Toxiocology Unit, Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Anambra State, Nigeria. email@example.com
The effect of bonny-light crude oil was assessed in adult albino rats. The rats were administered with 200, 400, and 800 mg/kg body weight of the crude oil orally for 7 days. Fluid intake was measured daily, initial and final animal body was recorded. The toxic effects on the kidneys were assessed and histological studies carried out. The results revealed that the kidney cells were damaged; crude oil caused a destruction of the renal reserve capacity. There was a significant increase (p ? 0.05) in creatinine in the high dose group (800mg/kg), and a significant decrease (p ? 0.05) in urea concentration. Histological examination indicates that crude oil induced severe pathologic changes in the forms of necrosis and oedema.
Environ Toxicol. 2011 Feb 9;: 21308946
Induction of oxidative stress in liver and kidney of rats exposed to Nigerian bonny light crude oil.
Drug Metabolism and Toxicology Research Laboratories, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Nigeria.
The local population of Niger-Delta in the Southern part of Nigeria have used bonny light crude oil (BLCO) as a remedy for various ailments and are exposed to some extent to this widespread environmental contaminant or its metabolites through the food chain. BLCO's hepatorenal toxicity was studied using oxidative stress indices to elucidate the precise nature and mechanism of action. BLCO was orally administered at concentrations of 0, 200, 400, and 800 mg kg(-1) to adult male rats for 7 days. After exposure, kidney weight was unaffected, but liver weight decreased significantly at 800 mg kg(-1) only compared with control. BLCO exposure resulted in dose-dependent elevation of serum aminotransferases, total bilirubin, urea, and creatinine. Activities of superoxide dismutase and catalase decreased significantly, whereas γ-glutamyltransferase activity and the level of glutathione increased significantly in BLCO-treated animals compared with control in both liver and kidney of rat. Renal activities of glucose-6-phosphatase and 5'-nucleotidase markedly decreased in a dose-dependent manner in BLCO-exposed rats. In addition, the levels of hydrogen peroxide and lipid peroxidation significantly increased, dose dependently, in liver and kidney of BLCO-treated rats compared with control. BLCO-treated rats showed marked degeneration of kidney evident in cortical hemorrhages, tubular necrosis, protein casts, and cellular infiltration. However, no treatment-related liver histopathology was observed. The results suggested that BLCO elicits disruption of antioxidant status and concomitant elevation of hydrogen peroxide and lipid peroxidation differentially in liver and kidney of rats. The hepatorenal toxicity of BLCO could be due to induction of oxidative stress in liver and kidney. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2011.
Department of Biochemistry, University of Ibadan, Nigeria. firstname.lastname@example.org
Nigerian Bonny light crude oil (BLCO) is commonly used by the local population in folklore medicine for the management of various forms of gastrointestinal problems and male reproductive capacity. The study investigated the effects of BLCO on the antioxidant systems of the testes and epidydimal sperm in rats by oral exposure to 0, 200, 400 and 800 mg/kg BLCO for 7 days. In testes and sperm, BLCO treatment at all doses significantly (p<0.05) decreased superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST) activities, whereas it markedly increased glucose 6-phosphate dehydrogenase (G6PD) and gamma glutamyl transferase (GGT) activities as well as increased glutathione (GSH), hydrogen peroxide, and malondialdehyde (MDA) levels in all treatment groups. Although epididymal sperm number (ESN), daily spermatozoa production (DSP), and sperm motility were significantly decreased, total sperm abnormalities were significantly increased without affecting sperm viability at all dose levels compared with controls. The adverse effect of BLCO on TSN was noted at the 800 mg/kg dose only. Histopathology results showed treatment-related lesions of the testes characterized by severe congestion of interstitial vessels, decreased germinal epithelium, and increased number of vacuolization. These results suggest that exposure to BLCO, such as its use in ailment management, may promote infertility by altering the function of the testes and sperm, particularly by way of induction of oxidative stress.
Department of Pharmacology and Therapeutics, Mbarara University of Science and Technology, Mbarara, Uganda.
ABSTRACT Vernonia amygdalina possesses several bioactive compounds and is used in traditional medicines of southwestern Uganda, along with other regions. Its analgesic potential has not been investigated thus far. The present study examines the antinociceptive potential of the aqueous leaf extract (50-200 mg/kg) using three models of nociception (acetic acid-induced writhing, formalin test, and tail-flick test), antiplasmodial activity, and toxicology of the extract. The results show the extract significantly inhibits acetic acid-induced writhing and the formalin test in mice but did not give a potent effect in the tail-flick test, suggesting that the extract may have peripheral and central analgesic properties. The extract also exhibited significant antiplasmodial activity in mice against Plasmodium berghei with 73% inhibition in the group that received a dose of 200 mg/kg i.p. daily for 4 days. Toxicology results show no clinical signs of toxicity or adverse toxicological effects in the treated groups, except for a significant decrease in red blood cell count and a dose-dependent increase in serum bilirubin. These changes were within control values based on historical reference ranges at doses of 500-2,000 mg/kg/day for 14 consecutive days as compared to the control. This study supports the traditional use of V. amygdalina as an alternative therapy for malaria and the symptomatic relief of pain usually associated with malaria.
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O E Orisakwe, O J Afonne, N A Ilondu, E Obi, C S Ufearo, P U Agbasi, S O Maduka, C N Orish, V N Orish
Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nnewi, Nigeria.
OBJECTIVE To find the effects of prokinetics, saline cathartics and different charcoal doses on the gastrointestinal transit and residence times of activated charcoal (AC). SETTING Five undergraduate volunteers of College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria, were studied. METHODS After an overnight fast, the volunteers were given 10 g and 20 g AC with and without saline cathartics, in a simple cross-over design in which the subjects served as their own control. In another experiment, the volunteers received 10 g AC and magnesium sulphate, with propantheline (as bromide 15 mg), metoclopramide (as hydrochloride 10 mg), placebo liquid or identical placebo capsule. Gastrointestinal transit and residence times of AC were recorded. RESULTS Increase in the dose of AC significantly (P < 0.05) decreased the transit, but not the residence time of AC. Addition of saline cathartics (Na2SO4 and MgSO4) decreased both the transit and residence times of AC significantly (P < 0.05). Also, administration of propantheline, but not metoclopramide, produced a significant (P < 0.05) decrease in both the transit and residence times of AC. The transit and residence times were statistically (P < 0.05) different in both the magnesium sulphate group, as well as in the placebo liquid and placebo capsule groups. CONCLUSION Cathartic efficiency is enhanced by alteration of gastrointestinal motility with propantheline.
Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi, Anambra State, Nigeria.
The actions and interactions of heavy metals on certain organ functions have been of concern, since occupational exposure to certain metals results in impairment of functions. Studies were carried out to determine the effects of zinc (Zn) and mercury (Hg) on murine liver. CD-1 male mice were administered 4 ppm HgCl2, 800 ppm ZnCl2, 4 ppm HgCl2+800 ppm ZnCl2 or deionized water in their drinking water for 12 weeks. Histological evaluation of the liver confirmed the toxic effects of Hg, as well as the normal morphology of the Zn-exposed animals. A combined treatment of both metals resulted in protection of the Hg-induced liver damage by Zn. The results of this experiment indicate that Hg has a toxic effect on liver, while Zn has a protective action against such toxic effects.
College of Health Sciences, Nnamdi Azikiwe University, P.M.B 5001, Nnewi, Anambra State, Nigeria. email@example.com
Lead, cadmium, nickel and other industrial metals used as part of paint varnishes have been reported to have adverse health implications. An evaluation study on some toxicological effects of occupational exposure to paint, among 25 occupationally exposed artisans and 25 students (control) of Ichi Technical College, Ichi Ekwusigo Local Government Area, Anambra State, Nigeria was carried out. Heavy metals were analysed by atomic absorption spectrophotometry and standard assay procedures were employed for biochemical parameters. The biochemical indices used include serum electrolytes urea, creatinine, alanine (ALT) and aspartate aminotransferases (AST), alkaline phosphatase (ALP), conjugated and total bilirubin. Others include blood lead, serum cadmium and nickel. Our results showed that occupational exposure of humans to paints increased the blood lead (39 +/- 4 microg/dL), serum cadmium (13 +/- 1 microg/dL) and nickel (63 +/- 1 microg/dL), when compared with non-paint factory workers (PFW) lead (17 +/- 4 microg/dL), serum cadmium (9 +/- microg/dL) and nickel (25 +/- 44 microg/dL), significantly at P < 0.05 lower values were observed for serum sodium (138.96 +/- 0.58 mmol/L), bicarbonate (26.88 +/- 0.39 mmol/L), urea (3.15 +/- 0.13 mmol/L) and creatinine (80.48 +/- 1.04 micromol/L) for paints factory workers when compared with non-paint factory workers, sodium (139.84 +/- 0.62 mmol/L), bicarbonate (26.20 +/- 0.22 mmol/L), urea (3.44 +/- 0.11 mmol/L) and creatinine (80.40 +/- 1.55 micromol/L); at P > 0.05. The activities of AST (10.36 +/- 0.58 micro/L), ALT(8.76 +/- 0.47 micro/L) and ALP (47.12 +/- 3.33 micro/L) in PFW were slightly elevated compared with non-PFW. Our result indicates that occupational exposure of humans to heavy metals in paints may have long term deleterious effects on liver and renal functions. In conclusion, it should be noted that occupational exposure to cadmium or lead among PFW, may compromise the liver and renal functions in man.
Acta Pol Pharm. ;59 (3):177-9 12230243
Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi, Anambra State, Nigeria. Connice@infoweb.abs.net
The effects of sodium chloride and sodium citrate on the in vitro adsorption of doxycycline to activated charcoal have been studied. Solutions of doxycycline alone and doxycycline with 7.5 mg/ml cathartic solutions were vortex-mixed for 30 s with different quantities of activated charcoal, incubated for 30 min at 37 degrees C and analyzed for free doxycycline spectrophotometrically at 348 nm. Addition of NaCl had a significant (p<0.05) increase while sodium citrate produced a significant (p<0.05) decrease in the adsorption of doxycycline on activated charcoal. In all, the adsorption doxycycline on activated charcoal obeyed quantity-dependent kinetics.
Toxicology Unit, Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi, Nigeria.
Some plasma pharmacokinetic parameters of isoniazid in the presence of a fluoroquinolone antibacterial agent.
Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, Nigeria.
The effects of ciprofloxacin (CP), a fluoroquinolone antibacterial agent, on the extent of absorption of isoniazid (INH) and on some of its pharmacokinetic parameters were investigated in six healthy female volunteers between the ages of 23 and 32 years. The presence of CP led to increase in the amount of INH and to a slight reduction in its peak plasma concentration (Cmax). There was a 1-hour increase in the time to attain Cmax (tmax) of INH, indicating absorption interaction between the two drugs. This absorption interaction was related to inhibition of cholinergic neurotransmission caused by CP, which is capable of inhibiting gastric motility, leading to a delay in gastric emptying. The rate of elimination (K) and plasma half-life (t1/2) of INH were not significantly affected (P = 0.05). The extent of absorption interaction that may have occurred (based on values of 24-hour values for area under the concentration curve, Cmax, Tmax, K, and t1/2) was considered to be of no therapeutic consequence, and the coadministration of the two drugs may be recommended in clinical practice.
Adsorptive capacity of activated charcoal for rifampicin with and without sodium chloride and sodium citrate.
Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi, Anambra State, Nigeria. firstname.lastname@example.org
The effects of two saline cathartics (sodium chloride and sodium citrate) on the adsorptive capacity of activated charcoal (AC) for rifampicin were studied. Solutions of rifampicin alone and rifampicin with 7.5 mg/ml cathartic solution were vortex-mixed for 30 s with different quantities of AC. These were incubated for 30 min at 37 degrees C and analyzed for free rifampicin spectrophotometrically at 320 nm. The addition of sodium citrate significantly increased (p<0.05) the adsorptive capacity of AC for rifampicin with a resulting decrease in B-50 values at both the therapeutic and simulated toxic doses. Sodium chloride addition reduced the binding of rifampicin to AC at the toxic doses. The adsorption of rifampicin to activated charcoal, both alone and with the two saline cathartics, obeyed quantity-dependent kinetics. AC may be co-administered with sodium citrate in the management of rifampicin overdose.
Toxicology Unit, Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria. Connice@infoweb.abs.net
We investigated the effect of ciprofloxacin on rifampicin pharmacokinetics in five healthy subjects. Each subject received 600 mg rifampicin with 350 mL of water, and in the second phase, each subject received 600 mg rifampicin plus 500 mg ciprofloxacin with 350 mL of water. In each of the two phases, plasma rifampicin levels were measured from 1 to 24 hours. Treatment with ciprofloxacin significantly increased the half-life and also significantly decreased the maximum peak concentration of rifampicin. Area under the curve time for peak plasma concentration and volume of distribution were not significantly affected. In this study, we found that ciprofloxacin increases the half-life and reduces the maximum concentration of rifampicin in humans.
Toxicology Unit, Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Nnewi, Anambra State, Nigeria. Connice@infoweb.abs.net
We investigated the effect of the oral binder-activated charcoal on the excretion of diethylcarbamazine. Six healthy volunteers were given 150 mg diethylcarbamazine with 350 mL water each. One and 2 weeks later, they received 150 mg diethylcarbamazine plus 7.5 and 15 g activated charcoal, respectively, in 350 mL water as a charcoal slurry. Urinary levels of diethylcarbamazine were measured spectrophotometrically from 1 to 72 hours after ingestion in three different periods. Treatment with activated charcoal led to 5.4% urinary recovery of diethylcarbamazine, decreased excretion rate, and a much lower plateau indicator of reduced absorption. Activated charcoal reduces the absorption and urinary excretion rate of diethylcarbamazine by adsorbing it in the gastrointestinal tract.
Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, P.M.B. 5001, Nnewi, Anambra State Nigeria. email@example.com
OBJECTIVES This investigation was set out to determine whether mercury at a very low dose (4ppm) induces testicular damage on murine testis, and if so whether the toxic effects of mercury could be prevented by zinc. STUDY DESIGN One of the following solutions was administered in the drinking water of CD-1 male mice:(1) 4ppm HgCl(2);(2) 800ppm ZnCl(2);(3) 4ppm HgCl(2)+800ppm ZnCl(2); or (4) deionised water; for 12 weeks. At the expiration of the treatment period, animals were sacrificed, testes excised and weighed, and epididymal sperm number taken. The testes were processed for histological examination. RESULTS Both zinc and mercury significantly (p<0.05) decreased the absolute and relative testicular weights, with mercury producing the highest reduction in weight. Mercury reduced significantly (p<0.05) the epididymal sperm number, while zinc and mercury/zinc produced statistically same effect with control on the sperm number. Histological study showed that mercury at the concentration employed produced remarkable degenerative lesions on the testes, as the zinc-treated group showed a normal morphology. Majority of the animals in the mercury/zinc-treated group exhibited complete or partial protection as evidenced by the morphology of the seminiferous tubules. CONCLUSION Zinc prevents mercury-induced testicular damage in mouse. These findings highlight the risks exposure to inorganic mercury might pose to male reproduction of mice, and suggests possible therapy with zinc. Study in humans is therefore advocated.
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Department of Zoology, School of Life Sciences, Khandari Campus, 282002 Agra.
In this study the effect of thiazide diuretic compound on the protein and cholesterol contents in the testes of albino rats as the experimental model. The drug thiazide was administered orally daily for 10,20 and 30 days at the dose of 100mg/kg body weight. Total protein decrease in the testes of rats were evidenced may be due to the side effects of thiazide drug compound which is linked with the hyponatremia and protein metabolism. An elevated level of cholesterol contents observed in thiazide treated rats also revealed that the side effect of drug compound thiazide and also may be due to the stimulation of catecholamine which is stimulated therefore, the biochemical estimation such as protein and cholesterol in the testes after the thiazide treatment determined the effectiveness of diuretic drug compound would provide clinical evidences of their side effects.
Food Chem Toxicol. 2012 Jul 27;: 22847132
Acute oral toxicity of 3-MCPD mono- and di-palmitic esters in Swiss mice and their cytotoxicity in NRK-52E rat kidney cells.
Man Liu, Bo-Yan Gao, Fang Qin, Ping-Ping Wu, Hai-Ming Shi, Wei Luo, Ai-Niu Ma, Yuan-Rong Jiang, Xue-Bing Xu, Liang-Li Lucy Yu
Institute of Food and Nutraceutical Science, Key Lab of Urban Agriculture (South), School of Agriculture & Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
The acute oral toxicity of 1-palmitoyl-3-chloropropanediol (3-MCPD 1-monopalmitate) and 1, 2-bis-palmitoyl-3-chloropropanediol (3-MCPD dipalmitate) in Swiss mice were examined, along with their cytotoxicity in NRK-52E rat kidney cells. LD(50)(median lethal dose) value of 3-MCPD 1-monopalmitate was determined 2676.81 mg/kg body weight (BW). The results showed that 3-MCPD 1-monopalmitate dose-dependently decreased the mean body weight, and caused significant increase of serum urea nitrogen and creatinine in dead mice compared to the control and survived mice. Major histopathological changes in mice fed 3-MCPD 1-monopalmitate were renal tubular necrosis, protein casts and spermatids decrease in the seminiferous tubules. According to the limit test for 3-MCPD dipalmitate, LD(50) value of 3-MCPD dipalmitate was presumed to be greater than 5000 mg/kg BW. Obvious changes were not observed on mean body weight, absolute and relative organ weight or serum urea nitrogen and creatinine levels in mice fed 3-MCPD dipalmitate. However, renal tubular necrosis, protein casts and spermatids decrease were also observed in the dead mice. In addition, MTT and LDH assay results only showed the cytotoxicity of 3-MCPD 1-monopalmitate in NRK-52E rat kidney cells in a dose-dependent manner. Together, the results indicated a greater toxicity of 3-MCPD 1-monopalmitate compared to 3-MCPD dipalmitate.
Toxicol Int. 2012 Jan ;19 (1):35-41 22736901
Department of Rasashastra, J. B. Roy State Ayurvedic Medical College and Hospital, Kolkata, India.
Aconite is one of the poisonous plants used therapeutically in practice of Ayurveda after proper treatment called as 'Shodhana'. To determine the effect of Shodhana treatment on chronic toxicity and to assess the effect of recovery period after chronic toxicity of aconite. Raw aconite (RV), urine treated aconite (SM), and milk treated aconite (SD) were administered in 6.25 mg/kg dose in Charles Foster strain albino rats for 90 days for chronic toxicity. Six rats from each were kept for another 30 days without test drugs treatment to observe recovery from chronic toxicity. RV was found to be highly toxic in chronic exposure, SM had no apparent toxicity, but SD had mild toxicity in kidney. The toxicities of RV and SD were reversible, but sudden withdrawal of SM caused adverse effects, suggestive of tapering withdrawal. Shodhana treatments remove toxic effects from raw aconite. Chronic toxicity of aconite is reversible. Confirmed the arrangement of abstract.
Effect of aqueous extract of cochlospermum planchonii rhizome on some kidney and liver functional indicies of albino rats.
Department of Biochemistry, University of Ilorin, Ilorin, Nigeria.
Aqueous extract of Cochlospermum planchonii Hook. Ef. x Planch rhizome was investigated for its toxic effects in albino rats using some liver and kidney functional indices as 'markers'. Thirty six albino rats weighing 200.08 ± 10.21 were randomly assinged into six groups (A-F) of six animals each. Animals in groups A-E were orally administered on daily basis with 1 ml of the extract corresponding to 50 mg/kg body weight of the extract for 1, 3, 5, 10 and 15 days while those in the control group received orally 1 ml of distilled water. Rats in all the groups were sacrificed 24 hours after the completion of their respective doses. The extract significantly (P<0.05) decreased alkaline phosphatase (ALP) activities in the liver leading to 80.95% loss by the end of the experimental period. While there was no consistent pattern in the kidney ALP activity and serum bilirubin level, the serum enzyme compared well (P>0.05) with the control value. There was no effect (P>0.05) on the acid phosphatase activity of the tissues and serum of the animals. The extract also reduced the urea, albumin and creatinine content in the serum of the animals. The alterations in the biochemical parameters by the aqueous extract of Cochlospermum planchoni may have consequential effects on the normal functioning of the liver and kidney of the animals. Therefore, the 50 mg/kg body weight of the aqueous extract of Cochlospermum planchoni rhizome may not be completley safe as an oral remedy.
Differential effects of alprazolam and clonazepam on the immune system and blood vessels of non-stressed and stressed adult male albino rats.
Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Egypt.
Benzodiazepines belongs to one of the most commonly used anxiolytic and anticonvulsant drugs in the world. Full description of toxic effects on different organs is lacking for nearly all the current benzodiazepines. The aim of the current work was to study the immunologic and vascular changes induced by sub-chronic administration of alprazolam and clonazepam in non-stressed and stressed adult male albino rats. Forty-two adult male albino rats were divided into 6 groups (I):(Ia) Negative control rats,(Ib): Positive control rats received distilled water,(II): Stressed rats,(III): Non-stressed rats received daily oral dose of clonazepam (0.5 mg/kg),(IV): Stressed rats received daily oral dose of clonazepam (0.5 mg/kg),(V): Non-stressed rats received daily oral dose of alprazolam (0.3 mg/kg).(VI): Stressed rats received daily oral dose of alprazolam (0.3 mg/kg). At the end of the 4th week, total leukocyte count (WBCs) and differential count were determined, anti-sheep RBC antibody (Anti-SRBC) titer and interleukin-2 (IL-2) level were assessed, thymus glands, lymph nodes, spleens and abdominal aortae were submitted to histopathological examination. Alprazolam was found to induce a significant increase in neutrophil count and a significant decrease in lymphocytes, anti-SRBC titer and IL-2 level with severe depletion of the splenic, thymal and nodal lymphocytes, accompanied by congestion and eosinophilic vasculitis of all organs tested in comparison to clonazepam treated rats. Stress enhanced the toxic effects. It was concluded that the immune system and blood vessels can be adversely affected to a greater extent by short-term chronic administration of alprazolam than by clonazepam, and these toxic effects are aggravated by stress.
Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA. firstname.lastname@example.org
Suboptimal kidney development resulting from a genetic deficit in nephron number can have lifelong consequences that may lead to cardiorenal complications upon exposure to secondary insults in later life. To determine whether the inherited reduced renal reserve compromises the ability to handle osmotic stress in the adult animal, we challenged the heterozygous 3H1 Brachyrrhine (Br/+) mouse, which displays heritable renal hypoplasia associated with reduced embryonic six2 expression, to a solution of 2% NaCl for 5 days or to fluid restriction for 48 h. Blood chemistry, fluid intake, and physiological parameters, including renal measurements, were determined. Systemic hypertonicity by prolonged salt loading led to significant increases in plasma osmolality and plasma Na(+), along with polydipsia and polyuria, with a significant urine-concentrating defect that was resistant to DDAVP treatment in the adult Br/+ mouse compared with wild-type littermates. The Br/+ mouse also developed a significant increase in blood urea nitrogen at baseline that was further elevated when 2% NaCl was given. Fluid restriction for 48 h further enhanced plasma osmolality and plasma Na(+) responses, although the Br/+ mouse was evidently able to produce a small amount of concentrated urine at this time. Hypothalamic c-Fos expression was appropriately activated in the Br/+ mouse in response to both osmotic challenges, indicating an intact central neuroendocrine pathway that was not affected by the lack of congenital six2 expression. Collectively, our results demonstrate impaired osmoregulatory mechanisms consistent with chronic renal failure in the Br/+ mouse and indicate that six2 haploinsufficiency has a direct effect on postnatal fluid and electrolyte handling associated with fluid imbalance.
Comparative nephrotoxicitiy induced by melamine, cyanuric acid, or a mixture of both chemicals in either Sprague-Dawley rats or renal cell lines.
Lan Choi, Min Young Kwak, Eun Hwa Kwak, Dong Hyun Kim, Eun Young Han, Taehyun Roh, Jung Yun Bae, Il Young Ahn, Jea Yeon Jung, Mi Jung Kwon, Dong Eun Jang, Seong Kwang Lim, Seung Jun Kwack, Soon Young Han, Tae Seok Kang, Seung Hee Kim, Hyung Sik Kim, Byung Mu Lee
Division of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-Do, Korea.
Acute nephrotoxicities of melamine (MEL), cyanuric acid (CA), and a mixture of both melamine and cyanuric acid (MC) were comparatively investigated in male Sprague-Dawley rats at 5 doses each with 10-fold dose interval as follows: MEL at 0.0315, 0.315, 3.15, 31.5, and 315 mg/kg; CA at 0.025, 0.25, 2.5, 25, and 250 mg/kg, and MC:[1×:(0.0315 + 0.025), 10×:(0.315 + 0.25), 100×:(3.15 + 2.5), 1000×:(31.5 + 25), and (315 + 250) mg/kg]. No marked adverse effects in renal function were observed in animals treated with MEL alone or CA alone, but evidence related to nephrotoxicity was noted in rats administered MC. Renal calculi and increased kidney weights were found in rats 7 d after daily oral administration of MC. Blood urea nitrogen (BUN) and creatinine were significantly elevated in the high dose MC groups at 100× or 1000×. In addition, elevated numbers of white blood cells (WBC), neutrophils, and lymphocytes in vivo and increased levels of prostaglandin E(2)(PGE(2)) in vitro were found in the MC group. Based on these data, the NOAEL (no-observed-adverse-effect level) for nephrotoxicity for MC was estimated to be 3.15 mg/kg body weight (bw)/d (MEL) plus 2.5 mg/kg bw/d (CA). If a safety factor of 1000 or more were applied to NOAEL, tolerable daily intake (TDI) would be 0.00315 and 0.0025 mg/kg/d or less for MEL and CA, respectively, which is far below the TDI of 0.2 mg/kg/d set by World Health Organization (WHO). In addition, in vitro cytotoxicity assays showed that the ACHN human renal adenocarcinoma cell line was more sensitive to MEL, CA, and MC than the MDCK canine kidney epithelial cell line. The 24-h half maximal inhibitory concentration (IC(50)) values for MEL (4792, 2792 μg/ml) were less than those of CA (9890, 6725 μg/ml, respectively) in MDCK and ACHN cell lines, suggesting that MEL may be more cytotoxic than CA. Furthermore, the 24-h IC(50) value for MC was found to be 208 μg/ml in ACHN cells. Data suggest that NOAELs based upon acute nephrotoxic parameters for MC were low, which might require further reassessment of the current TDI.
Potential estrogenic effect(s) of parabens at the prepubertal stage of a postnatal female rat model.
Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
In this study, a female pubertal assay on the effects of parabens, including methyl-, ethyl-, propyl-, isopropyl-, butyl-, and isobutylparaben, was performed in a female Sprague-Dawley rat model during the juvenile-peripubertal period. The rats were orally treated with these parabens from postnatal day 21 to 40 in a dose-dependent manner (62.5, 250 and 1,000mg/kg body weight [BW]/day). 17alpha- ethinylestradiol (1mg/kg BW/day) was used as a positive control and corn oil as a vehicle. A high dose of methyl- and isopropylparaben (1,000mg/kg BW/day) resulted in a significant delay in the date of vaginal opening and a decrease in length of the estrous cycle. In measurements of organ weight and body weight, we observed significant weight changes in ovaries, adrenal glands, thyroid glands, liver, and kidneys; conversely, body weight was not altered following paraben treatment. The potential effects of parabens on estrogenicity were shown in histopathological abnormities in the reproductive organs. Histological analysis of the ovaries from the peripubertal rats revealed a decrease of corpora lutea, increase in the number of cystic follicles, and thinning of the follicular epithelium. In addition, morphological studies of the uterus revealed the myometrial hypertrophy by a high dose of propyl- and isopropylparaben (1,000mg/kg/day), and in all dose groups of butyl- and isobutylparabens. However, no significant histopathological changes were observed in the other organs (i.e. adrenal and thyroid glands). We also observed a significant decrease in serum estradiol and thyroxine concentrations in methyl-, ethyl-, propyl-, isopropyl-, and isobutylparaben-treated groups. A receptor-binding assay indicated that the relative binding affinities of parabens to estrogen receptors occurred in the order: isobutylparaben>butylparaben>isopropylparaben=propylparaben>ethylparaben. These values were much lower than the binding affinity for 17beta-estradiol. Taken together, long-term exposure to parabens, which show less estrogenic activity than estradiol, can produce suppressive effects on hormonal responsiveness and can disrupt the morphology of reproductive target tissues. In addition, the relation between thyroid weight and thyroid hormone may influence circulating levels of parabens, suggesting the effects of parabens as thyrotoxic during this critical stage of development in female rats.
Differential developmental toxicities of di-n-hexyl phthalate and dicyclohexyl phthalate administered orally to rats.
The objective of this study was to evaluate the developmental toxic potential of di-n-hexyl phthalate (DnHP) and dicyclohexyl phthalate (DCHP) in rats. Pregnant Sprague-Dawley rats were exposed to DnHP or DCHP at doses of 0 (olive oil), 250, 500 and 750 mg kg(-1) per day, by gavage, on gestational days (GD) 6-20. Maternal food consumption and body weight gain were significantly reduced at 750 mg kg(-1) per day of DnHP and at the two high doses of DCHP. Slight changes in liver weight associated with peroxisomal enzyme induction were seen in dams treated with DnHP or DCHP. DnHP caused dose-related developmental toxic effects, including marked embryo mortality at 750 mg kg(-1) per day, and presence of malformations (mainly cleft palate, eye defects and axial skeleton abnormalities) and significant decreases in fetal weight at 500 and 750 mg kg(-1) per day. Significant delay of ossification and increase in the incidence of skeletal variants (e.g. supernumerary lumbar ribs) also appeared at 250 mg kg(-1) per day. DCHP produced fetal growth retardation at 750 mg kg(-1) per day, as evidenced by significant reduction of fetal weight. DnHP and DCHP induced a significant and dose-related decrease in the anogenital distance of male fetuses at all doses, and there was a significant increase in the incidence of male fetuses with undescended testis at 500 and 750 mg kg(-1) per day of DnHP. In conclusion, DnHP showed clear embryolethality and teratogenicity, but not DCHP. There was evidence that both phthalates could alter the development of the male reproductive system after in utero exposure, DnHP being much more potent than DCHP. Copyright (c) 2009 John Wiley & Sons, Ltd.
Sublethal effects of subacute exposure to RDX (1,3,5-trinitro-1,3,5-triazine) in the northern bobwhite (Colinus virginianus).
Michael J Quinn Jr, Matthew A Bazar, Craig A McFarland, Edward J Perkins, Kurt A Gust, Mark S Johnson
U.S. Army Center for Health Promotion and Preventive Medicine, Health Effects Research Program, Aberdeen Proving Ground, Maryland 21010, USA. email@example.com
Northern bobwhite (Colinus virginianus) were orally exposed via gavage to 0, 0.5, 3, 8, 12, or 17 mg/kg of RDX (1,3,5-trinitro-1,3,5-triazine) in corn oil daily for 14 d to evaluate sublethal effects of this explosive in birds. Mortality occurred at a rates of 100, 67, and 25% for the 17, 12, and 8 mg/kg/d dose groups, respectively. Death was preceded by clonic and tonic convulsions and weight loss caused by gastrointestinal effects. Increases in serum globulin and total leukocytes were observed in the two highest-dose groups. Degeneration of testicular and splenic tissue also was observed. The no-observed-adverse-effects and lowest-observed-adverse-effects levels were determined as 3.0 and 8.0 mg/kg/d, respectively.