Disposition of diiosononyl phthalate and its effects on sexual development of the male fetus following repeated dosing in pregnant rats

Pregnant Sprague-Dawley rats received 50, 250, and 500 mg/kg/day diisononyl phthalate (DiNP) from GD 12 to 19 via corn oil gavage to study the dose response for effects on fetal male rat sexual development as well as metabolite disposition in the dam and fetus. Monoisononyl phthalate (MiNP), mono(carboxy-isooctyl) phthalate (MCiOP), mono(hydroxyl-isononyl) phthalate (MHiNP), mono(oxo-isononyl) phthalate (MOiNP), and monoisononyl phthalate glucuronide (MiNP-G) were found in all measured tissues. MCiOP was the major metabolite, followed in decreasing order by MiNP, MHiNP, MOiNP, and MiNP-G. Percentage of dose absorbed decreased at 750 mg/kg/day. Testosterone concentration in the fetal testes was reduced at 250 and 750 mg/kg/day. Multinucleated germ cells were increased in the testes of rats at 250 and 750 mg/kg/day. The no observed effect level (NOEL) for this study was 50 mg/kg/day based on increased MNGs and reduced testes testosterone concentration in the fetal rat.     

Kinetics of selected di-n-butyl phthalate metabolites and fetal testosterone following repeated and single administration in pregnant rats

Human exposure to phthalic acid diesters occurs through a variety of pathways as a result of their widespread use in consumer products and plastics. Repeated doses of di-n-butyl phthalate (DBP) from gestation day (GD) 12 to 19 disrupt testosterone synthesis and male sexual development in the fetal rat. Currently little is known about the disposition of DBP metabolites, such as monobutyl phthalate (MBP) and its glucuronide conjugate (MBP-G), during gestation after repeated exposure to DBP. In order to gain a better understanding of the effect of repeated dosing on maternal and fetal metabolism and distribution, pregnant Sprague–Dawley rats were given a single dose of 500 mg/kg DBP on GD 19 or daily doses of 50, 100, and 500 mg/(kg day) from GD 12 to 19 via corn oil gavage. Dose–response evaluation revealed a non-linear increase in maternal and fetal plasma concentrations of MBP. Maternal and fetal MBP levels were slightly lower in animals after 8 days of dosing at 500 mg/(kg day). Fetal plasma MBP levels closely followed maternal plasma, while the appearance and elimination of MBP-G in fetal plasma were significantly delayed. MBP-G accumulated over time in the amniotic fluid. Inhibition of testosterone was rapid in fetal testes when exposed to DBP (500 mg/(kg day)) on GD 19. Within 24 h, the level of inhibition in the fetus was similar between animals exposed to a single or multiple daily doses of 500 mg/(kg day). Examination of testosterone time-course data indicates a rapid recovery to normal levels within 24 h post-dosing at DBP doses of 50 and 100 mg/(kg day), with a rebound to higher than normal concentrations at later time-points. MBP kinetics in fetal testes allows direct comparison of active metabolite concentrations and testosterone response in the fetal testes.     

Taiwan food scandal: The illegal use of phthalates as a clouding agent and their contribution to maternal exposure

In 2011 the Taiwan Food and Drug Administration reported that plasticizers di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP), endocrine disruptors, were illegally added to clouding agents used in foods and beverages. 965 products were found contaminated, of which 206 were exported to 22 countries. This study’s purpose was to obtain English names for 28 contaminated products for which DEHP levels were reported, calculate estimated average daily intake (mg/kg/day) for a 50 kg woman consuming one portion, and compare to U.S. and E.U. guidelines for daily intake. We found that drinking just one bottle (500 ml) of sports drinks would result in an average DEHP intake of 0.14 mg/kg bw/day (range 0.091–0.341), which exceeds by several fold government guidelines (0.02–0.06 mg/kg bw/day). One (2 g) serving from 4/14 samples of contaminated dietary supplements exceeds the guideline of 0.02 mg/kg bw/day. In conclusion, consuming even one portion of tainted drinks and some powders would lead to daily intake of DEHP that greatly exceeds established safety guidelines, raising concerns about potential adverse effects, particularly reproductive tract development in the male fetus. Global distribution of DEHP-contaminated and other adulterated products should prompt governments to become proactive in food safety regulations and chemical testing.     

Possible involvement of nitric oxide mechanism in the neuroprotective effect of rutin against immobilization stress induced anxiety like behaviour,oxidative damage in mice

Dietary supplements are widely used to manage stress and related consequences. However, the exact pathological mechanism and cellular cascades involved in the action of these supplements are not properly understood so far. Therefore, the present study has been designed to explore the neuroprotective mechanism of rutin against immobilization stress-induced anxiety-like behavioural and oxidative damage in mice. Laboratory Animal Centre A-strain (laca) mice were used in the present study. Rutin (20, 40, and 80 mg/kg), l-arginine (100 mg/kg), l-nitroarginine methyl ester (l-NAME) (5 mg/kg) and vitamin-E (50 mg/kg) were administered for 5 days before 6 h immobilization stress on 6th day. Various behavioural parameters (mirror chamber test, locomotor activity) followed by biochemical parameters (lipid peroxidation, nitrite concentration, reduced glutathione and catalase) in brain and then serum corticosterone level were assessed. 6 h immobilization stress produced anxiety-like behavioural in mirror chamber test, raised corticosterone level and oxidative stress (as evidenced by rise in lipid peroxidation, nitrite concentration, depletion of reduced glutathione and catalase activity) significantly as compared to naive group. 5 days pre-treatment with rutin (40 and 80 mg/kg) causes a significant attenuation of locomotor activity, corticosterone level, oxidative stress as compared to control. Further, l-arginine (100 mg/kg) pre-treatment significantly reversed the protective effect of rutin (40 mg/kg) in 6 h immobilized animals. However, l-NAME (5 mg/kg) pre-treatment with rutin (40 mg/kg) potentiated their protective effect which was significant as compared to their effect per se. The present study suggests the involvement of nitric oxide mechanism in the neuroprotective effect of rutin against immobilization stress-induced anxiety-like behaviour and oxidative damage in mice.     

l-Theanine alleviates the neuropathological changes induced by PCB (Aroclor 1254) via inhibiting upregulation of inflammatory cytokines and oxidative stress in rat brain

The present study is aimed at evaluating the protective role of l-theanine on aroclor 1254-induced oxidative stress in rat brain. Intraperitoneal administration of Aroclor 1254 (2 mg/kg b.wt. for 30 days) caused oxidative stress in rat brain and also caused neurobehavioral changes. Oxidative stress was assessed by determining the levels of lipid peroxide (LPO), protein carbonyl content, and changes in activities of creatine kinase (CK), acetylcholinesterase (AchE), and ATPases in the hippocampus, cerebellum and cerebral cortex of control and experimental rats. Histopathological results showed that PCB caused neuronal loss in all three regions. PCB upregulated the mRNA expressions of inflammatory cytokines. Oral administration of l-theanine (200 mg/kg b.wt.) increased the status of antioxidants, decreased the levels of LPO, nitric oxide (NO) and increased the activities of CK, AchE and ATPases. l-Theanine restored normal architecture of brain regions and downregulated the expression of inflammatory cytokines. In conclusion, l-theanine shows a protective role against PCBs-induced oxidative damage in rat brain.     

Effect of dibutyl phthalate on expression of connexin 43 and testosterone production of leydig cells in adult rats

To investigate the adverse effect of dibutyl phthalate (DBP) on Leydig cells and its mechanism related to gap junction, Leydig cells isolated from adult rats were treated with 0.1% dimethylsulfoxide (DMSO), 50 mg/L DBP, 50 mg/L DBP + 10 μM prostaglandin E2 (PGE2) and 40 μM flutamide respectively. Radioimmunoassay, semi-quantitative RT-PCR, immunofluorescence and Western blot were applied to determine the expression of testosterone and Connexin 43 (Cx43) in Leydig cells. The expression of testosterone and Cx43 were both decreased in DBP group (P < 0.05). While Cx43 was up-regulated after administered to PGE2, there was no significant change in testosterone. However, testosterone was down-regulated with a significant decrease of Cx43 in flutamide group. The results indicated that the inhibitory effect of DBP on testosterone production was not through the down-regulation of Cx43. On the contrary, the change of testosterone can influence the expression of Cx43 in Leydig cells.     

Short term exposure to di-n-butyl phthalate (DBP) disrupts ovarian function in young CD-1 mice

Di-n-butyl phthalate (DBP) is present in many beauty and medical products. Human exposure estimates range from 0.007–0.01 mg/kg/day in the general population and up to 0.233 mg/kg/day in patients taking DBP-coated medications. Levels of phthalates tend to be higher in women, thus, evaluating ovarian effects of DBP exposure is of great importance. Mice were given corn oil (vehicle) or DBP at 0.01, 0.1, and 1000 mg/kg/day (high dose) for 10 days to test whether DBP causes ovarian toxicity. Estrous cyclicity, steroidogenesis, ovarian morphology, and apoptosis and steroidogenesis gene expression were evaluated. DBP exposure decreased serum E₂ at all doses, while 0.1DBP increased FSH, decreased antral follicle numbers, and increased mRNA encoding pro-apoptotic genes (Bax, Bad, Bid). Interestingly, mRNAs encoding the steroidogenic enzymes Hsd17b1, Cyp17a1 and Cyp19a1 were increased in all DBP-treated groups. These novel findings show that DBP can disrupt ovarian function in mice at doses relevant to humans.     

Effects of maternal exposure to di-n-butyl phthalate during pregnancy and breastfeeding on ovarian development and function of F1 female rats

This study aimed to investigate the effects of maternal exposure to di-n-butyl phthalate (DBP) during pregnancy and breastfeeding on F1 ovarian development and function. A rat model of maternal exposure to DBP during pregnancy and breastfeeding was established by gavage feeding female Sprague Dawley rats with 0, 10, 100, or 600 mg/kg/day DBP from gestational day (GD) 12 to postnatal day (PND) 21. F1 offspring were weaned on PND21 and were not exposed to DBP afterward. The age of vaginal opening and estrus onset, estrous cyclicity, c-Kit-ligand expression on ovarian granulosa cells, and the weight of ovaries and uterus of F1 female offspring were not affected, whereas serum levels of estradiol and progesterone were increased significantly by maternal exposure to 10 mg/kg/day DBP from GD12 to PND21. Although F1 ovarian function may not be adversely affected by maternal exposure to DBP, the increased reproductive hormone levels may interfere in F1 rat fertility.     

Identification of gene expression changes in postnatal rat foreskin after in utero anti-androgen exposure

In utero human phthalate exposure has been associated with male reproductive disorders in epidemiological studies, but discovering relationships is hindered by the lack of identifying markers. This study identified gene expression changes following in utero dibutyl phthalate (DBP) and flutamide exposures in Sprague-Dawley rat foreskin. Dams were exposed to 100 or 500 mg/kg/day dibutyl phthalate or 5 mg/kg/day flutamide from gestational days 16–20. Microarray analysis was performed on foreskin tissue from gestational day 20 and postnatal day 5. Expression changes found following DBP exposure were not present following flutamide treatment, indicating that expression changes were specific to DBP exposure and not caused by altered androgen signaling. Genes that were expressed at lower levels in tissue from pups treated with the low dose of DBP were reduced more in pups treated with the high dose of DBP, demonstrating a dose response effect of this compound. Changes in expression of Marcks, Pum1, Nupr1, and Penk caused by in utero phthalate exposure were confirmed by qRT-PCR. Changes in expression of these genes were maintained after birth and consequently their expression could serve as markers of chemical exposure and biological response.     

Taurine mitigates cognitive impairment induced by chronic co-exposure of male Wistar rats to chlorpyrifos and lead acetate

Organophosphate pesticides and heavy metals are ubiquitous environmental pollutants and neurotoxicants. We investigated the effects of taurine (an antioxidant; TA) on oxidative stress and cognition in male Wistar rats co-treated with chlorpyrifos (an organophosphate pesticide; CPF) and lead acetate (heavy metal; LA). The Wistar rats were divided into 5 groups of 10 rats each. The first two groups were administered with distilled water and soya oil respectively. The remaining three groups were administered with taurine (TA), 50 mg/kg body weight, CPF + LA group [CPF (4.25 mg/kg, 1/20 LD50] and LA (233.25 mg/kg, 1/20 LD50) and TA + CPF + LA group [TA (50 mg/kg), CPF (4.25 mg/kg) and LA (233.25 mg/kg)]. The xenobiotics were administered once daily by oral gavage for 16 weeks. The results showed reductions in the activities of brain antioxidant enzymes and acetylcholinesterase, increased lipoperoxidation and histopathological alterations of the cerebral cortex in the CPF + LA group. However, TA mitigated perturbations in the activities of the antioxidant enzymes and acetylcholinesterase, counteracted oxidative stress and brain lipoperoxidation and attenuated neuronal degeneration induced by joint CPF and LA-induced neurotoxicity. The results suggested that TA is neuroprotective following chronic co-exposure of rats to CPF and LA.     

Trolox ameliorates 3-nitropropionic acid-induced neurotoxicity in rats

3-nitropropionic acid (3-NPA) is a naturally occurring neurotoxin produced by legumes of the genus Astragalus and Arthrium fungi. Acute exposure to 3-NPA results in striatal astrocytic death and variety of behavior dysfunction in rats. Oxidative stress has been reported to play an important role in 3-NPA-induced neurotoxicity. Trolox is a potent free radical chain breaking antioxidant which has been shown to restore structure and function of the nervous system following oxidative stress. This rapid and efficient antioxidant property of trolox was attributed to its enhanced water solubility as compared with alpha-tocopherol. This investigation was aimed to study the effect of trolox against 3-NPA-induced neurotoxicity in female Wistar rats. The animals received trolox (0, 40 mg, 80 mg and 160 mg/kg, orally) daily for 7 days. 3-NPA (25 mg/kg, i.p.) was administered daily 30 min after trolox for the same duration. One additional group of rats served as control (vehicle only). On day 8, the animals were observed for neurobehavioral performance. Immediately after behavioral studies, the animal's brains were dissected out for histological studies. Lesions in the striatal dopaminergic neurons were assessed by immunohistochemical method using tyrosine hydroxylase immunostaining. Administration of 3-NPA alone caused significant depletion of striatal dopamine and glutathione, whereas, the levels of thiobarbituric acid reactive substance (TBARS) and nitric oxide (NO) were significantly increased suggesting an elevated level of oxidative stress. Trolox significantly and dose-dependently protected animals against 3-NPA-induced neurobehavioral, neurochemical and structural abnormalities. These results clearly suggest that protective effect of trolox against 3-NPA-induced neurotoxicity is mediated through its free radical scavenging activity.     

A dose response study to assess effects after dietary administration of diisononyl phthalate (DINP) in gestation and lactation on male rat sexual development

Male rat sexual development was evaluated after dietary administration of 0, 760, 3800, 11,400 ppm diisononyl phthalate (DiNP) and 7600 ppm dibutyl phthalate (DBP) from gestation day (GD) 12 to postnatal day (PND) 14. Maternal weight was reduced on GD 20, PND 2 and 14 at 11,400 ppm DiNP. Pup weight was reduced on PND 2 and 14 at 11,400 and 3800 ppm DiNP. DBP induced multinucleated germ cells (MNGs) and Leydig cell aggregates (LCAs) in PND 2 testes. 7600 ppm DBP reduced anogenital distance (AGD) on PND 2 and 14, and increased nipple retention and reproductive tract malformations on PND 49. DiNP induced MNGs (3800 ppm) and LCAs (11,400 ppm) on PND 2, and reduced AGD (11,400 ppm) on PND 14. DiNP did not alter AGD, nipple retention or reproductive tract malformations on PND 49. Global endpoint analysis showed no evidence of a rat “phthalate syndrome” on PND 49 with DiNP administration.     

Protective effect of HMG CoA reductase inhibitors against running wheel activity induced fatigue,anxiety like behavior,oxidative stress and mitochondrial dysfunction in mice

BackgroundChronic fatigue stress (CFS) is an important health problem with unknown causes and unsatisfactory prevention strategies, often characterized by long-lasting and debilitating fatigue, myalgia, impairment of neuro-cognitive functions along with other common symptoms. The present study has been designed to explore the protective effect of statins against running wheel activity induced fatigue anxiety.MethodsMale albino Laca mice (20–30 g) were subjected to swim stress induced fatigue in a running wheel activity apparatus. Atorvastatin (10, 20 mg/kg, po) and fluvastatin (5, 10 mg/kg, po) were administered daily for 21 days, one hour prior to the animals being subjected to running wheel activity test session of 6 min. Various behavioral tests (running wheel activity, locomotor activity and elevated plus maze test), biochemical parameters (lipid peroxidation, nitrite concentration, glutathione levels and catalase activity) and mitochondrial complex enzyme dysfunctions (complex I, II, III and IV) were subsequently assessed.ResultsAnimals exposed to 6 min test session on running wheel for 21 days showed a significant decrease in number of wheel rotations per 6 min indicating fatigue stress like behavior. Treatment with atorvastatin (10 and 20 mg/kg) and fluvastatin (10 mg/kg) for 21 days significantly improved the behavioral alterations [increased number of wheel rotations and locomotor activity, and anxiety like behavior (decreased number of entries and time spent in open arm)], oxidative defence and mitochondrial complex enzyme activities in brain.ConclusionPresent study suggests the protective role of statins against chronic fatigue induced behavioral, biochemical and mito-chondrial dysfunctions.     

Alpha-lipoic acid protects oxidative stress,changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats

We investigated protective efficacy of α-lipoic acid (LA), an antioxidant against arsenic and DDVP co-exposed rats. Biochemical variables suggestive of oxidative stress, neurological dysfunction, and tissue histopathological alterations were determined. Male rats were exposed either to 50 ppm sodium arsenite in drinking water or in combination with DDVP (4 mg/kg, subcutaneously) for 10 weeks. α-Lipoic acid (50 mg/kg, pos) was also co-administered in above groups. Arsenic exposure led to significant oxidative stress along, hepatotoxicity, hematotoxicity and altered brain biogenic amines levels accompanied by increased arsenic accumulation in blood and tissues. These altered biochemical variables were supported by histopathological examinations leading to oxidative stress and cell death. These biochemical alterations were significantly restored by co-administration of α-lipoic acid with arsenic and DDVP alone and concomitantly. The results indicate that arsenic and DDVP induced oxidative stress and cholinergic dysfunction can be significantly protected by the supplementation of α-lipoic acid.     

Oxidative damage induced by chlorpyrifos in the hepatic and renal tissue of Kunming mice and the antioxidant role of vitamin E

Chlorpyrifos is a broad-spectrum, chlorinated organophosphate pesticide employed for pest control in various agricultural and animal husbandries. Acute and chronic exposure to CPF can elicit several adverse effects, including oxidative stress. We investigated neurotoxicity of CPF-treated mice, and evaluated the antioxidant effect of vitamin E against oxidative stress and histological changes in the livers and kidneys of CPF-treated mice. Kunming mice were divided randomly into five exposure groups of six: (A) peanut oil; (B) 3 mg/kg CPF; (C) 6 mg/kg CPF; (D) 12 mg/kg CPF; (E) vitamin E (100 mg/kg), 3 h after administration of CPF (12 mg/kg) and used as a post-treatment group. Oral administration of high-dose groups (12 mg/kg) CPF led to a significant increase in levels of reactive oxygen species, DNA–protein crosslinks, 8-hydroxy-2-deoxyguanosine and malondialdehyde, decreases in acetylcholinesterase activity and glutathione level, as well as causing hepatic and renal histopathological change. Except for AChE activity levels, administration of vitamin E to CPF-treated mice restored these biochemical parameters to within normal levels, and resulted in overall improvement in damage to livers and kidneys. These data suggest that oxidative stress is involved in CPF-induced toxicity and that vitamin E can protect against the tissue damage induced by CPF.     

Phenolic acid protects of renal damage induced by ochratoxin A in a 28-days-oral treatment in rats

The present study aimed to characterize the chlorogenic acid (ChlA) capacity to reverse the toxic effects induced by ochratoxin A (OTA) in a subacute toxicity test in rats. Male Wistar rats were fed orally by gavage for 28 days with OTA (0.4 mg/kg bw/day), ChlA (5 mg/kg bw/day) or the combination OTA (0.4 mg/kg bw/day) + ChlA (5 mg/kg bw/day). No deaths, no decrease in feed intake or body weight in any experimental group were recorded. The negative control group and the animals treated with ChlA alone showed no changes in any parameters evaluated. In OTA-treated group significant changes such as decrease in urine volume, proteinuria, occult blood, increase in serum creatinine values; decrease in absolute and relative kidney weight and characteristics histopathological lesions that indicated kidney damage were observed. However, limited effect on oxidative stress parameters were detected in kidneys of OTA-treated group. Animals treated with the combination OTA + ChlA were showed as negative control group in the evaluation of several parameters of toxicity. In conclusion, ChlA, at given concentration, improved biochemical parameters altered in urine and serum and pathological damages in kidneys induced by OTA exposure, showing a good protective activity, but not by an apparent antioxidant mechanism.     

Tissue-specific induction of oxidative stress in goldfish by 2,4-dichlorophenoxyacetic acid: Mild in brain and moderate in liver and kidney

This study investigated the effects of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) on free radical-related processes in tissues of goldfish given 96 h exposures to 1, 10 or 100 mg/L of 2,4-D as well as 96 h recovery from the 100 mg/L treatment. In liver, 2,4-D exposure increased levels of protein carbonyls and lipid peroxides by 36–53% and 24–43%, respectively, but both parameters reverted during recovery, whereas in brain glutathione status improved in response to 2,4-D. Lipid peroxide content in kidney was enhanced by 40–43% after exposure to 2,4-D with a decrease during recovery. Exposure to 2,4-D also reduced liver acetylcholinesterase activity by 31–41%. The treatment increased catalase activity in brain, but returned it to initial levels after recovery. In kidney, exposure to 100 mg/L of 2,4-D caused a 33% decrease of superoxide dismutase activity. Thus, goldfish exposure to 2,4-D induced moderate oxidative stress in liver and kidney and mild oxidative stress in brain.     

Reversal of propoxur-induced impairment of step-down passive avoidance,transfer latency and oxidative stress by piracetam and ascorbic acid in rats

Propoxur, a carbamate pesticide has been shown to adversely affect memory and induce oxidative stress. The present study was designed to correlate the effect of propoxur, piracetam (a nootropic drug) and ascorbic acid (an antioxidant) on oxidative stress and cognitive function. Cognitive function was assessed using step-down latency (SDL) on a passive avoidance apparatus and transfer latency (TL) on elevated plus maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and non-protein thiol (NP-SH) levels. A significant reduction in SDL and prolongation of TL was found for the propoxur-treated group at weeks 6 and 7 as compared with control (p < 0.001). One week treatment by piracetam (400 mg/kg/d, i.p.) or ascorbic acid (120 mg/kg/d, i.p.) antagonized the effect of propoxur on SDL as well as TL. Both piracetam and ascorbic acid attenuated the propoxur-induced increase in brain MDA levels and decrease in brain NP-SH levels. Results of the present study show that ascorbic acid and piracetam have the potential to reverse cognitive dysfunction and oxidative stress induced by propoxur in the brain.     

Prenatal developmental toxicity studies on diundecyl and ditridecyl phthalates in Sprague-Dawley rats

This study evaluates the developmental toxicity of two high molecular weight dialkyl phthalate esters, diundecyl phthalate (DUDP) and ditridecyl phthalate (DTDP). Sprague-Dawley rats were administered 0, 0.25, 0.50, or 1 g/kg/day of DUDP or DTDP, by gavage, on gestation days 6–20. DUDP and DTDP had no adverse effects on maternal body weight and food consumption. The number of live fetuses, percent of post-implantation loss and of resorptions, fetal sex, and fetal body weights were not affected by either phthalate. There was no evidence of teratogenicity, whatever treatment. Small decreases in the anogenital distance of male fetuses were noted at 0.5 and 1 g DUDP/kg/day. The incidence of fetuses with supernumerary lumbar ribs was significantly higher than control at 0.5 and 1 g DUDP/kg/day. Thus, DTDP was not developmentally toxic up to 1 g/kg/day and there were signs of DUDP-induced fetal effects at 0.5 and 1 g/kg/day.     

Differential effects of low-dose fenofibrate treatment in diabetic rats with early onset nephropathy and established nephropathy

We have previously shown that low-dose fenofibrate treatment has an ability to prevent diabetes-induced nephropathy in rats. We investigated here the comparative pre- and post-treatment effects of low-dose fenofibrate (30 mg/kg/day p.o.) in diabetes-induced onset of nephropathy. Rats were made diabetics by single administration of streptozotocin (STZ, 55 mg/kg i.p.). The development of diabetic nephropathy was assessed biochemically and histologically. Moreover, lipid profile and renal oxidative stress were assessed. Diabetic rats after 8 weeks of STZ-administration developed apparent nephropathy by elevating serum creatinine, blood urea nitrogen and microproteinuria, and inducing glomerular-capsular wall distortion, mesangial expansion and tubular damage and renal oxidative stress. Fenofibrate (30 mg/kg/day p.o., 4 weeks) pretreatment (4 weeks after STZ-administration) markedly prevented diabetes-induced onset of diabetic nephropathy, while the fenofibrate (30 mg/kg/day p.o., 4 weeks) post-treatment (8 weeks after STZ-administration) was less-effective. However, both pre-and post fenofibrate treatments were effective in preventing diabetes-induced renal oxidative stress and lipid alteration in diabetic rats though the pretreatment was slightly more effective. Conversely, both pre-and post fenofibrate treatments did not alter elevated glucose levels in diabetic rats. It may be concluded that diabetes-induced oxidative stress and lipid alteration, in addition to a marked glucose elevation, play a detrimental role in the onset of nephropathy in diabetic rats. The pretreatment with low-dose fenofibrate might be a potential therapeutic approach in preventing the onset of nephropathy in diabetic subjects under the risk of renal disease induction. However, low-dose fenofibrate treatment might not be effective in treating the established nephropathy in diabetic subjects.