Human & Experimental Toxicology

Brick kilns in the suburban areas in developing countries pose a big threat to the environment and hence the health of their workers and people residing around them. The present study was planned to assess the lung functions, oxidative stress parameters and DNA damage in brick kiln workers. A total of 31 male subjects working in brick kiln, and 32 age, sex and socioeconomic status matched controls were included in the study. The lung volumes, capacities and flow rates, namely, forced expiratory volume in first second (FEV₁), forced vital capacity (FVC), FEV₁/FVC, expiratory reserve volume, inspiratory capacity (IC), maximal expiratory flow when 50% of FVC is remaining to be expired, maximum voluntary ventilation, peak expiratory flow rate and vital capacity were significantly decreased in the brick kiln workers. Increased oxidative stress as evidenced by increased malonedialdehyde levels and reduced glutathione content, glutathione S-transferase activity and ferric reducing ability of plasma were observed in the study group when compared with controls. Our results indicate a significant correlation between oxidative stress parameters and pulmonary dysfunction, which may be due to silica-induced oxidative stress and resulting lung damage.

Divalproex sodium is an antiepileptic drug. Hepatotoxicity is one of the most common side effects induced by divalproex sodium. Impaired fatty acid metabolism is considered to play an important role in the drug-induced hepatotoxicity. The sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor α (PPARα) are two key transcription factors involved, respectively, in fatty acid synthesis and degradation in liver. In the present study, we investigated the hepatotoxicity induced by divalproex sodium and its potential mechanism. The results indicated that divalproex sodium significantly decreased the cell viability and increased lactate dehydrogenase leakage in hepatocytes. The activities of alanine aminotransferase and aspartate transaminase were increased in hepatocytes treated with divalproex sodium. Furthermore, divalproex sodium activated SREBP-1c and increased the mRNA expressions of acetyl-CoA carboxylase 1, fatty acid synthase and stearoyl-CoA desaturase 1. Divalproex sodium also inhibited PPARα and decreased the messenger RNA expressions of 3-hydroxy-3-methylglutaryl-CoA synthase 2 and carnitine palmitoyltransferase 1A. These results suggest that the hepatotoxicity induced by divalproex sodium may be related with fatty acid synthesis and degradation mediated by SREBP-1c and PPARα in hepatocytes.

In this research, we investigated the toxicity responses of rat following a continuous 4 h inhalation exposure of only the head and nose to iron oxide nanoparticles (Fe₃O₄ NPs, size = 15–20 nm). The rats for the investigation were exposed to a concentration of 640 mg/m³ Fe₃O₄ NPs. Markers of lung injury and proinflammatory cytokines (interleukin-1β, tumor necrosis factor-α, and interleukin-6) in bronchoalveolar lavage fluid (BALF) and blood, oxidative stress in lungs, and histopathology were assessed on 24 h, 48 h, and 14 days of postexposure periods. Our results showed a significant decrease in the cell viability, with the increase in the levels of lactate dehydrogenase, total protein, and alkaline phosphatase in the BALF. Total leukocyte count and the percentage of neutrophils in BALF increased within 24 h of postexposure. Immediately following acute exposure, rats showed increased inflammation with significantly higher levels of lavage and blood proinflammatory cytokines and were consistent throughout the observation period. Fe₃O₄ NPs exposure markedly increased malondialdehyde concentration, while intracellular reduced glutathione and antioxidant enzyme activities were significantly decreased in lung tissue within 24-h postexposure period. On histological observation, the lung showed an early activation of pulmonary clearance and a size-dependant biphasic nature of the Fe₃O₄ NPs in causing the structural alteration. Collectively, our data illustrate that Fe₃O₄ NPs inhalation exposure may induce cytotoxicity via oxidative stress and lead to biphasic inflammatory responses in Wistar rat.

High blood pressure, obesity, abnormal lipid profile, which often coexist with diabetes, tend to be associated with preclinical cardiovascular abnormalities and may contribute to the association of diabetes with cardiovascular events. Many studies have proved that streptozotocin (STZ) is responsible for type-2-diabetes-induced cardiovascular complications. Long-term perindopril therapy in patients with hypertension and diabetes has been observed to correct carotid remodeling by reducing hypertrophy. We studied the effect of perindopril (1 mg/kg/d orally [po]) on cardiovascular complications in neonatal model of rats, which was induced by administering STZ (90 mg/kg, intraperitoneally [ip]), in 5-d-old wistar rats and cardiac hypertrophy induced by isoprenaline (ISO; 5 mg/kg, ip) for 10 d. Various biochemical, cardiac, and hemodynamic parameters were measured at the end of 8 weeks of treatment in diabetes model and 10 d in hypertrophy model. STZ produced hyperglycemia, hyperinsulinemia, dyslipidemia, hypertension, bradycardia, increased creatinine kinase (CK-MB), lactate dehydrogenase enzymes (LDH) and C-reactive protein (CRP) levels, cardiac hypertrophy, and oxidative stress. Chronic treatment with perindopril significantly prevented STZ-induced hyperglycemia and hyperinsulinemia and controlled dyslipdemia in diabetic rats. Further, perindopril produced a significant reduction in elevated levels of CRP, LDH, and CK. STZ-induced hypertension and bradycardia were also prevented by perindopril treatment. Perindopril also produced beneficial effect by preventing cardiac hypertrophy as evident from cardiac hypertrophy index and left ventricular hypertrophic index. Perindopril also prevented STZ-induced oxidative stress. Similar results were obtained in ISO-induced cardiac hypertrophic model, which confirms the beneficial role of perindopril in cardiac hypertrophy. In conclusion, our data from both studies suggest that perindopril produced beneficial effect on cardiac complications.

The comet assay is a well-established, simple and sensitive method to measure DNA damage in single cell and is commonly used in human trials to investigate the effects of pollution, occupational hazards and potential genoprotective agents. Peripheral blood lymphocytes are most commonly used in human biomonitoring studies, but lymphocytes collected from the mouth offer a potentially attractive, noninvasive alternative. The aim of the current study was to develop a buccal cell lymphocyte comet assay procedure. Cells were collected from mouthwash of three healthy volunteers and tested individually. The comet assay was performed under different pH and times of alkaline treatment, electrophoresis run times and hydrogen peroxide concentrations. Optimal conditions for buccal lymphocytes in comet assay were found to be pH >13 for unwinding and electrophoresis buffers, 10-min alkaline unwinding treatment and 20-min electrophoresis run time. We successfully utilized our optimized assay conditions to demonstrate the genoprotective activity of quercetin. This newly established procedure offers an alternative noninvasive sampling method for the investigation of DNA protection and/or damaging effect.

The wide use and wide-spectrum toxicity of synthetic pyrethroid (SP) insecticides make them an emerging ecotoxicological concern. The objective of the current study was aimed to investigate the involvement of oxidative stress in lambda-cyhalothrin (LTC)–induced cerebellum damages in adult rats and to evaluate the possible protective effect of vitamin C (vit C) as antioxidant. Exposure of rats to LTC during 3 weeks caused a significant (p < 0.05) increase in the levels of lipid peroxidation (LPO), nitric oxide (NO) and protein carbonyls (PCO) along with a significant (p < 0.05) decrease in the levels of reduced glutathione (GSH) and the activities of acetylcholinesterase, superoxide dismutase, catalase, glutathione peroxidase and gluthione-S-transferase (p < 0.05) when compared with the control group. The oral administration of vit C (200 mg/kg per d) to LTC-treated rats significantly (p < 0.05) diminished the levels of LPO, NO and PCO and significantly (p < 0.05) increased the activities of GSH and antioxidant enzymes. Our results showed that the administration of vit C could ameliorate some of the oxidative damage in the cerebellum induced by SPs exposure, suggesting that the ascorbic acid could exhibit a potential antioxidant activity against neurotoxicity induced by pesticides exposure.

The toxicity of exposure to polycyclic aromatic hydrocarbons (PAHs) or phytoestrogen is relatively well characterized. However, the toxicity of combined exposure to PAHs and phytoestrogen is not well investigated. In the present study, benzo(a)pyrene (B(a)P) and benzo(k)fluorathene (B(k)F), genistein, along with 17β-estradiol (E2), were investigated for their single and combined developmental toxicity using zebrafish embryos as model system. We demonstrated that two representative PAHs, both B(a)P (≥1 μM) and B(k)F (≥10 μM), can cause significant malformation and mortality in developing zebrafish embryos. The toxicity effect of B(a)P was in general higher than that of B(k)F. Developmental exposure to high level of genistein (>20 μM) or E2 (>10 μM), also caused significant malformation and mortality in zebrafish larvae at 120 hours post fertilization (hpf). However, different toxic effects were observed for the combined exposure to PAHs and phytoestrogen in zebrafish. Lower doses of genistein (1 and 10 μM) and E2 (0.1 and 1 μM), when used in combination with high concentration of B(a)P (1 μM) or B(k)F (20 μM), can significantly suppress the toxicity effect of B(a)P and B(k)F in developing zebrafish embryos. The beneficial effect of genistein may be due to the inhibition of cytochrome P450 enzymes via directly interacting with aryl-hydrocarbon receptor (AhR) pathway, or disturbing the AhR pathway through interacting with estrogen receptor pathway.

High doses of gadolinium-based contrast media are reported to induce deterioration of renal function. We assessed whether prophylactic 0.9% saline hydration inhibits high-dose gadodiamide-induced renal damage in rats. Twelve Sprague-Dawley rats were randomly divided into two groups, which are given gadodiamide (5 mmol/kg) with (hydration group) or without (control group) 0.9% saline hydration. The saline (4 mL/kg) was infused as a bolus into the peritoneum every 4 h, starting 12 h before and continuing for 12 h after the gadodiamide injection. Urine was collected to calculate creatinine clearance (Ccr) 24 h before and 48 h after the gadodiamide injection. The kidneys were harvested and stained for pathologic analysis. High-dose gadodiamide induced acute kidney injury as shown by decreased Ccr and renal histology with tubular cell injuries 48 h postinjection in both the groups. However, the extent of Ccr reduction was significantly (p = 0.02) less in the hydrated rats (−15% in the hydration group vs. −39% in the control group). Renal tubular cell injuries characterized by vacuolization, loss of brush borders, sloughing of tubular cells into the lumen, and flattening of the tubular epithelium were less frequently seen in the hydration group; only vacuolization (p = 0.01) and epithelial sloughing (p = 0.02) of the proximal tubules differed significantly between the two groups. We conclude that prophylactic 0.9% saline hydration significantly inhibited high-dose gadodiamide-induced nephropathy.

In the eastern Iran including Birjand and Greater Khorasan areas, a special traditional solid pie, locally called Majoon Birjandi (MB), is frequently abused by youngsters to induce a feel of high, special, euphoria, and energy. Cannabioid ingredients of this illicit solid lozenge are confirmed by clinical findings as well as positive urinary delta-q-tetrahydrocannabinol (THC) test. Because of its solid nature, it is easily smuggled and stored for a long time. Due to its localized usage in the eastern Iran, diagnosis of MB abuse is not known to toxicologists even from other parts of this country. We would like to bring to the attention of the readers the effects and cannabioid composition of this concoction and present the potential recreational ingestion root of processed cannabis for the first time.