Exposure to hydrocarbons and renal disease: an experimental animal model.

The association between hydrocarbon exposure and chronic glomerulonephritis is still a controversial scientific issue. Recent epidemiological evidence suggests a role of exposure to hydrocarbons in the progression of glomerulonephritis towards chronic renal failure. The present experimental study on rats has been designed to assess the possible role of styrene in the progression of adriamycin (ADR) nephrosis, a well known model of renal fibrosis following nephrotic syndrome induced by ADR. Female Sprague-Dawley rats were exposed to styrene, 300 ppm, 6 h/day, 5 days/week for 12 weeks (group 1); treated with ADR, 2 mg/Kg, i.v., twice on day 1 and day 15 of the study (group 2); Additional groups of animals received both the styrene and ADR treatments (group 3) or served as controls (group 4). The urinary excretion of total and single proteins (albumin, Retinol-Binding Protein (RBP), Clara Cell 16 Kd protein (CC16), fibronectin) was measured monthly, whereas histopathology and determinations requiring blood sampling were carried out at the end of the experiment. A progressive increase in total proteinuria, falling in the nephrotic range already by the 6th week was observed in ADR-treated groups. Styrene exposure caused up to a 3- to 5-fold increase as compared to controls. Co-exposure to ADR and styrene also resulted in a proteinuria much greater than that caused by ADR alone. The interactive effect of styrene and ADR was statistically significant for albuminuria and urinary fibronectin. A similar response was observed for glomerular filtration rate at the end of the experiment, styrene-exposed animals showing hyperfiltration as compared to their respective control group. At the end of the experiment, histopathological scoring for interstitial infiltration and fibrosis was also significantly higher in styrene-treated animals as compared to their respective control groups. In ADR-treated rats, low molecular weight proteinuria (l.m.w.p.) was only slightly affected, suggesting minimal tubular dysfunction associated with extensive tubular atrophy. However, styrene-exposed animals showed l.m.w.p. higher than their respective controls. In summary, in this animal model we were able to confirm both styrene-induced microproteinuria, mainly albuminuria and minor increases in l.m.w.p., observed among occupationally exposed workers and the role of hydrocarbon exposure as a factor accelerating the progression of renal disease suggested by epidemiological investigations in patients suffering from chronic renal disease. Whereas in rats exposed to styrene only, microproteinuria was stable over time and minor histopathological changes were noted at the end of the experiment, evidence of a role of solvent exposure in the progression of ADR nephropathy was obtained in terms of both renal dysfunction and interstitial fibrosis. The mechanistic basis of styrene-ADR interaction is unclear. However, experimental evidence is consistent with epidemiological findings suggesting the need to avoid solvent exposure in patients suffering from renal diseases

Effects of gestational and lactational exposure to PCB126 and methylmercury on circulating steroid hormone levels at weaning and puberty in the rat

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MAM-2201 acute administration impairs motor, sensorimotor, prepulse inhibition, and memory functions in mice: a comparison with its analogue AM-2201

Rationale1-[(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl) methanone (MAM-2201) is a potent synthetic cannabinoid receptor agonist illegally marketed in "spice" products and as "synthacaine" for its psychoactive effects. It is a naphthoyl-indole derivative which differs from its analogue 1-[(5-Fluoropentyl)-1H-indol-3-yl](1-naphthylenyl) methanone (AM-2201) by the presence of a methyl substituent on carbon 4 (C-4) of the naphthoyl moiety. Multiple cases of intoxication and impaired driving have been linked to AM-2201 and MAM-2201 consumption.ObjectivesThis study aims to investigate the in vitro (murine and human cannabinoid receptors) and in vivo (CD-1 male mice) pharmacodynamic activity of MAM-2201 and compare its effects with those induced by its desmethylated analogue, AM-2201.ResultsIn vitro competition binding studies confirmed that MAM-2201 and AM-2201 possess nanomolar affinity for both CD-1 murine and human CB1 and CB2 receptors, with preference for the CB1 receptor. In agreement with the in vitro binding data, in vivo studies showed that MAM-2201 induces visual, acoustic, and tactile impairments that were fully prevented by pretreatment with CB1 receptor antagonist/partial agonist AM-251, indicating a CB1 receptor mediated mechanism of action. Administration of MAM-2201 also altered locomotor activity and PPI responses of mice, pointing out its detrimental effect on motor and sensory gating functions and confirming its potential use liability. MAM-2201 and AM-2201 also caused deficits in short- and long-term working memory.ConclusionThese findings point to the potential public health burden that these synthetic cannabinoids may pose, with particular emphasis on impaired driving and workplace performance

A Review of the Mycotoxin Enniatin B

Mycotoxin enniatin B (ENN B) is a secondary metabolism product by Fusarium fungi. It is a well-known antibacterial, antihelmintic, antifungal, herbicidal, and insecticidal compound. It has been found as a contaminant in several food commodities, particularly in cereal grains, co-occurring also with other mycotoxins. The primary mechanism of action of ENN B is mainly due to its ionophoric characteristics, but the exact mechanism is still unclear. In the last two decades, it has been a topic of great interest since its potent mammalian cytotoxic activity was demonstrated in several mammalian cell lines. Moreover, the co-exposure in vitro with other mycotoxins enhances its toxic potential through synergic effects, depending on the concentrations tested. Despite its clear cytotoxic effect, European Food Safety Authority stated that acute exposure to ENNs, such as ENN B, does not indicate concern for human health, but a concern might be the chronic exposure. However, given the lack of relevant toxicity data, no firm conclusion could be drawn and a risk assessment was not possible. In fact, very few studies have been carried out in vivo and, in these studies, no adverse effects were observed. So, research on toxicological effects induced by ENN B is still on-going. Recently, some studies are dealing with new advances regarding ENN B. This review summarizes the information on biochemical and biological activity of ENN B, focusing on toxicological aspects and on the latest advances in research on ENN B

How Do Inflammatory Mediators, Immune Response and Air Pollution Contribute to COVID-19 Disease Severity? A Lesson to Learn

Inflammatory and immune processes are defensive mechanisms that aim to remove harmful agents. As a response to infections, inflammation and immune response contribute to the pathophysiological mechanisms of diseases. Coronavirus disease 2019 (COVID-19), whose underlying mechanisms remain not fully elucidated, has posed new challenges for the knowledge of pathophysiology. Chiefly, the inflammatory process and immune response appear to be unique features of COVID-19 that result in developing a hyper-inflammatory syndrome, and air pollution, the world's largest health risk factor, may partly explain the behaviour and fate of COVID-19. Understanding the mechanisms involved in the progression of COVID-19 is of fundamental importance in order to avoid the late stage of the disease, associated with a poor prognosis. Here, the role of the inflammatory and immune mediators in COVID-19 pathophysiology is discussed

Mercapturic acids and ethanol consumption

Advances in Occupational Medicine and Rehabilitation Serie

Human co-culture model of neurons and astrocytes to test acute cytotoxicity of neurotoxic compounds

Alternative methods and their use in planning and conducting toxicology experiments has become essential for modern toxicologists, thus reducing or replacing living animals. Although in vitro human coculture models allow the establishment of biologically relevant cell-cell interactions that recapitulate the tissue microenvironment and better mimic its physiology, the number of publications is limited specifically addressing this scientific area and utilizing this test method which could provide an additional valuable model in toxicological studies. In the present study, an in vitro model based on CNS cell co-cultures was implemented using a trans-well system combining human neuronal cells (SH-SY5Y cell-line) and glial cells, namely astrocytes (D384 cell-line), to investigate neuroprotection of D384 on SH-SY5Y and vice-versa. The model was applied to test acute (24-48h) cytotoxicity of three different neurotoxicants: (i) methylmercury (1-2.5 μM); (ii) Fe3O4-nanoparticles (1-100 μg/ml); (iii) methylglyoxal (0.5-1 mM). Data were compared to monocultures evaluating the mitochondrial function and cell morphology. The results clearly showed that all compounds tested affected the mitochondrial activity and cell morphology in both mono- and co-culture conditions. However, astrocytes, when cultured together with neurons, diminish the neurotoxicant-induced cytotoxic effects that occurred in neurons cultured alone, and astrocytes become more resistant in the presence of neurons. This human CNS co-culture system seems a suitable cell model to feed high-throughput acute screening platforms and to evaluate both human neuronal and astrocytic toxicity and neuroprotective effects of new and emerging materials (e.g., nanomaterials) and new products with improved sensitivity due to the functional neuron-astrocyte metabolic interactions. Key Words: SH-SY5Y neurons, D384 astrocytes, methylglyoxal, methylmercury; magnetite nanoparticles; mitochondrial function.JRC.F.3-Chemicals Safety and Alternative Method

In Vitro Toxicity Evaluation of Engineered Cadmium-Coated Silica Nanoparticles on Human Pulmonary Cells

Cytotoxicity of cadmium-containing silica nanoparticles Cd-SiO2NPs (0.05–100 µg/mL) versus SiO2NPs and CdCl2 was evaluated by an in vitro test battery in A549 by assessing (i) mitochondrial function, (ii) membrane integrity/cell morphology, (iii) cell growth/proliferation, (iv) apoptotic pathway, (v) oxidative stress, after short- (24–48 h) and long-term (10 days) exposure. Both Cd-SiO2NPs and CdCl2 produced dose-dependent cytotoxic effects: (i) MTT-assay: similar cytotoxicity pattern was observed at both 24 and 48 h, with a more Cd-SiO2NPs pronounced effect than CdCl2. Cd-SiO2NPs induced mortality (about 50%) at 1 μg/mL, CdCl2 at 25 μg/mL; (ii) calcein-AM/PI staining: decrease in cell viability, noticeable at 25 μg/mL, enhanced markedly at 50 and 100 μg/mL, after 24 h. Cd-SiO2NPs induced higher mortality than CdCl2 (25% versus 4%, resp., at 25 μg/mL) with further exacerbation after 48h; (iii) clonogenic assay: exposure for longer period (10 days) compromised the A549 proliferative capacity at very low dose (0.05 μg/mL); (iv) a progressive activation of caspase-3 immunolabelling was detected already at 1 μg/mL; (v) GSH intracellular level was modified by all compounds. In summary, in vitro data demonstrated that both Cd-SiO2NPs and CdCl2 affected all investigated endpoints, more markedly after Cd-SiO2NPs, while SiO2NPs influenced GSH only