In utero arsenic exposure is associated with impaired thymic function in newborns possibly via oxidative stress and apoptosis

Prenatal arsenic exposure is associated with increased infant morbidity and reduced thymus size, indicating arsenic-related developmental immunotoxicity. We aimed to evaluate effects of prenatal arsenic exposure on thymic function at birth and related mechanisms of action. In a Bangladeshi cohort, arsenic was measured in urine (U-As, gestational week (GW) 8 and 30) and blood (B-As, GW14) in 130 women. Child thymic index was measured by sonography at birth and thymic function by signal-joint T-cell receptor-rearrangement excision circles (sjTRECs) in cord blood mononuclear cells (CBMC). In a subsample (n = 44), sjTRECs content in isolated CD4(+) and CD8(+) T cells, expression of oxidative-stress defense and apoptosis-related genes in CBMC, arsenic concentrations (urine, placenta, and cord blood), and oxidative stress markers in placenta and cord blood were measured. In multivariable-adjusted regression, ln U-As (GW8) was inversely associated with ln sjTRECs in CBMC (B = -0.25; 95% confidence interval [CI] -0.48 to -0.01). Using multivariable-adjusted spline regression, ln U-As (GW30) and ln B-As (GW14) were inversely associated with ln sjTRECs in CBMC (B = -0.53; 95% CI -0.93 to -0.13 and B = -1.27; 95% CI -1.89 to -0.66, respectively) below spline knots at U-As 150 μg/l and B-As 6 μg/kg. Similar inverse associations were observed in separated CD4(+) and CD8(+) T cells. Arsenic was positively associated with 8-hydroxy-2'-deoxyguanosine in cord blood (B = 0.097; 95% CI 0.05 to 0.13), which was inversely associated with sjTRECs in CD4(+) and CD8(+) T cells. In conclusion, prenatal arsenic exposure was associated with reduced thymic function, possibly via induction of oxidative stress and apoptosis, suggesting subsequent immunosuppression in childhood.     

Rutin ameliorates oxidative stress and preserves hepatic and renal functions following exposure to cadmium and ethanol

Context: Rutin (RUT) is an antioxidant flavonoid with well-known metal chelating potentials.

Objective: This study was designed to evaluate the protective effects of RUT against cadmium (Cd)?+?ethanol (EtOH)-induced hepatic and renal toxicity in rats.

Materials and methods: Wistar rats were treated with Cd (50?mg/kg) alone or in combination with EtOH (5?mg/kg) and RUT (25, 50 and 100?mg/kg) for 15?days. After treatment, the liver, kidney and serum were removed for biochemical assays by spectrophotometric methods.

Results: Serum, hepatic and renal malondialdehyde (MDA) levels were highest in the Cd?+?EtOH group and lowest in Cd?+?EtOH animals co-treated with the highest dose of RUT (2.98?±?0.34, 10.08?±?2.32, 4.99?±?1.21 vs. 1.69?±?0.33, 6.13?±?0.28, 3.66?±?1.12?μmol MDA/mg protein, respectively). The serum level of Cd was increased in the Cd?+?EtOH treated animals compared to Cd?+?EtOH animals co-treated with 100?mg/kg RUT (2.54?±?0.08 vs. 1.28?±?0.04?ppm). Furthermore, RUT at the highest dose protected against Cd?+?EtOH-induced elevation of bilirubin and uric acid levels as well as activities of lactate dehydrogenase and γ-glutamyl transferase (62.86?±?2.74 vs. 122.52?±?6.35?µmol/L; 1.77?±?0.35 vs. 3.23?±?0.55?mmol/L; 9.56?±?1.22 vs. 16.21?±?1.64?U/L; 288.92?±?40.12 vs. 159.8?±?18.01?U/L). The histo-pathological changes in the liver and kidney were also reduced in the Cd?+?EtOH animals co-treated with RUT in a dose-dependent manner.

Discussion and conclusion: RUT protected against the combined effects of Cd?+?EtOH on hepatic and renal functions and improved the antioxidant defence system in the blood.     

Generation of oxidative stress in human cutaneous models following in vitro ozone exposure.

Ozone, one of the main components of photochemical smog, represents an important source of environmental oxidative stress. The skin, being the outermost barrier of the body, is directly exposed to environmental oxidant toxicants. Skin sebum and cellular plasma membrane lipids contain polyunsaturated fatty acids which are primary targets for ozone and free radical attack induced lipid peroxides. These ozonation processes in skin can also generate aldehydes, hydroxyhydroperoxides and specific Criegee's ozonides. In order to evaluate in vitro human skin susceptibility to ozone, we have exposed cultured immortalized human keratinocytes (DK7-NR) and the reconstructed human epidermis Episkin to 10 ppm of ozone in a specific incubator. We measured the formation of protein carbonyls by an ELISA method and monitored the oxidative stress using the fluorogenic probe 2',7'-dichlorofluorescin-diacetate (DCFH-DA). Results showed a time-dependent increase of fluorescence levels (linked to oxidative stress) in both models exposed to ozone. Using this protocol, we investigated the protective potential of different products including vitamin C, a thiol derivative and a plant extract. All products dramatically reduced oxidative responses during ozone exposure. Decreases observed in fluorescence levels were between 60 and 90% as compared to non-protected controls. These results demonstrate: (a) cutaneous in vitro models are remarkably susceptible to oxidative stress generated by an environmental air pollutant as ozone, and (b) raw antioxidants, thiols and vitamin C were efficient products to prevent ozone induced cellular oxidative damage.     

In utero exposure to tobacco and alcohol modifies neurobehavioral development in mice offspring: consideration a role of oxidative stress.

OBJECTIVE: To determine whether in utero tobacco and alcohol exposure induces long-term neurobehavioral alterations and whether oxidative stress/damage is a possible causal factor. METHODS: Gravid mice were subjected to tobacco smoking and alcohol consumption. Their offspring were subsequently evaluated in developmental and behavioral tests. Antioxidative enzymes and erythrocyte membrane fluidity of adult offspring were measured. RESULTS: The intrauterine tobacco and alcohol exposure has resulted in significant reduced postnatal body and organ weights accompanied by reduced gestational body weight gain in their mothers. Such exposure also induced remarkable developmental delay in neonatal reflexes and notable behavioral deficit in adulthood, namely reduced motive coordination and locomotor activity as well as impaired learning and memory abilities. Furthermore, the formation of malondialdehyde (MDA) increased significantly whereas the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), catalase (Cat) and glutathione S-transferases (GST) decreased in the cerebral cortex and liver of prenatal intoxicated offspring. The embryonic intoxication also markedly reduced erythrocyte membrane fluidity in offspring. CONCLUSION: Our study shows the long-term neurotoxicity associated with prenatal tobacco and alcohol exposure, and suggests that the deleterious outcome may be in relation to increased free radicals formation and oxidative stress.     

Effect of combined exposure to lead and ethanol on some biochemical indices in the rat

We investigated the effect of daily oral administration to young rats of lead (10 mg/kg) and ethanol (10%, v/v, in drinking water), either alone or in combination, for 8 weeks on the uptake of lead in tissues, brain biogenic amines, hepatic alcohol dehydrogenase and cytosolic and mitochondrial aldehyde dehydrogenase and some selected lead-sensitive variables. Lead given in combination with ethanol produced more pronounced inhibition in the activities of hepatic glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) as compared to lead alone treatment. Simultaneous exposure to lead and ethanol produced a greater depression of dopamine (DA) and 5-hydroxytryptamine (5-HT) levels in the whole brain of rats, compared to rats treated with lead alone. The concentrations of lead in blood, liver and brain were significantly higher in rats exposed simultaneously to lead and ethanol. Though ethanol treatment alone inhibited the activities of hepatic alcohol dehydrogenase and cytosolic and mitochondrial aldehyde dehydrogenase, no effect of lead treatment alone on these variables was observed. The results suggested that animals exposed to ethanol and lead are more vulnerable to the neurologic and hepatotoxic effects and the systemic toxicity of lead.     

In vitro fructose exposure overactivates NADPH oxidase and causes oxidative stress in the isolated rat aorta

Fructose acutely interferes with cardiovascular function in humans and in animals, but the mechanisms remain unclear. Thus, we tested whether fructose can affect endothelial function without the interference of its metabolic effect by exposing the rat aorta to a high fructose concentration and then evaluate the vascular responses to vasoactive agents. We observed that fructose exposure causes overactivation of NADPH oxidase, which enhances superoxide anion production and increases NO degradation. Additionally, the enhanced vasoconstrictor action of hydrogen peroxide might exacerbate contractile responses. This vasoactive imbalance might be the key role by which fructose induces vascular dysfunction.     

The combined effects of developmental lead and ethanol exposure on hippocampus dependent spatial learning and memory in rats: Role of oxidative stress

Either developmental lead or ethanol exposure can impair learning and memory via induction of oxidative stress, which results in neuronal damage. we examined the effect of combined exposure with lead and ethanol on spatial learning and memory in offspring and oxidative stress in hippocampus. Rats were exposed to lead (0.2% in drinking water) or ethanol (4 g/kg) either individually or in combination in 5th day gestation through weaning. On postnatal days (PD) 30, rats were trained with six trials per day for 6 consecutive days in the water maze. On day 37, a probe test was done. Also, oxidative stress markers in the hippocampus were also evaluated. Results demonstrated that lead + ethanol co-exposed rats exhibited higher escape latency during training trials and reduced time spent in target quadrant, higher escape location latency and average proximity in probe trial test. There was significant decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and increase of malondialdehyde (MDA) levels in hippocampus of animals co-exposed to lead and ethanol compared with their individual exposures. We suggest that maternal consumption of ethanol during lead exposure has pronounced detrimental effects on memory, which may be mediated by oxidative stress.     

Concomitant exposure to arsenic and organophosphates on tissue oxidative stress in rats

Increased use of organophosphates (OPs) and ever increasing arsenic levels in drinking water and their co-existence in the environment could be potentially hazardous. The present study examines the effects of dichlorvos (DDVP) or monocrotophos (MCP) and sodium meta arsenite, individually or in combination for 16 weeks on variables indicative of hematological and tissue oxidative injury in rats. Co-exposure to DDVP, MCP or arsenic produced significant inhibition of brain and serum AChE levels suggesting synergism. Significant increase in hepatic reactive oxygen species and brain thiobarbituric acid reactive substances was observed in arsenic and OPs exposed animals. Co-exposure to arsenic and OPs exhibited synergism in case of ROS while antagonism was noted in case of TBARS. Serum transaminases increased significantly on exposure to OPs and arsenic suggesting liver injury which was less pronounced in case of co-exposure to DDVP and arsenic. WBC counts too showed less pronounced increase on co-exposure to arsenic with OPs compared to all other exposure. Blood arsenic level decreased on co-exposure to arsenic with OPs. The present study points to some interesting observations regarding interaction between arsenic and organophosphates. While, exposure to arsenic, DDVP and MCP lead to significant oxidative stress, their co-exposure not necessarily produce synergistic effects.     

Long-term effects of fetal ethanol exposure on pituitary-adrenal response to stress

Pregnant female rats were fed either a 5.0–5.5% w/v ethanol-containing liquid diet ad lib or pair-fed the isocaloric control diet during gestation weeks 2 and 3. At 75–105 days of age, female offspring of the ethanol-treated dams showed significantly greater corticosterone responses than pair-fed- or normally-derived offspring to the stress of cardiac puncture or of noise and shaking, while pituitary-adrenal responses to exposure to a novel environment, cold or 2–3 days of fasting were normal. Adrenal sensitivity to ACTH in dexamethasone-suppressed adult offspring was unaffected by the prenatal treatment. The results demonstrate that fetal ethanol exposure enhances adult pituitary-adrenal responses to certain stressors, including alcohol as demonstrated previously, and suggest that the long-term effects may be mediated by developmental actions of alcohol on central neural mechanisms involved in the regulation of this neuroendocrine system.     

Ozone exposure activates oxidative stress responses in murine skin

Ozone (O(3)) is among the most reactive environmental oxidant to which skin is exposed. O(3) exposure has previously been shown to induce antioxidant depletion as well as lipid and protein oxidation in the outermost skin layer, the stratum corneum (SC), but little is known regarding the potential effects of O(3) on the skin epidermis and dermis. To evaluate such skin responses to O(3), SKH-1 hairless mice were exposed for 2 h to 8.0 ppm O(3) or to ambient air. O(3) exposure caused a significant increase in skin carbonyls (28%) compared to the skin of air exposed control animals. An evident increase in 4-hydroxynonenal-protein adducts was detected after O(3) exposure. O(3) exposure caused a rapid up-regulation of HSP27 (20-fold), and more delayed induction of HSP70 (2.8-fold) and heme oxygenase-1 (5-fold). O(3) exposure also led to the induction of nitric oxide synthase (iNOS) 6-12 h following O(3) exposure. We conclude that skin exposure to high levels of O(3) not only affects antioxidant levels and oxidation markers in the SC, but also induces stress responses in the active layers of the skin, most likely by indirect mechanisms, since it is unlikely that O(3) itself penetrates the protective SC layers.     

Effects of benzo[a]pyrene exposure on oxidative stress and apoptosis of gill cells of Chlamys farreri in vitro

As a common pollutant in marine environment, benzo[a]pyrene (B[a]P) has high toxicity to economic shellfish. In order to explore the mechanism of oxidative stress and apoptosis, the effects of 0, 2, 4, 8 μg/mL B[a]P on gill cells of C. farreri at 12 and 24 h were studied. The results showed that B[a]P decreased the activity of gill cells, increased the content of reactive oxygen species (ROS) and the expression of antioxidant defense genes. Besides, B[a]P could induce oxidative damage to nucleus and mitochondria. The gene expression and enzyme activity of apoptosis pathway related factors were changed. In conclusion, these results showed that B[a]P could cause oxidative stress and oxidative damage in gill cells of C. farreri, and mediate gill cell apoptosis through mitochondrial pathway and death receptor pathway. This article provides a theoretical basis for clarifying the molecular mechanism of PAHs-included oxidative stress and apoptosis in bivalves.     

In vitro exposure to cigarette smoke induces oxidative stress in follicular cells of F1 hybrid mice

This study assessed the influence of cigarette smoke condensate (CSC) and benzo(a)pyrene [B(a)P] on the levels of two oxidative stress biomarkers [8‐isoprostane (8‐IsoP) and 8‐hydroxy‐2‐deoxy Guanosine (8‐OH‐dG)], in in‐vitro spent media of follicle cells. Follicles (100–130 µm) isolated from ovaries of F₁ hybrid (C57Bl/6j × CBA/Ca) mice were cultured for 13 days in media exposed to B(a)P [0 ng ml^–1 (control) to 45 ng ml^–1] or CSC [0 µg ml^–1 (control) to 130 µg ml^–1]. The concentrations of oxidative stress biomarkers in spent media were quantified by enzyme‐linked immune sorbent assays (ELISA). CSC and B(a)P treatment induced a significant, dose‐dependent increase in the concentrations of 8‐IsoP and 8‐OH‐dG in the spent media. We conclude that CSC and B(a)P exposure can induce oxidative stress in ovarian follicles, an effect that may contribute to the previously documented decline in follicle development and premature ovarian failure in women who smoke. © Her Majesty the Queen in Right of Canada 2013.     

Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero

Maternal undernutrition during critical periods of organ development is known to impair fetal growth and predispose to the development of adulthood diseases, such as hypertension, coronary heart disease and type II diabetes that are linked to low birth weight and are characterized by endothelial dysfunction. Increased oxidative stress, in rats submitted to intrauterine undernutrition, provides a potential explanation for the endothelial dysfunction development. The aim of this study was to determine the oxidative stress and its consequence on mesenteric arteriolar responses to vasoactive agents in offspring from diet-restricted dams. For this, female pregnant Wistar rats were fed either normal or 50% of normal intake diets, during the whole gestational period. In male offspring, arterial blood pressure was determined by the tail cuff method in anesthetized rats, mesenteric arteriolar reactivity and superoxide anion generation were studied using intravital microscopy and superoxide dismutase activity was determined in mesentery by spectrophotometric assay. Intrauterine undernutrition induced hypertension, decreased vasodilation to acetylcholine and bradykinin but did not alter the responses to sodium nitroprusside. Topical application of superoxide dismutase and superoxide dismutase mimetic manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin significantly improved the altered arteriolar responses to acetylcholine and bradykinin. A decreased superoxide dismutase activity and an increased superoxide anion concentration were observed in the offspring of diet-restricted dams. This study shows for the first time that intrauterine undernutrition enhances oxidative stress in vivo and relates this to the impaired endothelium-dependent vasodilation.     

Effects of non-steroidal antiinflammatory drugs on D-serine-induced oxidative stress in vitro

Inflammation is deleterious for organs with reduced capacity of regeneration, such as the brain. Recently, studies have focused on investigating the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Excitotoxicity is the pathological process when receptors for the excitatory neurotransmitter glutamate, such as the N-methyl-D-aspartate (NMDA), receptors are overactivated. This process may be involved in neurodegenerative diseases. D-serine is one of the coagonist of NMDA receptors, and increased levels of D-serine are associated with excitotoxicity. In our study, the potential neuroprotective effects of mefenamic acid, acetaminophen, and naproxen sodium were investigated against D-serine-induced oxidative stress in the rat brain in vitro. To show their potential neuroprotective properties, NSAIDs were incubated with D-serine and reactive oxygen species (ROS), malondialdehyde, and protein carbonyl content of the brain after different treatments were measured. Our results demostrate that NSAIDs used in the present study significantly reduced ROS production, lipid peroxidation, and protein oxidation against D-serine treatment.     

Effects of long term ethanol consumption mediated oxidative stress on neovessel generation in liver

Angiogenesis, the growth of new blood vessels, is essential during tissue repair. Though most molecular mechanisms of angiogenesis are common to the liver and other organs, there was no report available whether alcoholic liver disease also causes angiogenesis. In this study, we examined the effects of long term ethanol (1.6?g/kg body weight/day) consumption on angiogenic responses in the liver of male Wistar strain albino rats (16-18 weeks old, weighing 200-220?g) up to 36 weeks. Chronic ethanol consumption was associated with not only elevated oxidative stress, and altered cytokines expression, but also developed large von Willebrand factor, fibrosis and activation of matrix metalloproteinases. Moreover, vascular endothelial growth factor-receptor 2 (VEGF-R2, fetal liver kinase 1: Flk-1/KDR) expression and neovessel generation in the rat liver were noted after 36 weeks of ethanol consumption. Thus our study provides novel evidence that long-term ethanol consumption is associated with angiogenesis through delicate and coordinated action of a variety of mediators.     

Community level exposure to chemicals and oxidative stress in adult population

Little information is available on the role of environmental chemical exposure in oxidative stress. This study was designed to investigate whether exposure to environmental chemicals, such as polycyclic aromatic hydrocarbons, volatile organic compounds, bisphenol A or phthalates, induces oxidative stress in urban adult populations. A total of 960 adults dwelling in urban areas were evaluated between April and December 2005. To assess environmental chemical exposure, we measured urinary levels of 1-hydroxypyrene, 2-naphthol, hippuric acid, methyl hippuric acid, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, and mono-butyl phthalate and bisphenol A. Urinary malondialdehyde and 8-hydroxydeoxyguanosine were also measured to evaluate oxidative stress. Significant dose-responsive relationship was found between urinary concentrations of the chemical exposure biomarkers and oxidative stress levels in simple regression analyses (P < 0.05). Regression coefficients of these exposure biomarkers except bisphenol A remained significantly in the multiple regression models after controlling for age, sex, weight, smoking, and exercise for at least one of the two oxidative stress biomarkers (P < 0.05). The oxidative stress biomarkers significantly affected the indicators of insulin resistance, particularly glucose level. This study indicates that environmental chemical exposure is associated with oxidative stress in urban adult populations and suggests that exposure to certain environmental chemicals might contribute to insulin resistance.     

Effects of long term ethanol consumption mediated oxidative stress on neovessel generation in liver

Angiogenesis, the growth of new blood vessels, is essential during tissue repair. Though most molecular mechanisms of angiogenesis are common to the liver and other organs, there was no report available whether alcoholic liver disease also causes angiogenesis. In this study, we examined the effects of long term ethanol (1.6?g/kg body weight/day) consumption on angiogenic responses in the liver of male Wistar strain albino rats (16–18 weeks old, weighing 200–220?g) up to 36 weeks. Chronic ethanol consumption was associated with not only elevated oxidative stress, and altered cytokines expression, but also developed large von Willebrand factor, fibrosis and activation of matrix metalloproteinases. Moreover, vascular endothelial growth factor-receptor 2 (VEGF-R2, fetal liver kinase 1: Flk-1/KDR) expression and neovessel generation in the rat liver were noted after 36 weeks of ethanol consumption. Thus our study provides novel evidence that long-term ethanol consumption is associated with angiogenesis through delicate and coordinated action of a variety of mediators.     

Mercury exposure in utero and during infancy

Mercury in blood samples was speicated from mothers and their infants up to 2 mo after delivery. There were significant correlations between umbilical cord blood and maternal blood for methylmercury (MeHg) and inorganic mercury (I-Hg) levels. The MeHg levels in cord blood were significantly higher than in maternal blood, while I-Hg levels were significantly higher than in maternal blood, while I-Hg levels were about the same. The maternal MeHg and I-Hg levels remained stable during the sampling period, whereas the MeHg concentration in infant blood decreased more than 45% between the 72-h and 2 mo sampling times. The I-Hg levels in infant blood were low at birth, and remained low during the sampling period. The results of the present study do not support I-Hg absorption through milk as a significant source of exposure. However, the number of observations is small, and a larger study is warranted in order to verify the data.     

Beneficial effects of clopidogrel on glycemic indices and oxidative stress in patients with type 2 diabetes

Objective of present study is to evaluate the possible role of clopidogrel in improving glycemic indices and oxidative stress in patients with type 2 diabetes.This study was performed on 42 uncontrolled type 2 diabetic patients at the specialized center for Endocrinology and Diabetes, Al-Rasafa Directorate of Health, Baghdad. All of the patients were treated with (glibenclamide 5 mg at morning) and randomized into two groups: the first group includes 22 patients treated with clopidogrel tablets (75 mg/day) for 2 months; the second group includes 20 patients treated with a placebo formula (sodium bicarbonate 200 mg/day) for the same period. Treatment with clopidogrel produced significant improvement (P < 0.05) in fasting serum glucose (FSG), fasting serum insulin level, quantitative insulin sensitivity check index (QUICKI); and oxidative stress markers: serum malondialdehyde (MDA) and serum reduced glutathione (GSH) compared to their baseline levels. There was significant elevation (P < 0.05) in both FSG and fasting serum insulin and the MDA level with significant reduction (P < 0.05) in QUICKI of placebo group compared to their baseline levels. However, clopidogrel produced significant elevation (P < 0.05) in AST and ALT levels but placebo formula caused no significant alteration (P > 0.05) in the serum levels of these two enzymes.In conclusion the treatment with clopidogrel improved glycemic indices and reduced oxidative stress in patients with type 2 diabetes.