson, G. A., Valli, V. E. O., McSherry, B. J. and Pepino, A. M., Can. J. Physiol. Pharmacol., 1968, 47, 343.

Effects of high dietary molybdenum in rabbits

To study the effects of high dietary molybdenum, rabbits were fed with commercial pellets and carrots containing 39 mg Mo/kg dry matter [Experiment 1] and with a commercial diet supplemented with 40 mg Mo/kg dry matter [Experiment 2] for 14 days. The high dietary Mo contents did not reduce the growth of rabbits. Supplemental Mo given in a dose of 40 mg/kg non-significantly decreased the apparent digestibility of crude protein and crude fibre compared to the control (73.63 +/- 2.49 and 18.56 +/- 5.10 vs. 74.31 +/- 3.03 and 21.38 +/- 6.48, respectively). Molybdenum ingested with feeds was mainly excreted (57%) via the urine. The highest Mo levels were found in kidney and liver samples (3.464 +/- 0.872; 5.27 +/- 0.95 mg/kg DM [Experiment 1] and 1.878 +/- 0.283; 1.62 +/- 0.16 mg/kg DM [Experiment 2], respectively), and Mo could also be detected in limb meat (0.336 +/- 0.205 mg/kg DM). The testes were more sensitive to Mo exposure than the female reproductive organs because the number of germ cells was reduced. Due to the high dietary Mo intake free radicals could be generated, resulting in a marked increase of creatine kinase activity.

Berssnyi, A., Berta, E., Kadar, I., Glavits, R., Szilagyi, M., and Fekete, S. G., Effects of high dietary molybdenum in rabbits, Acta Veterinaria Hungarica, 2008, 56, 41-55.

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