Toxicopathological evaluation in Wistar rats (Rattus norvegicus) following repeated oral exposure to acephate.

The present study was carried out to evaluate the effects of exposure at different doses of acephate on hematology, blood biochemistry, oxidative stress and immune system of Wistar rats. The experiment was carried out on 40 Wistar rats, which were divided in four groups. Animals of the three treatment groups were given with different sublethal doses (1/40th, 1/20th, 1/10th of lethal dose 50 value) of acephate by oral gavage. The hematology, blood biochemistry, oxidative stress marker, humoral immune response and cell-mediated immunity were evaluated following acephate exposure. Significant alteration in hematological parameters was not observed following different doses of acephate; however, significant alteration in alkaline phosphatase, gamma glutamyl transferase, acetyl cholinesterase, lipid peroxidase and superoxide dismutase was observed in medium- and high-dose group animals. Nonsignificant decrease in antibody titer in animals exposed to high dose has been observed compared with animals of control group. However, significant alteration in cell-mediated immunity was not observed in animals treated with acephate at different doses.

Long-term tributyltin exposure alters behavior, oocyte maturation, and histomorphology of the ovary due to oxidative stress in adult zebrafish.

Tributyltin (TBT), an organotin endocrine-disrupting substance, is recognized as one of the important toxic environmental pollutants. The present study was carried out to investigate the toxic effects of TBT on behavior and the ovary of adult zebrafish with a focus on oxidative stress markers and oocyte maturation. Adult zebrafish were exposed to three different concentrations (125, 250, and 500 ng/L of water) of TBT for 28 days. TBT exposure produced a concentration-dependent negative effect on the body weight and behavior (anxiety-like symptoms) of adult zebrafish. Alterations in the activity of superoxide dismutase (SOD) and catalase (CAT), the total antioxidant capacity of ovarian tissue by the highest exposure level of TBT resulted in lipid peroxidation as indicated by increased malondialdehyde (MDA) level. The numbers of early-vitellogenic oocytes were significantly increased in zebrafish exposed to TBT as low as 125 ng/L. However, the numbers and size of fully-grown (mature) oocytes were significantly reduced in the highest exposure group only. Correlation between the MDA level and pre-vitellogenic oocytes in the 500 ng/L group indicated that lipid peroxidation prevented the maturation of pre-vitellogenic oocytes. TBT exposure produced significant histological changes in the ovary as evidenced by disturbed maturation of oocytes. In conclusion, TBT adversely affected the maturation of oocytes in zebrafish ovary through oxidative stress-mediated mechanisms.

Neurotoxicity of 4-nonylphenol in adult zebrafish: Evaluation of behaviour, oxidative stress parameters and histopathology of brain.

Nonylphenol and its derivatives use as plasticizer or additives in manufacturing industries. Effluents originated from industrial areas are being added to soil, ground water, river and marine water intentionally or unintentionally. Complex mixture of these contaminants enter the food chain and produce sub-lethal deleterious effects mainly on nervous and reproductive systems of aquatic animals and human beings. The information pertaining to oxidative stress-mediated alterations in brain of zebrafish would be helpful to understand the toxicity potential of such compounds in aquatic animals. The aim of the present study was to evaluate the behavioural changes, status of oxidative stress markers; sod, cat, and NF-E2-related factor 2 (nrf2) mRNA gene expression profile; and histopathological changes in the brain of adult zebrafish exposed to 4-nonylphenol (4NP) at concentration of 100 and 200 µg/L of water for 21 days. Zebrafish were divided into four groups viz; control (C1), vehicle (C2, ethanol 10 µg/L of water), treatment 1 (T1, 4-NP, 100 µg/L) and treatment 2 (T2, 4-NP, 200 µg/L). Both exposure levels of 4-NP adversely affected the exploratory behaviour of zebrafish and produced anxiety-like symptom. Concentration-dependent reduction in activity of superoxide dismutase and catalase; and glutathione level, with increased level of malondialdehyde recorded in the brain of exposed zebrafish. Gene expression analysis showed down regulation of sod, cat, nrf2 genes in brain of zebrafish from toxicity groups indicating 4-NP induced oxidative stress in brain. However, noticeable histological alterations were not observed in 4-NP exposed brain of zebrafish.

Neurotoxicity of acrylamide in adult zebrafish following short-term and long-term exposure: evaluation of behavior alterations, oxidative stress markers, expression of antioxidant genes, and histological examination of the brain and eyes.

In the present work, 224 adult female zebrafish (56 fish in each group) were randomly divided into four groups (two control groups and two toxicity groups) as per duration of exposure (7 and 21 days). All fish of the two toxicity groups were exposed to 0.610 mM acrylamide (ACR) concentration for 7 and 21 days. The effects of ACR exposure on behavior, oxidative stress biomarkers, molecular expression of antioxidant genes (sod, cat, and nrf2), and histopathological examination of the brain and eye were examined. Our result shows that ACR exposure for 7 days produced an anxiety-like behavior in zebrafish. Short-term exposure of ACR resulted in alterations of oxidative stress markers (SOD and CAT activity, and the level of GSH and MDA) in the brain and eye of zebrafish. However, the antioxidant defense system of adult female zebrafish could be able to counteract the free radicals generated in long-term ACR exposure as indicated by non-significant difference in oxidative insult following short-term and long-term exposure. ACR exposure downregulated the mRNA expression of the sod, cat, and nrf2 (nuclear factor erythroid 2-related factor 2) genes in the brain and eye without significant difference between the two toxicity groups. Mild histological changes in the dorsal telencephalic area, tectum opticum, medulla, and hypothalamus area of the brain of zebrafish have been observed following short-term and long-term ACR exposure. In the eye, marked histological changes in the retinal pigmented epithelium layer (RPE), structural changes of the photoreceptor layer (PRL) with disorganized layer of rods and cones, and reduction of the relative thickness of the RPE, PRL, outer nuclear layer (ONL), and inner nuclear layer (INL) have been noted following ACR exposure for 21 days as compared to 7 days. ACR produced neurobehavioral aberrations and oxidative stress within 7 days of exposure, while various histological changes in the brain and eyes have been observed following long-term exposure (21 days) to ACR.

Long-term exposure of the binary mixture of cadmium and mercury damages the developed ovary of adult zebrafish.

The toxicity of the binary mixture of cadmium (Cd) and mercury (Hg) on the ovary of adult zebrafish was evaluated in the present study. Adult female zebrafish were exposed to cadmium chloride (1 mg/L), mercury chloride (30 µg/L), and a binary mixture of both metals for 21 days. The toxic effects of both metals on the ovary were investigated by evaluating the oxidative stress markers and related gene expression in ovarian tissue along with the histopathological examination. The significantly decreased level of GSH and increased level of MDA in ovarian tissue of adult female zebrafish exposed to Cd + Hg indicated that the exposure of binary mixture of Cd and Hg caused more lipid peroxidation in the ovary. The significant changes in expression of mRNA of catalase (CAT) and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) were not observed in the ovary of zebrafish exposed to the binary mixture. Upon histological evaluation, a decreased number of full-growth (mature) oocytes along with degenerative changes due to Cd exposure were noticed, while ovary of zebrafish of the Hg-exposed group had shown a decreased number of pre-and early vitellogenic oocytes along with atretic previtellogenic oocytes compared to the control group. The ovary of zebrafish of the Cd + Hg-exposed group had shown a decreased number of previtellogenic oocytes with marked pathological changes in mature oocytes. Present findings elucidate that simultaneous long-term exposure of Cd and Hg compared to individual exposure significantly damaged the various stages of oocytes of an ovary of adult zebrafish.

Effect of piperine and quercetin alone or in combination with marbofloxacin on CYP3A37 and MDR1 mRNA expression levels in broiler chickens.

After oral route of administration, drug absorption is unpredictable and is governed by various factors such as multi drug resistance-1 (MDR1) an efflux transporter and drug metabolizing enzymes (like CYP3A4, CYP3A37, CYP2D6) at intestine and liver. Naturally available phyto chemicals like piperine and quercetin as well as some floroquinolones are known to inhibit MDR1 and CYP3A37 activity and increases bioavailability of co-administered drugs. This study was carried out to investigate the effect of piperine and quercetin alone or in combination with marbofloxacin on CYP3A37 and MDR1 mRNA expression levels in liver and intestine of broiler chicken. After oral administration of piperine and quercetin for 3 consecutive days followed by with or without oral administration of marbofloxacin for 5 days, CYP3A37 and MDR1 mRNA expression levels were determined using quantitative real-time PCR. Total of 36 broiler chickens in seven individual groups were treated with different regimen and the mRNA expression levels at duodenum and liver were analyzed with apt statistical tools. After piperine and quercetin combined treatment with marbofloxacin, CYP3A37 mRNA expression levels were significantly down regulated by 20.57 (p = .034) and 25.95 (p = .003) folds; and MDR1 mRNA expression levels were also significantly down regulated by 11.33 (p = .012) and 33.59 (p = .006) folds in liver and duodenum, respectively. Down regulation of CYP3A37 and MDR1 mRNA in liver and duodenum indicate the combined pretreatment of piperine and quercetin may be useful for improving the pharmacokinetics of orally administered drugs which are substrates for CYP3A37 and MDR1.

Disposition Kinetic of Moxifloxacin following Intravenous, Intramuscular, and Subcutaneous Administration in Goats.

The present study was carried out to investigate disposition kinetics of moxifloxacin following single-dose intravenous (i.v.), intramuscular (i.m.), and subcutaneous (s.c.) administration at a dose rate of 5 mg/kg of body weight (b.wt.) in goats. Plasma samples collected after treatments were analyzed for drug concentration using high-performance liquid chromatography (HPLC). After i.v. administration, distribution of the drug was rapid and wide as reflected by high steady-state volume of distribution. Drug elimination was relatively faster with a total body clearance of 0.59 ± 0.03 L/h/kg. Following i.m. injection, the drug has shown the rapid and near-to-complete absorption with bioavailability of 98.20 ± 3.96 per cent. The maximum plasma drug concentration (Cmax) of 1.21 ± 0.04 µg/mL was attained at 1 h (Tmax). The drug was widely distributed as reflected by high apparent volume of distribution. The elimination half-life (t 1/2ß ) of the drug was 6.26 ± 0.08 h. Following s.c. administration, the drug was rapidly absorbed (Cmax: 1.16 ± 0.02 µg/mL; tmax: 1 h) and slowly eliminated from the body. The elimination half-life and total body clearance (ClB) were 5.61 ± 0.10 h and 0.60 ± 0.03 L/h/kg, respectively. The bioavailability of moxifloxacin following s.c. administration was 90.44 ± 3.96 per cent.

Effect of moxifloxacin administration on pharmacokinetics of tolfenamic acid in rats

Pharmacokinetics of tolfenamic acid as a single drug (4 mg/kg, intramuscularly) and its co-administration with moxifloxacin (5 mg/kg, intramuscularly) in wistar rats were studied. The plasma drug concentration of tolfenamic acid was assayed by LC-MS/MS. Following intramuscular administration of tolfenamic acid as single drug and in combination with moxifloxacin in male rats, the mean values of observed peak plasma drug concentration (Cmax), area under plasma drug concentration-time curve (AUC(0-¥) ), volume of distribution (Vz), half-life (t½) and clearance (Cl) were 4111.44 ± 493.15 and 3837.69 ± 351.83 ng/ml, 20280.77 ± 3501.67 and 15229.18 ± 678.80 ng.h/ml, 822.17 ± 115.38 and 1249.64 ± 139.52 ml, 2.59 ± 0.16 and 3.27 ± 0.32 hr, and 218.39 ± 25.47 and 265.18 ± 11.36 ml/hr, respectively. The peak plasma drug concentration (Cmax) was significantly higher in female rats compared to male rats. The volume of distribution (Vz) of the drug was significantly higher (P < 0.05) in moxifloxacin-treated male rats compared to female rats. Concomitant administration of moxifloxacin may alter the disposition of tolfenamic acid in male rats.