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Di-n-butyl phthalate (DBP) is commonly used as a plasticizer and its usage continues to increase in conjunction with plastic consumption. DBP is readily released into air, drinking water, and soil, and unfortunately, is a potent endocrine disrupter that impairs central nervous system functions. Previously DBP was found to (1) arrest the cell cycle of C17.2 neural progenitor cells (NPCs) at the G1 phase, (2) reduce numbers of newly generated neural stem cells in the mouse hippocampus, and (3) adversely affect learning and memory. Other investigators also noted DBP-mediated neurotoxic effects, but as yet, no study has addressed the adverse effects of DBP on neuronal differentiation. Data demonstrated that at 200 μM DBP induced apoptosis in rat embryo primary neurons by increasing reactive oxygen species levels and inducing mitochondrial dysfunction. However, no significant effect was detected on neurons at concentrations of ≤100 μM. In contrast, doublecortin/microtubule associated protein-2 (DCX/MAP2) immunocytochemistry showed that DBP at 100 μM delayed neuronal maturation by increasing protein levels of DCX (an immature neuronal marker), without markedly affecting cell viability. Further in vivo studies confirmed that DCX+ cell numbers were significantly elevated in the hippocampus of DBP-treated mice, indicating that DBP delayed neuronal maturation, which is known to be associated with impaired memory retention. Data demonstrated that DBP might disrupt neuronal maturation, which is correlated with reduced neurocognitive functions. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate changes in the intracellular metabolism resulting from cisplatin (CDDP)-induced nephrotoxicity in normal kidney tubular epithelial NRK-52E cells. Cytotoxicity, cell cycle analysis, and apoptotic cell death were all evaluated in NRK-52E cells treated with CDDP. Subsequently, proton nuclear magnetic resonance (1H-NMR) spectroscopy was used to investigate cellular metabolic profiles. CDDP-induced nephrotoxicity was determined in vivo model. Cytotoxicity in the NRK-52E cells significantly rose following treatment with CDDP and these increases were found to be concentration-dependent. Both p53 and Bax protein expression was increased in CDDP-treated NRK-52E cells, correlating with enhanced cellular apoptosis. In addition, a number of metabolites were altered in both media and cell lysates in these cells. In cell lysates, citrate, creatinine, and acetate levels were dramatically reduced following treatment with 20 µM CDDP concentrations, while glutamate level was elevated. Lactate and acetate levels were significantly increased in culture media but citrate concentrations were reduced following high 20 µM CDDP concentrations incubation. In addition, excretion of clusterin, calbindin, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), selenium binding protein 1 (SBP1), and pyruvate kinase M2 (PKM2) into the culture media was significantly increased in CDDP-treated cells while expression of acetyl CoA synthetase 1 (AceCS1) was markedly reduced in these cells. These findings suggest that acetate-dependent metabolic pathway may be a reliable and useful biomarker for detecting CDDP-induced nephrotoxicity. Taken together, data demonstrate that the discovery of novel biomarkers by metabolite profiling in target cells may contribute to the detection of nephrotoxicity and new drug development. [ABSTRACT FROM AUTHOR]

The objective of this study was to elucidate the effect of hepatic damage on cisplatin (CDDP)-induced acute kidney injury (AKI). Thioacetamide (TAA, 150 mg/kg), a hepatotoxicant, was intraperitoneally (i.p.) injected to male Sprague-Dawley rats for 3 d prior to CDDP (5 mg/kg, i.p.) injection. All animals were sacrificed 5 d after CDDP treatment, and urine or blood was obtained to measure various parameters. No significant changes in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity were observed after CDDP treatment. However, pretreatment with TAA significantly elevated ALT and AST activity. Serum blood urea nitrogen and creatinine levels significantly increased in CDDP-treated group compared to control. In addition, urinary excretion of novel protein-based biomarkers such as neutrophil gelatinase-associated lipocalin, vascular endothelial growth factor, kidney injury molecule-1, and tissue inhibitor of metalloproteinase-1 rose markedly in the CDDP-treated group. In particular, pretreatment with TAA markedly elevated CDDP-induced urinary excretion of protein-based nephrotoxic biomarkers compared with CDDP alone. Hematoxylin and eosin staining demonstrated that pretreatment with TAA following CDDP injection led to more severe tubular damage and apoptosis in rats compared with CDDP alone. Antioxidant status was significantly reduced in kidneys following pretreatment with TAA prior to CDDP. These findings indicate that liver injury enhanced the vulnerability of kidney to CDDP-induced AKI and this phenomenon may be associated with severe apoptotic damage. [ABSTRACT FROM AUTHOR]

Acrylamide (ACR) is a neurotoxin known to produce neurotoxicity characterized by ataxia, skeletal muscle weakness, cognitive impairment, and numbness of the extremities. Previously, investigators reported that high-dose (50 mg/kg) ACR impaired hippocampal neurogenesis and increased neural progenitor cell death; however, the influence of subchronic environmentally relevant low dose-(2, 20, or 200 μg/kg) ACRs have not been examined in adult neurogenesis or cognitive function in mice. Accordingly, the aim of the present study was to investigate whether low-dose ACR adversely affected mouse hippocampal neurogenesis and neurocognitive functions. Male C57BL/6 mice were orally administered vehicle or ACR at 2, 20, or 200 μg/kg/day for 4 weeks. ACR did not significantly alter the number of newly generated cells or produce neuroinflammation or neuronal loss in hippocampi. However, behavioral studies revealed that 200 μg/kg ACR produced learning and memory impairment. Furthermore, incubation of ACR with primary cultured neurons during the developmental stage was found to delay neuronal maturation without affecting cell viability indicating the presence of developmental neurotoxicity. These findings indicate that although exposure to in vivo low-dose ACR daily for 4 weeks exerted no apparent marked effect on hippocampal neurogenesis, in vitro observations in primary cultured neurons noted adverse effects on learning and memory impairment suggestive of neurotoxic actions. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is associated with increased mortality rate in patients but clinically available biomarkers for disease detection are currently not available. Recently, a new biomarker, selenium-binding protein 1 (SBP1), was identified for detection of nephrotoxicity using proteomic analysis. The aim of this study was to assess the sensitivity of urinary SBP1 levels as an early detection of AKI using animal models such as cisplatin or ischemia/reperfusion (I/R). Sprague–Dawley rats were injected with cisplatin (6 mg/kg, once i.p.) and sacrificed at 1, 3, or 5 days after treatment. Ischemia was achieved by bilaterally occluding both kidneys with a microvascular clamp for 45 min and verified visually by a change in tissue color. After post-reperfusion, urine samples were collected at 9, 24, and 48 hr intervals. Urinary excretion of protein-based biomarkers was measured by Western blot analysis. In cisplatin-treated rats, mild histopathologic alterations were noted at day 1 which became severe at day 3. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly increased at day 3. Levels of urinary excretion of SBP1, neutrophil gelatinase-associated lipocalin (NGAL), and a tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly elevated at day 3 and 5 following drug treatment. In the vehicle-treated I/R group, serum levels of BUN and SCr and AST activity were significantly increased compared to sham. Urinary excretion of SBP1 and NGAL rose markedly following I/R. The urinary levels of SBP1, NGAL, TIMP-1, and KIM-1 proteins excreted by AKI patients and normal subjects were compared. Among these proteins, a marked rise in SBP1 was observed in urine of patients with AKI compared to normal subjects. Based upon receiver-operator curves (ROC), SBP1 displayed a higher area under the curve (AUC) scores than levels of SCr, BUN, total protein, and glucose. In particular, SBP1 protein was readily detected in small amounts of urine without purification. Data thus indicate that urinary excretion of SBP1 may be useful as a reliable biomarker for early diagnosis of AKI in patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate urinary metabolomic profiles associated with cadmium (Cd)-induced nephrotoxicity and their potential mechanisms. Metabolomic profiles were measured by high-resolution1H-nuclear magnetic resonance (NMR) spectroscopy in the urine of rats after oral exposure to CdCl2(1, 5, or 25 mg/kg) for 6 wk. The spectral data were further analyzed by a multivariate analysis to identify specific urinary metabolites. Urinary excretion levels of protein biomarkers were also measured and CdCl2accumulated dose-dependently in the kidney. High-dose (25 mg/kg) CdCl2exposure significantly increased serum blood urea nitrogen (BUN), but serum creatinine (sCr) levels were unchanged. High-dose CdCl2(25 mg/kg) exposure also significantly elevated protein-based urinary biomarkers including osteopontin, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecules-1 (Kim-1), and selenium-binding protein 1 (SBP1) in rat urine. Under these conditions, six urinary metabolites (citrate, serine, 3-hydroxyisovalerate, 4-hydroxyphenyllactate, dimethylamine, and betaine) were involved in mitochondrial energy metabolism. In addition, a few number of amino acids such as glycine, glutamate, tyrosine, proline, or phenylalanine and carbohydrate (glucose) were altered in urine after CdCl2exposure. In particular, the metabolites involved in the glutathione biosynthesis pathway, including cysteine, serine, methionine, and glutamate, were markedly decreased compared to the control. Thus, these metabolites are potential biomarkers for detection of Cd-induced nephrotoxicity. Our results further indicate that redox metabolomics pathways may be associated with Cd-mediated chronic kidney injury. These findings provide a biochemical pathway for better understanding of cellular mechanism underlying Cd-induced renal injury in humans. [ABSTRACT FROM PUBLISHER]