Cerebellar Oscillations in Familial and Sporadic Essential Tremor.

Enhanced cerebellar oscillations have recently been identified in essential tremor (ET) patients as a key pathophysiological change. Since ET is considered a heterogeneous group of diseases, we investigated whether cerebellar oscillations differ in ET subtypes (familial vs. sporadic). This study aims to determine cerebellar physiology in familial and sporadic ET. Using surface electroencephalogram, we studied cerebellar physiology in 40 ET cases (n = 22 familial and n = 18 sporadic) and 20 age-matched controls. Both familial and sporadic ET cases had an increase in the intensity of cerebellar oscillations when compared to controls. Interestingly, cerebellar oscillations correlated with tremor severity in familial ET but not in sporadic ET. Our study demonstrated that ET cases have enhanced cerebellar oscillations, and the different relationships between cerebellar oscillations and tremor severity in familial and sporadic ET suggest diverse cerebellar pathophysiology.

[Bifidobacterium bifidum TMC3115 Promotes Early Life Intestinal Microbiota Building to Alleviate Symptoms of Inflammatory Bowel Disease].

Objective: To investigate the effects of using Bifidobacterium bifidum TMC3115 in early life on intestinal microbiota and immune functions and the long-term impact on inflammatory bowel disease. Methods: Fourteen pregnant BALB/c mice were purchased and 84 newborn BALB/c mice were subsequently obtained. Then, the newborn mice were randomly assigned to a normal saline (NS) group and a TMC3115 group, given via oral gavage normal saline and TMC3115, respectively, at a daily volume of 0.2 mL for each mouse. About 42 mice were assigned to each group. The gavage was stopped after 3 weeks. At this point, half of the mice in each group were sacrificed, and then the remaining mice in each group were randomly divided into NS-water group, NS-DSS group, TMC3115-water group, and TMC3115-DSS group, with about 10 mice in each group. The mice were given regular feed until the end of week 6 when they were given 3% dextran sulphate sodium (DSS) ad libitum for 4 days to establish the enteritis model, while the non-modeling groups were given pure water ad libitum. The experiment ended after 6 weeks and 4 days. The weekly body mass changes of the mice were documented. The intestinal tissue at the end of the experiment and the fecal samples, spleen and serum of the mice at 3 weeks and at the end of the experiment were collected to determine the pathology scores of colonic inflammation, the composition of fecal gut microbiota, spleen organ index and the mass concentration of serum cytokines. Results: 1) At the end of the experiment, the inflammatory pathology score was significantly lower in the TMC3115-DSS group compared with that of the Saline-DSS group ( P<0.05), with less disruption of colonic crypt structures and other structures, less inflammatory infiltration, and more intact epithelial structures. 2) At 3 weeks, in comparison with those of the NS group, the relative abundance of Bifidobacteriumwas significantly higher in the feces of the TMC3115 ( P<0.05), the relative abundance of both Enterococcusand Staphylococcuswas lower ( P<0.05), the splenic organ index was significantly higher ( P<0.05), and interleukin (IL)-10 was significantly decreased ( P<0.05), while there was no significant change in IL-6 or TNF-α ( P>0.05). At the end of the experiment, in comparison with those of the NS-DSS group that undergone DSS induction, the TMC3115-DSS group had reduced relative abundance of Staphylococcus, Staphylococcus tumefaciens and Escherichia/ Shigellain the feces ( P<0.05), while the splenic organ index was significantly higher ( P<0.05), and there were no significant changes in IL-6 or TNF-α ( P>0.05). Conclusion: The use of TMC3115 in early life promotes the construction of gut microbiota in neonatal mice, thereby producing a long-term effect that alleviates colitis in mice, but the mechanisms involved are still not fully understood.

Subchronic Oral Toxicity Evaluation of Lanthanum: A 90-day, Repeated Dose Study in Rats.

OBJECTIVE: The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level (NOAEL), which is a critical factor in the establishment of an acceptable dietary intake (ADI). METHODS: In accordance with the Organization for Economic Co-operation and Development (OECD) testing guidelines, lanthanum nitrate was administered once daily by gavage to Sprague-Dawley (SD) rats at dose levels of 0, 1.5, 6.0, 24.0, and 144.0 mg/kg body weight (BW) per day for 90 days, followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups. Outcome parameters were mortality, clinical symptoms, body and organ weights, serum chemistry, and food consumption, as well as ophthalmic, urinary, hematologic, and histopathologic indicators. The benchmark dose (BMD) approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum. RESULTS: Significant decreases were found in the 144.0 mg/kg BW group in the growth index, including body weight, organ weights, and food consumption. This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day. Importantly, the 95% lower confidence value of the benchmark dose (BMDL) was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males. CONCLUSION: The present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements (REEs).

Subchronic toxicity study of yttrium nitrate by 90-day repeated oral exposure in rats.

Concerns regarding the adverse effects of long-term exposure to low levels of rare earth elements (REEs) from foods on human health have arisen in recent years. Nevertheless, no official acceptable daily intake (ADI) has yet been proposed for either total REEs or individual REE. In accordance with the Organization for Economic Co-operation and Development (OECD) testing guideline, the present study was undertaken to evaluate the subchronic toxicity of yttrium, a representative heavy REE with higher contaminated level in foods in China, to achieve a no observed adverse effect level (NOAEL) which is a critical basis for the establishment of an ADI. Yttrium nitrate was orally administered to rats at doses of 0, 10, 30 and 90 mg/kg/day for 90 days followed by a recovery period of 4 weeks. The following toxicity indices were measured: mortality, clinical signs, daily food consumption and weekly body weight; urinalysis, hematology, blood coagulation, clinical biochemistry and histopathology at the end of administration and recovery periods. No toxicologically significant changes were found in any yttrium-treated group as compared to the concurrent control group. Under the present experimental condition, the NOAEL in rats was thus set at 90 mg/kg for yttrium nitrate, i.e. 29.1 mg/kg for yttrium.

AMPK activator acadesine fails to alleviate isoniazid-caused mitochondrial instability in HepG2 cells.

Isoniazid (INH) is a first-line antituberculosis drug that is adversely associated with hepatotoxicity. Recently, impairment of mitochondrial homeostasis involved in this side effect has been noticed. Mitochondrial homeostasis is achieved by the balance between the generation of functional mitochondria by biogenesis and elimination of dysfunctional mitochondria by autophagy. AMP-activated protein kinase (AMPK) can maintain mitochondrial stability through positive control of these two processes. In this study, we showed that AMPK activator acadesine (AICAR) alleviated INH-caused impairment of mitochondrial biogenesis by activation of silent information regulator two ortholog 1 (SIRT1)-peroxisome proliferator-activated receptor γ coactivator 1α (PGC1 α) pathway in HepG2 cells. However, mitochondrial instability and apoptosis were caused by AICAR along with an unexpected decrease in INH-induced cytoprotective autophagy. Therefore, AICAR failed to alleviate INH-caused mitochondrial instability in HepG2 cells due to its inhibitory effect on autophagy induced by INH. Copyright © 2017 John Wiley & Sons, Ltd.

Combined exposure to nano-silica and lead induced potentiation of oxidative stress and DNA damage in human lung epithelial cells.

Growing evidence has confirmed that exposure to ambient particulate matters (PM) is associated with increased morbidity and mortality of cardiovascular and pulmonary diseases. Ambient PM is a complex mixture of particles and air pollutants. Harmful effects of PM are specifically associated with ultrafine particles (UFPs) that can adsorb high concentrations of toxic air pollutants and are easily inhaled into the lungs. However, combined effects of UFPs and air pollutants on human health remain unclear. In the present study, we elucidated the combined toxicity of silica nanoparticles (nano-SiO2), a typical UFP, and lead acetate (Pb), a typical air pollutant. Lung adenocarcinoma A549 cells were exposed to nano-SiO2 and Pb alone or their combination, and their combined toxicity was investigated by focusing on cellular oxidative stress and DNA damage. Factorial analyses were performed to determine the potential interactions between nano-SiO2 and Pb. Our results showed that exposure of A549 cells to a modest cytotoxic concentration of Pb alone induced oxidative stress, as evidenced by elevated reactive oxygen species generation and lipid peroxidation, and reduced glutathione content and superoxide dismutase and glutathione peroxidase activities. In addition, exposure of A549 cells to Pb alone induced DNA damage, as evaluated by alkaline comet assay. Exposure of A549 cells to non-cytotoxic concentration of nano-SiO2 did not induce cellular oxidative stress and DNA damage. However, exposure to the combination of nano-SiO2 and Pb potentiated oxidative stress and DNA damage in A549 cells. Factorial analyses indicated that the potentiation of combined toxicity of nano-SiO2 and Pb was induced by additive or synergistic interactions.

Effects of Helicobacter pylori and Moluodan on the Wnt/ß-catenin signaling pathway in mice with precancerous gastric cancer lesions.

BACKGROUND: Helicobacter pylori (H. pylori) is the primary risk factor for gastric cancer (GC), the Wnt/ß-Catenin signaling pathway is closely linked to tumourigenesis. GC has a high mortality rate and treatment cost, and there are no drugs to prevent the progression of gastric precancerous lesions to GC. Therefore, it is necessary to find a novel drug that is inexpensive and preventive to against GC. AIM: To explore the effects of H. pylori and Moluodan on the Wnt/ß-Catenin signaling pathway and precancerous lesions of GC (PLGC). METHODS: Mice were divided into the control, N-methyl-N-nitrosourea (MNU), H. pylori + MNU, and Moluodan groups. We first created an H. pylori infection model in the H. pylori + MNU and Moluodan groups. A PLGC model was created in the remaining three groups except for the control group. Moluodan was fed to mice in the Moloudan group ad libitum. The general condition of mice were observed during the whole experiment period. Gastric tissues of mice were grossly and microscopically examined. Through quantitative real-time PCR (qRT-PCR) and Western blotting analysis, the expression of relevant genes were detected. RESULTS: Mice in the H. pylori + MNU group showed the worst performance in general condition, gastric tissue visual and microscopic observation, followed by the MNU group, Moluodan group and the control group. QRT-PCR and Western blotting analysis were used to detect the expression of relevant genes, the results showed that the H. pylori + MNU group had the highest expression, followed by the MNU group, Moluodan group and the control group. CONCLUSION: H. pylori can activate the Wnt/ß-catenin signaling pathway, thereby facilitating the development and progression of PLGC. Moluodan suppressed the activation of the Wnt/ß-catenin signaling pathway, thereby decreasing the progression of PLGC.

Neuronal population activity in the olivocerebellum encodes the frequency of essential tremor in mice and patients.

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.

[Pollution Characteristics and Source Apportionment of Typical and Emerging Per- and Polyfluoroalkylated Substances in Tuojiang River Basin].

Forty-eight surface water samples were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in order to study the pollution characteristics and source apportionment of per- and polyfluoroalkylated substances (PFASs) in the Tuojiang River. The results showed that ΣPFASs in the Tuojiang River ranged from 12.5-3789 ng·L-1, and perfluorooctanoic acid (PFOA) was the predominant PFAS, with a concentration of 9.97-3764 ng·L-1 (73.6%-99.8%), suggesting that legacy PFASs were still the dominant PFASs in the Tuojiang River. The most frequently detected emerging PFASs was 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (F-53B), with a detection frequency of 100%, suggesting the wide use of F-53B in the Tuojiang River. Sodium 1H, 1H, 2H, 2H-perfluorooctane sulfonate (6:2 FTS) displayed the highest concentration among all emerging PFASs[nd-27.3 ng·L-1, mean:(9.12±7.70) ng·L-1], and the concentrations were at the higher levels compared to those in other rivers around the world. In addition, ΣPFASs showed the highest concentrations of ΣPFASs at the fluorochemical manufacturing park (FMP), followed by those in the Luzhou section (in the lower reaches of the Tuojiang River), indicating that the emission of FMP and human daily production activities were the main influencing factors of PFASs pollution in the Tuojiang River. The estimated flux of PFASs from the Tuojiang River to the Yangtze River was 353 kg·a-1, and PFOA displayed the greatest mass loading (348 kg·a-1), which could provide the basic data for controlling PFASs in the Tuojiang River.

Revision of the genus Homa Distant (Hemiptera: Cicadellidae: Typhlocybinae).

The leafhopper genus Homa Distant is revised. Four new species, H. osificata Xu, Dietrich Qin sp. nov., H. oretinia Xu, Dietrich Qin sp. nov., H. asilata Xu, Dietrich Qin sp. nov., and H. algulata Xu, Dietrich Qin sp. nov., are described from Thailand. H. haematoptilus (Kirkaldy) is redescribed based on specimens from the Oriental Region. All included species are illustrated and a key is provided to separate species for which males are known.

Foodborne botulinum type E intoxication associated with dried bean curd: first case report in Taiwan.

PURPOSE: Botulism type E intoxication is a rare condition among human botulism. We aim to describe a first case of botulism type E intoxication in Taiwan. CASE REPORT: We report a 36-year-old young man with foodborne botulism type E associated with commercially vacuum packaged dried bean curd. He developed bilateral ptosis, diplopia and dysphagia 4 days after taking the dried bean curd. Electrophysiologic findings demonstrated waxing responses to 3 Hz repetitive nerve stimulation and decreased compound muscle action potentials on peripheral nerve conduction study. A bioassay for botulism in mice demonstrated that the patient had botulism caused by type E botulinum toxin. Antibodeis to C. botulinum type E were identified from his serum, confirming the diagnosis. CONCLUSIONS: This is the first known case of foodborne type E botulism in Taiwan. The potential source of this foodborne botulism should consider contaminated food made of soy beans.

Two new empoascine leafhopper genera, Thaioasca and Mjolnirus, from Thailand (Hemiptera: Cicadellidae: Typhlocybinae), with a checklist of Empoascini in Thailand.

Two new microleafhopper genera of Empoascini, Thaioasca Wang, Xu Qin, gen. nov. and Mjolnirus Wang, Xu Qin, gen. nov., based on the type species, Thaioasca contaminata Wang, Xu Qin, sp. nov. and Mjolnirus mediolobus Wang, Xu Qin, sp. nov. are described from Thailand. Male habitus photos and illustrations of male genitalia of these two new species are given. A checklist of Empoascini from Thailand is also provided.

[Effects of metallothionein on rifampicin (RFP)-induced hepatotoxicity in mice].

OBJECTIVE: To investigate the effect of metallothionein (MT) on rifampicin (RFP)-induced hepatotoxicity and the possible mechanisms. METHODS: Male MT- I / II null (MT-/-) and wild type (MT+/+) mice were randomly divided into 4 groups, respectively, and were orally administered RFP (50, 100 or 200 mg/kg) or equal volumes of solvent daily for 15 consecutive days. Levels of plasma alanine aminotransferase (ALT), alkaline phosphatase (ALP) and direct bilirubin (DB) were determined. Liver indexes were calculated and liver histopathologic changes were examined by hematoxylin and eosin (HE) staining. The content of glutathione (GSH) as well as the activities of glutathione peroxydase (GPx) and glutathione reductases (GR) were measured in the liver homogenates. RESULTS: RFP treatment induced significant increases in plasma ALT, AST and DB, as well as liver index. Significant histopathologic changes which were charactered as fatty degeneration in liver were noteced. Moreover, augmentations of GSH content and GR activity and attenuation of GPx activity were observed. More severe hepatic injuries in MT-/- mice were observed as compared to MT+/+ mice, which were evidenced by higher liver/body weight ratio and GR activity, lower GSH content and GPx activity, and more serious fatty degeneration. CONCLUSION: RFP-induced hepatotoxicity was associated with cholestasis and oxidative damage. MT -/- mice were more susceptible than MT +/+ mice to RFP-induced hepatotoxicity and the enhanced hepatotoxicity involves increased oxidative stress.

[Therapeutic effect of scalp acupuncture combined with rehabilitation training on balance dysfunction in children with spastic hemiplegia].

OBJECTIVE: To investigate the therapeutic effect of scalp acupuncture and rehabilitation training on balance dysfunction in children with spasmodic hemiplegia so as to provide the reference to the optimization of treatment scheme. METHODS: A total of 60 children with spastic hemiplegia were divided into a routine group and a scalp acupuncture group, 30 cases in each one according to random number table. In the routine group, the rehabilitation training was provided, including exercise training, balance training, spasmotherapy apparatus, electromyography biofeedback apparatus and orthoses. In the scalp acupuncture group, on the base of the treatment as the routine group, scalp acupuncture was supplemented at motor area, foot motor sensory area, equilibrium area and parietal temporal anterior oblique line. Separately, before the treatment, after 3 months treatment and after 6 months treatment, the dimension D and E of the gross motor function measure-88 (GMFM-88) and Berg balance scale (BBS) were adopted to evaluate balance related motor functions and equilibrium function. The differences in the above 3 indicators at different time stages were compared in children between the two groups. RESULTS: Compared with the score before the treatment, BBS score was obviously increased after 3 and 6 months treatment in the patients of the two groups respectively (P<0.05). The score in the dimension D and E after 6-month treatment was increased significantly as compared with the score before treatment and after 3-month treatment in the same group respectively (P<0.05). Compared with the routine group, the score of dimension D and E of GMFM-88 as well as BBS score were all increased obviously in the scalp acupuncture group after 3 and 6 months treatment (P<0.05). CONCLUSION: On the base of routine rehabilitation training, scalp acupuncture can improve balance function of children with spastic hemiplegia better.

Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology.

Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)-to-Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.

Basal expression of metallothionein suppresses butenolide-induced oxidative stress in liver homogenates in vitro.

Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is a Fusarium mycotoxin which is frequently detected in foodstuffs and feedstuffs for human and animal consumption. It can evoke a broad spectrum of toxicities, thus posing a potential health risk to both humans and animals. Previous study showed that this mycotoxin produced a significant oxidative stress, and several antioxidants abated this effect. Metallothionein (MT) has been proposed as a potent antioxidant, therefore, this study attempts to determine whether endogenous expression of MT protects against butenolide-induced hepatic oxidative stress by using an in vitro incubation system of liver homogenates prepared from MT-I/II null (MT-/-) mice, and the corresponding wild type (MT+/+) mice. The results showed that butenolide elicited significant oxidative stress in both MT-/- mice and MT+/+ mice; however, MT-/- mice were more sensitive than MT+/+ mice to butenolide-induced hepatic oxidative stress, as evidenced by more production of thiobarbituric acid reactive substances and nitric oxide, and by more severe reductions of glutathione, superoxide dismutase and glutathione peroxidase in the liver homogenates of MT-/- mice than those of MT+/+ mice. These findings implicated the antioxidant potency of basal expression of MT in suppression of the oxidative stress of butenolide.

Chlorpyrifos induces delayed cytotoxicity after withdrawal in primary hippocampal neurons through extracellular signal-regulated kinase inhibition.

In this study, the delayed effect and related mechanism after chlorpyrifos (CPF) withdrawal was studied in primary rat hippocampal neurons. The results showed that 10 muM CPF induced no detectable cytotoxicity during 96 h continuous exposure while its withdrawal after 48 h exposure induced evident cytotoxicity, as indexed by decreased methyl thiazolyl tetrazolium (MTT) metabolism, increased loss of neurons immunostained by neuron-specific enolase (NSE) antibody, and the increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) positive cell rate in the following 24 h and 48 h incubation in the absence of CPF. Extracellular signal-related kinase (ERK)1/2 activation by phosphorylation was observed and persisted during CPF exposure. However, CPF withdrawal after 48 h exposure led to inhibition of ERK1/2 phosphorylation. Carbacol and nerve growth factor (NGF), which are ERK1/2 activators, protected the neurons after CPF withdrawal, while atropine and PD98059, which are ERK1/2 inhibitors, exacerbated the cytotoxicity, indicating the involvement of inhibition of ERK1/2 phosphorylation in CPF-induced delayed cytotoxicity. In conclusion, CPF withdrawal after exposure induced delayed cytotoxicity in cultured neurons. Inhibition of ERK1/2 phosphorylation was found to be related to the delayed cytotoxicity. This finding may provide a new insight into the toxicological mechanism of organophosphorus pesticides, especially chronic organophosphate-induced neuropsychiatric disorder characterized by delayed occurrence.

Chronic organophosphate (OP)-induced neuropsychiatric disorder is a withdrawal syndrome.

Chronic organophosphate-induced neuropsychiatric disorder is a less well-characterized syndrome, which is usually delay-occurred, persists long and is similar to the symptom of cholinergic deficit, its mechanism is unclear. The characteristics of chronic organophosphate-induced neuropsychiatric disorder are somewhat opposite to the direct action of OP pesticide, since withdrawal effect is usually opposite to the original effect of a drug, hypothesis that chronic organophosphate-induced neuropsychiatric disorder is a kind of withdrawal syndrome is suggested.

Combined effects of repeated administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated biphenyls on kidneys of male rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent environmental contaminants that exist as complex mixtures in the environment, but the possible interactions of TCDD and PCBs have not been systematically investigated. The main objective of this study was to investigate the combined nephrotoxic effects of TCDD and PCBs on rats and to reveal the potential interactions between TCDD and PCBs. Male Sprague-Dawley rats were intragastrically administered TCDD (10 microg/kg), PCBs (Aroclor 1254, 10 mg/kg), or the combination (10 microg/kg TCDD + 10 mg/kg Aroclor 1254). After 12 consecutive days of exposure, all treatments induced nephrotoxicity, as evidenced by significant increases in the levels of serum creatinine and blood urea nitrogen, changes of kidney histopathology, and significant renal oxidative stress. Most of these effects were more remarkable in the combined-exposure group. Furthermore, all treatments induced renal cytochrome P450 1A1 (CYP1A1) protein expression, and the induction was more conspicuous in the combined-exposure group. These findings suggested that the nephrotoxicity induced by TCDD and PCBs in the present study might be attributable to the high expression of CYP1A1. In addition, the result of the two-way analysis of variance revealed that the combined effects of TCDD and PCBs were complicated, being additive, synergistic, or antagonistic depending on the selection of toxicity end points under the present experimental condition. This study demonstrates that combined exposure to TCDD and PCBs induced significant nephrotoxicity in rats, and there were complicated interactions between the two pollutants on the nephrotoxicity.

Effects of Fusarium mycotoxin butenolide on myocardial mitochondria in vitro.

Fusarium mycotoxin toxicosis has been implicated in the etiology of Keshan disease, an endemic mitochondrial cardiomyopathy prevailing in certain areas of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is one of the Fusarium mycotoxins which are frequently detected from cereal grains in endemic areas. A recent study indicates that this mycotoxin induces rat cardiotoxicity, but its effect on the myocardial mitochondria remains unclear. The present study is therefore undertaken to explore the toxic effect potential of butenolide on the myocardial mitochondria. Exposure of cultured cardiac myocytes to 50 microg/ml of butenolide provoked dissipation of mitochondrial membrane potential. Incubation of isolated rat myocardial mitochondria with butenolide of 100 microg/ml for 60 min resulted in mitochondrial swelling, indicating the occurrence of mitochondrial permeability transition. Furthermore, marked oxidative damage in myocardial mitochondria was observed after incubation of isolated myocardial mitochondria with butenolide ranging from 0 to 50 microg/ml for 60 min, as manifested by concentration-dependent increases in the production of thiobarbituric acid reactive substances, the indicator of lipid peroxidation. Contrarily, a representative antioxidant glutathione significantly alleviated this oxidative mitochondrial damage induced by butenolide. In conclusion, these observations clearly show that butenolide can induce dysfunction of myocardial mitochondria, and oxidative damage appears to play a crucial role in these deleterious effects. The present study supports the hypothesis that mycotoxin toxicosis is a probable etiological factor of Keshan disease, the mitochondrial cardiomyopathy.