Renal Fibrosis and Oxidative Stress Induced by Silica Nanoparticles in Male Rats and Its Molecular Mechanisms.

Background: The utilization of amorphous silica nanoparticles (SiNPs) is gaining popularity in various applications, but it poses a potential risk to human and environmental health. However, the underlying causes and mechanisms of SiNPs-induced kidney damage are still largely unknown. Objectives: This study aimed to investigate the SiNPs-induced damage in the kidney and further explore the possible mechanisms of SiNPs-induced nephrotoxicity. Methods: Thirty adult male rats were divided into 3 different groups. Rats in groups 2 and 3 were administered SiNPs at 2 dosage levels (25 and 100 mg/kg of body weight), while the rats in the control group received no treatment for 28 days. Reactive oxygen species (ROS), antioxidant enzyme activities (glutathione peroxidase [GPx], superoxide dismutase [SOD], and catalase [CAT]), glutathione (GSH) levels, and oxidation markers (such as lipid peroxidation [malondialdehyde (MDA)] and protein oxidation [protein carbonyl (PCO)]) were analyzed in the kidney tissue. Additionally, renal fibrogenesis was studied through histopathological examination and the expression levels of fibrotic biomarkers. Results: The findings revealed that in vivo treatment with SiNPs significantly triggered oxidative stress in kidney tissues in a dose-dependent manner. This was characterized by increased production of ROS, elevated levels of MDA, PCO, and nitric oxide (NO), along with a significant decline in the activities of SOD, CAT, GPx, and reduced GSH. These changes were consistent with the histopathological analysis, which indicated interstitial fibrosis with mononuclear inflammatory cell aggregation, tubular degeneration, glomerulonephritis, and glomerular atrophy. The fibrosis index was confirmed using Masson's trichrome staining. Additionally, there was a significant upregulation of fibrosis-related genes, including transforming growth factor-beta 1 (TGF-ß1), matrix metalloproteinases 2 and 9 (MMP-2/9), whereas the expression of tissue inhibitor of metalloproteinase 2 (TIMP2) was downregulated. Conclusions: This study provided a new research clue for the role of ROS and deregulated TGF-ß signaling pathway in SiNPs nephrotoxicity.

Punicalagin attenuates myocardial oxidative damage, inflammation, and apoptosis in isoproterenol-induced myocardial infarction in rats: Biochemical, immunohistochemical, and in silico molecular docking studies.

Myocardial infarction (MI) is a life-threatening ischemic disease and is one of the leading causes of morbidity and mortality worldwide. Punicalagin (PU), the major ellagitannin found in pomegranates, is characterized by multiple antioxidant activities. The aim of this study is to assess the protective effects of PU against isoproterenol (ISO)-induced acute myocardial damage and to investigate its underlying vascular mechanisms using rat model. METHODS: Rats were randomly divided into five groups and were treated orally (p.o.) with PU (25 and 50 mg/kg) for 14 days. ISO was administered subcutaneously (S.C.) (85 mg/kg) on the 15th and 16th days to induce Myocardial infarction. Cardiac markers, oxidative stress markers, and inflammatory cytokines levels were determined in the heart tissue. Immunohistochemistry analysis was performed to determine the protein expression pathways of inflammation, apoptosis and oxidative stress (Nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (HO-1) in all the groups. In silico study was carried out to evaluate the molecular interaction of PU with some molecular targets. RESULTS: Our results showed that ISO-induced cardiac tissue injury was evidenced by increased serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH), associated with several histopathological changes. ISO also induced an increase of MDA, PCO, NO, and 8-hydroxy-2-deoxyguanosine (8-OHdG), along with a decrease of antioxidant enzyme activities in the myocardial tissues. In addition, an increase of TNF-α, NF-κB, IL-6, IL-1ß, iNOS, Nrf2 and (HO-1) was observed. Pre-treatment with PU reduced myocardial infract area, ameliorated histopathological alterations in myocardium, and decreased activities of myocardial injury marker enzymes in ISO-induced rats. In addition, PU remarkably restored ISO-induced elevation of lipid peroxidation and decrease of antioxidants, significantly reduced myocardial pro-inflammatory cytokines concentrations in this animal model. Molecular docking analysis of PU with protein targets showed potent interactions with negative binding energies. In conclusion, PU can protect the myocardium from oxidative injury, inflammatory response, and cell death induced by ISO by upregulating Nrf2/HO-1 signaling and antioxidants.

Increased anti-inflammatory activity and enhanced phytochemical concentrations in superfine powders obtained by controlled differential sieving process from four medicinal plants.

Anti-inflammatory effect of Rosa canina, Salix alba, Scrophularia nodosa and Hedera helix were studied in LPS-stimulated primary peripheral blood mononuclear cells (PBMCs) from mice (n=18) by comparing homogeneous powders of small microparticles (50-100 µm, 100-180 µm and 180-315 µm) obtained from plants via a controlled differential sieving process (CDSp) versus total plant materials obtained via hydroethanolic (HE) extraction. Further, phytochemical composition of the fine powders and HE extracts was determined by LC-PDA-ESI/MS analyses. Results showed that a one-hour pretreatment of PBMCs with fine powders, particularly those with superfine particle sizes (i.e. 50-100 µm and 100-180 µm), significantly inhibited TNFα, IL-1ß, IL-6 and NO production in LPS-stimulated PBMCs, by at least ca. 20% more than HE extracts (all, p<0.05). For each of the plants studied, their superfine powdered fractions were more concentrated in phenolic contents than their HE extracts. Overall, our results further confirm CDSp, as an environmentally friendly method, for improving the concentration of bioactive compounds as well as their biological activities.

Oxidative stress status and vitamin D levels of asymptomatic to mild symptomatic COVID-19 infections during the third trimester of pregnancy: A retrospective study in Metz, France.

It is believed that the subtle equilibrium between tolerance and immunity during the unique biological state of pregnancy, which is characterized by further physiological and hormonal changes, rends pregnant women more vulnerable to coronavirus disease 2019 (COVID-19). In this retrospective study, confirmed COVID-19-positive pregnant women (n = 15) during their third trimester, comprising asymptomatic (n = 7) and mild symptomatic (n = 8), and healthy pregnant controls (n = 20), were enrolled between June 1, 2020 and  June 1, 2021 from the Hospital CHR Metz-Thionville in Metz, France. Vitamin D concentrations, C-reactive protein (CRP), and oxidative stress markers including superoxide dismutase (SOD), catalase (CAT), reduced (GSH) and oxidized (GSSG) glutathione levels, hydrogen peroxide (H2 O2 ), and the total antioxidant capacity, measured the ferric reducing ability of plasma (FRAP), were evaluated in the serum of patients and controls. Results showed that all pregnant women (patients and controls) enrolled in this study were vitamin D deficient (<20 ng/ml). However, mild COVID-19 pregnant women were severely vitamin D deficient (<12 ng/ml), which may suggest a link between vitamin D deficiency and the symptomatology of COVID-19 illness in singleton pregnancy. No differences between the levels of CRP and the majority of the studied oxidative stress markers in COVID-19-positive pregnant women (asymptomatic and/or mildly symptomatic patients) versus COVID-19-negative pregnant women were found, suggesting the absence or a low magnitude of oxidative stress in pregnant women with COVID-19. This may also explain the absence of severe courses of COVID-19 infection. More studies are warranted to investigate the role of vitamin D supplementation and antioxidant-rich diets in the prevention against severe forms of COVID-19 in pregnant women.

Reduction of paw edema and liver oxidative stress in carrageenan-induced acute inflammation by Lobaria pulmonaria and Parmelia caperata, lichen species, in mice.

Paw edema volume reduction is a useful marker in determining the anti-inflammatory effect of drugs and plant extracts in carrageenan-induced acute inflammation. In this study, the anti-inflammatory effect of Lobaria pulmonaria (LP) and Parmelia caperata (PC), two lichen species, was examined in carrageenan-induced mouse paw edema test. Compared to the controls in carrageenan-induced inflammation (n = 5/group), our results showed that pretreatment by single oral doses with PC extract (50-500 mg/kg) gives better results than LP extract (50-500 mg/kg) in terms of anti-edematous activity, as after 4 h of carrageenan subplantar injection, paw edema formation was inhibited at 82-99% by PC while at 35-49% by LP. The higher anti-inflammatory effect of PC, at all doses, was also observed on the time-course of carrageenan-induced paw edema, displaying profile closely similar to that obtained with diclofenac (25 mg/kg), an anti-inflammatory drug reference (all p < 0.001). Both LP and PC, at all doses, significantly ameliorated liver catalase (CAT) activity (all p < 0.05). However, superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity and glutathione (GSH) levels were found increased in liver of PC- compared to LP-carrageenan-injected mice. Our findings demonstrated on one hand higher preventive effects of PC compared to LP in a mouse carrageenan-induced inflammatory model and suggested, on the other hand, that anti-inflammatory effects elicited by the two lichens were closely associated with the amelioration in the endogenous antioxidant status of liver.

Potentiation of the apoptotic signaling pathway in both the striatum and hippocampus and neurobehavioral impairment in rats exposed chronically to a low-dose of cadmium.

Cadmium (Cd) is a highly toxic heavy metal. It accumulates in biological tissues, especially in fish which constitutes a first rank food for humans, particularly in the coastal areas. This study investigates the effect of long-term exposure to low Cd concentration (17 µg/kg/day) in rat striatum and hippocampus. In this study, the neurobehavioral ability changes were assessed by applying cognitive standard testing at the end of the rats' exposure period. In addition, the examination of mitochondrial swelling was performed at the same time of evaluation of its redox status in the brain regions studied through stress parameters (GSH, MDA, GST, and CAT). This study examined also whether this long-term exposure can modify the apoptotic signaling pathway via assessment of apoptotic markers (caspase-8 and 9, Bax, Bcl-2, and Cyt-c) in cell lysates. The results of this study showed changes in neurobehavioral abilities of animals and a stronger mitochondrial swelling associated with a significant decrease in antioxidant systems (GSH, GST, and CAT) and conversely an increase in the lipoperoxidation end product (MDA) in both the striatal and hippocampal mitochondria. In addition, the results revealed a significant increase in pro-apoptotic intracellular components such as caspase-9, Cyt-c, and Bax, and showed also an evident decrease in Bcl-2 levels. In conclusion, our results reported that chronic exposure to Cd produces behavioral and cognitive perturbations, enhances oxidative stress associated with mitochondrial edema and Cyt-c leakage, and, ultimately, potentiates apoptosis signaling pathway in both brain regions in rats.

Chronic depression-like phenotype in male offspring mice following perinatal exposure to naturally contaminated eels with a mixture of organic and inorganic pollutants.

Previously, we demonstrated that maternal exposure to high, intermediate, or lowly contaminated European eels with a mixture of chemicals, during pregnancy and lactation, resulted in adult despair-like behavior, selectively in male offspring mice. Here, we investigate if depression-like behavior in offspring males was transient or permanent by monitoring immobility behavior, a measure of behavioral despair, at three distinct stages of life, including young adult (post-natal day (PND) 55), mature adult (PND 200) and middle (PNDs 335-336) age, in the forced swimming (FST) and the tail suspension (TST) tests. Oxidative stress markers including malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were evaluated in the hippocampus, prefrontal cortex, and cerebellum of middle-aged animals. Findings showed a significant enhancement of immobility behavior in the TST performed at young adult age (all p < 0.05) in the FST carried out at mature adult age (all p < 0.001) and in both behavioral tests realized at middle age (all p < 0.05, except one p = 0.06) in mice perinatally exposed to eels compared with non-exposed controls. Antioxidant-related enzyme activities, including SOD and CAT, were only elevated in the hippocampus of middle-aged males perinatally exposed to the two more polluted eels (all p < 0.05). Further, lipid peroxidation, assessed by MDA levels, was not found to be differentially regulated in the selected areas of middle-aged brains of exposed mice (all p > 0.05). Collectively, this suggested limited oxidative metabolism disturbances in middle-aged brains exposed to eels. In summary, our results highlighted that offspring males perinatally exposed to naturally contaminated reared and river eels with persistent organic pollutants (POPs) and heavy metals displayed chronic depression-like phenotype. As extrapolation of data to humans should be done with precaution, retrospective and prospective epidemiological studies are needed to clarify this potential relationship, stressed in our animal model, between maternal polluted fish consumption and chronically low mood in offspring.

Evidence that hydrogen peroxide, a component of oxidative stress, induces high-anxiety-related behaviour in mice.

The link between oxidative stress and high-anxiety-related behaviour is uncontested; but the cause-effect relationship has yet to be completely elucidated. Here, the behavioural effects of hydrogen peroxide (H2O2), given to mice (n = 10 per group) in drinking water at 1%, were assessed in the light/dark choice test, the open field, the elevated-plus maze and the hole-board test. Compared to controls (drinking only water), subacute exposure (10-15 days) of mice to H2O2, the major component of reactive oxygen species (ROS) and the precursor of potent oxidants (hydroxyl radical and hypochlorous acid), affected emotional responses by inducing an anxious behaviour associated with hyperactivity. Our findings clearly showed that H2O2-treated mice exhibited anxiogenic behaviour in the light/dark choice test and in the hole-board test. Moreover, H2O2-treated mice displayed a hyperactive behaviour, revealed by a significant increase in the number of crossings made in the open field test relative to controls. Although H2O2-exposed mice made significantly less head-dippings in the open arms than controls, H2O2-induced hyperactivity may have blurred anxiogenic-like behaviour in H2O2-treated mice in the elevated-plus maze. Our findings provide the evidence that H2O2, an oxidizing component, caused high-anxiety-related behaviour associated with hyperactivity in mice. Antioxidants may play a role in preventing or attenuating oxidative stress-related anxiety.

Powders with small microparticle size from Hedera helix and Scrophularia nodosa exhibited high preventive antioxidant activity against H2O2-induced oxidative stress in mouse primary spleen cells.

The purpose of this study was to examine the effects of powder particle size on the cytoprotective and antioxidant activity of Hedera helix (HH) and Scrophularia nodosa (SN), two medicinal plants more commonly known as ivy and figwort, against H2O2-induced oxidative stress in mouse primary spleen cells. Thus, the preventive effects of powders of 3 different granulometric classes (50-100 µm, 100-180 µm and 180-315 µm) and those of the hydroethanolic (HE) extract from HH and SN on oxidative stress were compared by monitoring reactive oxygen species (ROS) formation, malondialdehyde (MDA) production, and the activity of enzymatic antioxidants including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Results showed that pretreatment with the 3 fine powders from both plants generally offered to H2O2-exposed spleen cells, a protection against oxidative stress, highlighted by a significant decrease of both ROS formation and the level of MDA (p < 0.001), and a significant increase of GPx activity (p < 0.05). The two superfine powders (i.e. 50-100 µm and 100-180 µm), at 250 µg/mL, were more effective in modulating all oxidative stress markers studied than both HE extracts (p < 0.01), and the powder with the highest particular size (i.e., 180-315 µm) (p < 0.01). Compared to untreated cells, our results suggest that pretreatment with powders, in particular the superfine fractions, has relatively restored the levels of antioxidant-related enzymes including GPx, CAT and SOD. In summary, our results suggest differential effects between the 3 different fine powders studied, with the best cytoprotective and antioxidant activities being in favor of the superfine powders.

Perinatal effects of exposure to PCBs on social preferences in young adult and middle-aged offspring mice.

In social species, social interactions between conspecifics constitute a fundamental component to establish relations, provide best chances to reproduce, and even improve survival rates. In this study, a three-chambered social approach test was used to estimate the level of sociability and level of preference for social novelty in both male and female young adult (postnatal day (PND) 50) and middle-aged (PND 330) offspring mice (n=10 per group) that were perinatally exposed to a mixture of six polychlorinated biphenyls (PCBs), 28, 52, 101, 138, 153, and 180, at environmentally low doses (10 and 1000ng/kg b.w. for dams during gestation and lactation), a profile that closely mimics human exposure to contaminated fish. Our results showed that PCBs bidirectionally modulated social preferences in offspring mice, and the effects were sex and age dependent. However, increased levels of social interactions were rather frequently detected in both assays of the three-chambered test. Reduced social interaction was only induced in 1000ng/kg PCB-exposed middle-aged males, which exhibited similar preferences to social and non-social stimuli when compared to middle-aged controls. Furthermore, results showed that plasma levels of both corticosterone and acetylcholinesterase activity were higher in all PCB-exposed middle-aged males and females than in their control counterparts. In summary, although the effects of PCBs were only of moderate magnitude, our results suggest that a PCB mixture can act as an endocrine disruptor in offspring mice, disturbing the formation of normal social habits.

Hippocampal-dependent memory deficit induced by perinatal exposure to polutted eels in middle-aged offspring mice: Sex differential effects.

The effects of perinatal exposure to low, intermediate, or highly polluted eels on neonatal, postnatal, adult and middle-aged brain inflammation, and on cognitive performances of middle-aged offspring mice were compared to those of offspring controls. Inflammatory markers in microglia were assessed in offspring on the postnatal days-PNDs 1, 21, 100 and 330. Activated p38MAPK, ERK-1/2 and p65, and acetylcholine levels were assessed in the middle-aged hippocampus. Plasma myeloperoxidase and corticosterone levels were evaluated at PND 330. Learning and its retention, and working memory in middle-aged offspring were assessed using the Morris water maze, and Y-maze. Our results showed enhanced microglia production of inflammatory markers across the lifespan of male as well as female exposed offspring. Inflammation and increased p38 MAPK activation were detected in the exposed middle-aged hippocampus of both exposed sexes. Significant levels of MPO, but not corticosterone, were found in middle-aged males and females perinatally exposed to eels. However, decreases in ERK1/2 and p65 activation, and acetylcholine levels were only detected in female hippocampus exposed to either intermediately or highly polluted eels. Sex selective effects were also detected with regard to memory, the only altered cognitive function. Thus, middle-aged females, but not males, perinatally exposed to either intermediately or highly polluted eels take longer to locate the escape platform, spend considerably less time in the platform and perform less visit to the platform in the retention test. Our results suggest perinatal programming of hippocampal-dependent memory deficit by inflammation in middle-aged offspring, in sex and dose dependent manner.

Alteration of membrane integrity and respiratory function of brain mitochondria in the rats chronically exposed to a low dose of acetamiprid.

The pesticides are used in several fields of agriculture and farms to protect crops against harmful insects and herbs. The increased and uncontrolled use of these pollutants is very hazardous for the population health. Consumption of contaminated food matrices with these pesticides could impair the cell integrity and its molecular function. The main aim of this present study was to evaluate the alteration of the integrity of mitochondrial membranes and respiratory chain potential in the brain of rats exposed during 90 days to acetamiprid (AC), organochlorine of the new generation. After oral administration of AC in rats with 3.14 mg/kg of body weight, the results of this current study showed enhance in mitochondrial oxidative stress status by significant decrease of glutathione (GSH) level, glutathione pyroxidase (GPx), and catalase (CAT) activities. On the other hand, there is an increase in the enzymatic activity of the glutathione s-transferase (GST) and superoxide dismutase (SOD); at the same time, the MDA level was also highly increased. Furthermore, evaluation results of brain mitochondrial integrity revealed a significant increase in membrane permeability and mitochondrial swelling in rats exposed chronically to AC. Instead, other results of this present work showed a significant decrease in mitochondrial respiration potent (O2 consumption) in acetamiprid-treated rats. In conclusion, the long duration exposition of the animals to AC has led to respiratory chain dysfunction, disturbance of matrix oxidative status, and a loss of mitochondrial membranes integrity.

Impairment of mitochondrial integrity and redox status in brain regions during a low-dose long-term exposition of rats to pyrethrinoïds: the preventive effect of quercetin.

Pyrethrinoïds are synthetic pesticides widely used in agriculture and farms to protect crops from weeds, insects, fungi, and molds. Increased and uncontrolled use of these pollutants can have harmful effects on human health via consumption of contaminated food products. In the present study, deltamethrin (DLT = 3.72 mg/kg) and Bifenthrin (BF = 2.6 mg/kg) were used during a long-term exposition in the rats to assess their effect on mitochondrial integrity and function in different brain areas (hippocampus, striatum, cortex, and cerebellum). The results of this study have shown that chronic treatment of rats by both DLT and BF, on their own or in a mixture, has induced a significant increase in mitochondrial MDA, but when quercetin (Que) was co-administered with pesticides, this enhancement has been prevented in the almost of treated rats compared to solvent and control groups. In hippocampus area, GSH has significantly increased in all treated rats, except for BF and DLT-Que.-treated groups. In striatum, GSH has been depleted in the BF and DLT-treated groups compared to control and solvent groups; in contrast, when Que. was associated with pesticides, the rate of this tripeptide has been maintained at normal levels. In the cortex and cerebellum, GSH has been depleted significantly in all treated animals but has increased in DLT-Que. and mixture-Que.-treated groups in the cerebral cortex, at the same time; it has been maintained at normal levels in BF-Que.-treated groups in the cerebellum compared to control and solvent rats. On the other side, the results of this study have shown a loss of catalase (CAT) and glutathione S-transferase (GST) activities in all brain regions of pesticide-treated rats, but such a fall in enzymatic activities has been prevented by Que. when it was co-administered to rats with pesticides at the dose of 5 mg/kg, except in the cerebellum. In addition, this study has shown mitochondria's swelling in almost all the brain areas with exception of the cerebellum, providing information about a loss of mitochondrial membrane integrity in brain neurons of rats exposed to pyrethrinoïds. Furthermore, preventive administration of Que., in association with pesticides (5 mg/kg) or their mixture (10 mg/kg), has prevented mitochondria swelling in almost all of the analyzed brain tissues.

Improvement of cytoprotective and antioxidant activity of Rosa canina L. and Salix alba L. by controlled differential sieving process against H2O2-induced oxidative stress in mouse primary splenocytes.

In this study, cytoprotective and antioxidant activities of Rosa canina (RC) and Salix alba (SA), medicinal plants, were studied on mouse primary splenocytes by comparing Controlled Differential Sieving process (CDSp), which is a novel green solvent-free process, versus a conventional technique, employing hydroethanolic extraction (HEE). Thus, preventive antioxidant activity of three plant powders of homogeneous particle sizes, 50-100 µm, 100-180 µm and 180-315 µm, dissolved directly in the cellular buffer, were compared to those of hydroethanolic (HE) extract, at 2 concentrations (250 and 500 µg/mL) in H2O2-treated spleen cells. Overall, compared to HE extract, the superfine powders, i. e., fractions < 180 µm, at the lowest concentration, resulted in greater reactive oxygen species (ROS) elimination, increased glutathione peroxidase (GPx) activity and lower malondialdehyde (MDA) production. Better antioxidant and preventive effects in pre-treated cells were found with the superfine powders for SA (i. e., 50-100 µm and 100-180 µm, both p < 0.001), and with the intermediate powder for RC (i. e., 100-180 µm, p < 0.05) versus HE extract. The activity levels of catalase (CAT) and superoxide dismutase (SOD) in pretreated splenocytes exposed to H2O2, albeit reduced, were near to those in unexposed cells, suggesting that pretreatment with the fine powders has relatively restored the normal levels of antioxidant-related enzymes. These findings supported that CDSp improved the biological activities of plants, avoiding the use of organic solvents and thus it could be a good alternative to conventional extraction techniques.

Perinatal programming of depressive-like behavior by inflammation in adult offspring mice whose mothers were fed polluted eels: Gender selective effects.

Several lines of evidence indicate that early-life inflammation may predispose to mental illness, including depression, in later-life. We investigated the impact of perinatal exposure to polluted eels on neonatal, postnatal, and adult brain inflammation, and on the resignation behavior of male and female adult offspring mice. The effects of maternal standard diet (laboratory food) were compared to the same diet enriched with low, intermediate, or highly polluted eels. Brain inflammatory markers including cytokines were assessed in offspring mice on the day of birth (i.e., on the postnatal day-PND 1), upon weaning (PND 21) and at adulthood (PND 100). Plasma myeloperoxidase and corticosterone levels were evaluated at PND 100. Immobility behavior of offspring was assessed in adulthood (i.e., at PNDs 95-100), using the tail suspension and forced swimming tests. Chronic brain inflammation was found in male and female offspring mice compared to controls, as assessed at PNDs 1, 21, and 100. The level of myeloperoxidase was found to be significantly higher in both adult males and females vs. control offspring. However, high corticosterone levels were only found in male offspring mice that were perinatally exposed to eels, suggesting a gender-selective dysregulation of the adult hypothalamic-pituitaryadrenal (HPA) axis. Gender-specific differences were also detected in adulthood in regard to offspring resignation behavior. Thus, compared to controls, males, but not females, whose mothers were fed eels during pregnancy and lactation exhibited a depressive-like behavior in adult age in both behavioral models of depression. Depressive symptoms were more pronounced in male mice perinatally exposed to either intermediate or highly polluted eels than those exposed to only lowly polluted eels. Our results indicate that early-life inflammatory insult is a plausible causative factor that induces the depressive phenotype exhibited by male adult offspring mice, most likely through a gender-specific HPA axis enhanced activation.

Neurobehavioral deficits and brain oxidative stress induced by chronic low dose exposure of persistent organic pollutants mixture in adult female rat.

Persistent organic pollutants (POPs) are long-lived organic compounds that are considered one of the major risks to ecosystem and human health. Recently, great concerns are raised about POPs mixtures and its potential toxicity even in low doses of daily human exposure. The brain is mostly targeted by these lipophilic compounds because of its important contain in lipids. So, it would be quite interesting to study the effects of exposure to these mixtures and evaluate their combined toxicity on brain cells. The present study was designed to characterize the cognitive and locomotors deficits and brain areas redox status in rat model. An orally chronic exposure to a representative mixture of POPs composed of endosulfan (2.6 µg/kg), chlorpyrifos (5.2 µg/kg), naphthalene (0.023 µg/kg) and benzopyrane (0.002 µg/kg); the same mixture with concentration multiplied by 10 and 100 was also tested. Exposed rats have shown a disturbance of memory and a decrease in learning ability concluded by Morris water maze and the open field tests results and anxiolytic behaviour in the test of light/dark box compared to control. Concerning brain redox homeostasis, exposed rats have shown an increased malondialdehyde (MDA) amount and an alteration in glutathione (GSH) levels in both the brain mitochondria and cytosolic fractions of the cerebellum, striatum and hippocampus. These effects were accompanied by a decrease in levels of cytosolic glutathione S-transferase (GST) and a highly significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in both cytosolic and mitochondrial fractions. The current study suggests that environmental exposure to daily even low doses of POPs mixtures through diet induces oxidative stress status in the brain and especially in the mitochondria with important cognitive and locomotor behaviour variations in the rats.

No evidence for oxidative stress in the cerebellar tissues or cells of juvenile male mice exposed via lactation to the 6 non-dioxin-like PCBs at levels below the regulatory safe limits for humans.

The developing central nervous system is particularly vulnerable to environmental contaminants such as non-dioxin-like polychlorinated biphenyls (NDL-PCBs). This study investigated the potential oxidative effects in mice pups exposed via lactation to the sum of the six indicator NDL-PCBs (∑6 NDL-PCBs) at 0, 1, 10 and 100 ng/kg per 14 days, constituting levels below the guidance values fixed by French food safety agencies for humans at 10 ng/kg body weight per day. For this purpose, the oxidative status was assessed by flow cytometry via dichloro-dihydro-fluorescein diacetate in the cerebellum of juvenile male offspring mice during brain growth spurt [postnatal day (PND) 14]. No significant differences were found in the levels of reactive oxygen species in the cerebellar neurons or glial cells (astrocytes, oligodendrocytes and microglia) of lactationally exposed male mice at PND 14 (p>0.05). Concordantly, oxidative-stress related gene expression was measured by qPCR for catalase, copper zinc superoxide dismutase 1, glyoxalase 1, glutathione peroxidase 1, and glutathione reductase 1, in the cerebellum at PND 14 appeared unaffected, as also verified at the protein level by immunoblots. Moreover, transcriptomic data from our previous work have not shown differences in the mRNA expressions of genes belonging to GO terms involved in oxidative stress in neurons of male mice exposed to ∑6 NDL-PCBs compared to controls; except for glyoxalase 1 which was downregulated in neurons isolated from exposed group compared to controls. Our findings suggest that lactational exposure to NDL-PCBs at environmental relevant concentrations may not cause significant oxidative effect on juvenile cerebellum.

Lactational exposure of mice to low levels of non-dioxin-like polychlorinated biphenyls increases susceptibility to neuronal stress at a mature age.

Lactational exposure to low levels of the sum of the six indicator polychlorinated biphenyls (Σ6 NDL-PCBs, 10ng/kg/day) is known to lead to persistent anxious behavior in young and adult offspring mice at postnatal days 40 and 160, respectively. At more advanced life stages, we evaluated the effects on the mouse brain of neuronal stress induced by the synaptotoxic amyloid-beta (Aß) peptide. Perinatal exposure of lactating mice to Σ6 NDL-PCBs did not affect short-term memory performances of their offspring male mice aged 14 months as compared to control PCB-naive mice. However, following intracerebroventricular injection of soluble Aß oligomers, significant impairments in long-term memory were detected in the mice that had been lactationally treated with Σ6 NDL-PCBs. In addition, immunoblot analyses of the synaptosomal fraction of hippocampal tissues from treated mice revealed a lower expression of the synaptic proteins synaptophysin and PSD-95. Though preliminary, our findings suggest for the first time that early exposure to low levels of NDL-PCBs induce late neuronal vulnerability to amyloid stress. Additional experiments are needed to confirm whether early environmental influences are involved in the etiology of brain aging and cognitive decline.