Exercise-induced heart mitochondrial cholesterol depletion influences the inhibition of mitochondrial swelling.

The significance of the reduction of the cholesterol pool in heart mitochondria after exercise is still unknown. Recently, published data have suggested that cholesterol may influence the components of mitochondrial contact site and affect mitochondrial swelling. Therefore, the aim of this study was to determine whether the decreased cholesterol content in heart mitochondria caused by prolonged swimming may provoke changes in their bioenergetics and result in an increased resistance to calcium chloride-induced mitochondrial swelling. Male Wistar rats were divided into a sedentary control group and an exercise group. The rats exercised for 3 h, burdened with an additional 3% of their body weight. Their hearts were removed immediately after completing the exercise. The left ventricle was divided and used for experiments. Mitochondrial cholesterol content, membrane fluidity and mitochondrial bioenergetics were measured in the control and exercised rat heart mitochondria. To assess whether mitochondrial modifications are linked to disruption of lipid microdomains, methyl-ß-cyclodextrin, a well-known lipid microdomain-disrupting agent and cholesterol chelator, was applied to the mitochondria of the control group. Cholesterol depletion, increased membrane fluidity and increased resistance to calcium chloride-induced swelling were observed in postexercise heart crude mitochondrial fraction. Similar results were achieved in control mitochondria treated with 2% methyl-ß-cyclodextrin. All of the mitochondrial bioenergetics parameters were similar between the groups. Therefore, the disruption of raft-like microdomains appears to be an adaptive change in the rat heart following exercise.

Early life permethrin exposure induces long-term brain changes in Nurr1, NF-kB and Nrf-2.

Pesticide exposure during brain development represents an important risk factor for the onset of brain-aging processes. Here, the impact of permethrin administered to rats from 6th to 21st day of life, at a dose near to "no observed adverse effect level" (NOAEL), was studied when animals reached 500 day-old. The permethrin treatment induced a decrease in Nurr1 gene expression in striatum, an increase in hippocampus and cerebellum, while the protein level changed only in striatum where it was increased. NF-kB p65 gene expression was increased in cerebellum, while its protein level augmented in cerebellum and in prefrontal cortex and decreased in hippocampus of treated rats compared to control ones. Nrf-2 gene expression resulted significantly higher only in cerebellum of treated animals. The results suggest that early life permethrin treatment induces long-lasting effects leading to dopaminergic neuronal disorders, monitored by Nurr1 alteration. Moreover the impairment of NF-kB and Nrf-2, important for the balance between pro- and anti-inflammatory systems, confirms that the neonatal permethrin treatment can influence genes involved with the onset of brain-ageing processes.

The impact of early life permethrin exposure on development of neurodegeneration in adulthood.

Early life environmental exposure to pesticides could play a critical role in the onset of age-related diseases. The present study aims to evaluate in brain, plasma and leukocytes of 300 day-old rats, the effect of a low dose of the insecticide permethrin administered during early life (1/50 LD(50), from 6th to 21st day of life). The outcomes show that Nurr1, mRNA and protein expression, as well as calcium and NO levels are decreased in striatum. Moreover, the pesticide induces an imbalance in glutamate, calcium and NO in hippocampus. Low calcium concentrations in leukocytes and in plasma were observed, while increased NO and decreased SOD plasma levels were measured. The results suggest that permethrin intake at a dose close to the NOAEL (25 mg/kg) during the perinatal period can interact with Nurr1 by reducing its expression on striatum nucleus. Consequently, the maintenance of dopaminergic neurons as well as Nurr1 inhibitory effect on the production of proinflammatory mediators fails. The changes in biological markers found in our animal model could represent the basis to study neurodegenerative diseases whose development depends on individual gene signature and life style.

Early life permethrin insecticide treatment leads to heart damage in adult rats.

Early life environmental exposure to xenobiotics could represent a critical period for the onset of permanent alterations in the structure and function of different organs. Cardiovascular diseases can be related to various factors including environmental toxicants. The aim of the present study was to evaluate the effect of early life permethrin treatment (1/50 LD(50), from 6th to 21st day of life) on heart of adult rats. Increased DNA damage, decreased heart cell membrane fluidity, increased cholesterol content, protein and lipid oxidation were measured in heart cells from adult rats treated with permethrin during the neonatal period with respect to control rats. Moreover, the same group showed higher levels of cholesterol, IL-1ß, IL-2, IFN-γ, rat-Rantes and IL-10 cytokines and decreased albumin content in plasma. Lower cholesterol levels and perturbation in the phospholipid lateral diffusion together with decreased GSH levels and increased GPx activity were measured in heart mitochondria of the treated group. Our findings support the evidence that the neonatal period has a critical role in the development of heart disease in adulthood. We hypothesize that the alterations observed in adult rats could depend on epigenetic changes that occurred during this period which influence gene expression throughout the rat's life, leading to alterations of certain parameters related to cardiac function.

Purine bases oxidation and repair following permethrin insecticide treatment in rat heart cells.

Pollutants including insecticides have been recently reported to be a risk factor involved in various diseases. Permethrin, a member of the family of synthetic pyrethroids, is widely used as insecticide in agriculture and other domestic applications. To investigate possible cardiotoxicity, we had examined different concentrations of permethrin on the freshly isolated rat heart cells using the alkaline comet assay. A significant difference in % tail DNA between all concentrations of permethrin (5, 10, 20 microM) and vehicle (control) without enzymes and with Fpg-treated cells were measured. The results indicated that permethrin induced oxidative damage to purine bases in the heart cells. Pyrimidines oxidation was evaluated using Endonuclease III (Endo III), but the results did not reveal any significant changes. After permethrin exposure, cells were studied to evaluate their DNA repair capacity. A complete DNA repair at 10 and 20 microM was measured after 30 and 60 min of repair intervals. Significant change in plasma membrane fluidity at different depths of bilayer was measured following permethrin treatment. Membrane fluidity in the hydrophilic-hydrophobic region was reduced, while the hydrophobic inner resulted more fluid following permethrin treatment of heart cells. This work points to standardize conditions applicable to ex vivo cells following in vivo treatment in order to study the cardiotoxicity of insecticide.