Environmental pollutants act as risk factors for Alzheimer's disease (AD), mainly affecting the aging population. We investigated early manifestations of AD-like pathology by a mixture of arsenic (As), cadmium (Cd), and lead (Pb), reported to impair neurodevelopment. We treated rats with As+Cd+Pb at their concentrations detected in groundwater of India, ie, 0.38, 0.098, and 0.22 ppm or 10 times of each, respectively, from gestation-05 to postnatal day-180. We identified dose-dependent increase in amyloid-beta (Aβ) in frontal cortex and hippocampus as early as post-weaning. The effect was strongly significant during early-adulthood, reaching levels comparable to an Aβ-infused AD-like rat model. The metals activated the proamyloidogenic pathway, mediated by increase in amyloid precursor protein (APP), and subsequent beta secretase (BACE) and presenilin (PS)-mediated APP-processing. Investigating the mechanism of Aβ-induction revealed an augmentation in oxidative stress-dependent neuroinflammation that stimulated APP expression through interleukin-responsive-APP-mRNA 5'-untranslated region. We then examined the effects of individual metals and binary mixtures in comparison with the tertiary. Among individual metals, Pb triggered maximum induction of Aβ, whereas individual As or Cd had a relatively non-significant effect on Aβ despite enhanced APP, owing to reduced induction of BACE and PS. Interestingly, when combined the metals demonstrated synergism, with a major contribution by As. The synergistic effect was significant and consistent in tertiary mixture, resulting in the augmentation of Aβ. Eventually, increase in Aβ culminated in cognitive impairments in the young rats. Together, our data demonstrate that exposure to As+Cd+Pb induces premature manifestation of AD-like pathology that is synergistic, and oxidative stress and inflammation dependent.

The key genes involved in the cell cycle of human T lymphocytes were identified by iterative searches of gene-related databases, as derived also from DNA microarray experimentation, revealing and predicting interactions between those genes, assigning scores to each of the genes according to numbers of interaction for each gene weighted by significance of each interaction, and finally applying several types of clustering algorithms to genes basing on the assigned scores. All clustering algorithms applied, both hierarchical and K-means, invariably selected the same six "leader" genes involved in controlling the cell cycle of human T lymphocytes. Relations of the six genes to experimental data describing switching between stages of cell cycle of human T lymphocytes are discussed.

In a cross-sectional study, a random sample of 197 male workers drawn from different sections of 10 leather tanneries in Kanpur were selected for the assessment of health risks. A control group comprising of 117 male subjects belonging to a similar age group and socioeconomic strata, who never had any occupational exposure in the leather tanneries, were also examined for the comparison purpose. The findings revealed a significantly higher prevalence of morbidity among the exposed workers in contrast to that observed in the controls (40.1% vs. 19.6%). The respiratory diseases (16.7%) were mainly responsible for a higher morbidity among the exposed workers whereas the gastrointestinal tract problems were predominant in the control group. The urinary and blood samples collected from the exposed group showed significantly higher levels of chromium, thereby reflecting the body burden of Cr in the exposed workers as a result of a high concentration of environmental Cr at the work place.

The peroxisome proliferator-activated receptor gamma (PPARγ), a group of ligand-activated transcriptional factors, is expressed in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Here, we investigated the role of PPARγ in regulating GFAP using a mixture of As, Cd and Pb (metal mixture, MM) that induces apoptosis and aberrant morphology in rat brain astrocytes. We observed a phospho PPARγ (serine 112 (S112)) (p-PPARγ (S112))-mediated downregulation of GFAP in the MM-exposed astrocytes. We validated this using pure PPARγ agonist, troglitazone (TZ). As reported with MM, TZ induced astrocyte damage owing to reduced GFAP. In silico analysis in the non-coding region of GFAP gene revealed two PPARγ response elements (PPREs); inverted repeat 10 and direct repeat 1 sequences. Gel shift and chromatin immunoprecipitation assays demonstrated enhancement in binding of p-PPARγ (S112) to the sequences, and luciferase reporter assay revealed strong repression of GFAP via PPREs, in response to both MM and TZ. This indicated that suppression in GFAP indeed occurs through direct regulation of these elements by p-PPARγ (S112). Signaling studies proved that MM, as well as TZ, activated the cyclin-dependent kinase 5 (CDK5) and enhanced its interaction with PPARγ resulting into increased p-PPARγ (S112). The p-CDK5 levels were dependent on proximal activation of extracellular signal-regulated protein kinase 1/2 and downstream Jun N-terminal kinase. Taken together, these results are the first to delineate downregulation of GFAP through genomic and non-genomic signaling of PPARγ. It also brings forth a resemblance of TZ with MM in terms of astrocyte disarray in developing brain.

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Oxidative stress status and Acetylcholinesterase (AChE) activity were studied in blood samples obtained from 61 agricultural workers engaged in spraying organophosphorus (OP) insecticides in the mango plantation, with a minimum work history of one year, in the age range of 12-55 years. Controls were age-matched, unexposed workers, who never had any exposure to OP pesticides. They were evaluated for oxidative stress markers MDA (end product of lipid peroxidation), reduced glutathione (GSH), and Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) levels in blood. The results showed a marked inhibition of the AChE and BChE activities in the sprayers as compared to the controls. The malondialdehyde(MDA), the last product of lipid peroxidation was found to be increased significantly in sprayers(p<0.05), while depletion in the concentration of antioxidant glutathione(GSH) was also observed in the sprayers but the difference was statistically not significant. It was concluded on the basis of biochemical analysis that pesticides sprayers are exposed to more oxidative stress as evidenced by the changes in antioxidant status. The measurement of the AChE and BChE activities in agricultural workers who spray OPs could be a good biomonitoring factor and is recommended to be performed on a regular basis.

The astrocyte marker, glial fibrillary acidic protein (GFAP), has essential functions in the brain, but may trigger astroglial scarring when expressed in excess. Docosahexaenoic acid (DHA) is an n-3 fatty acid that is protective during brain development. However, the effect of DHA on GFAP levels of developing brain remains unexplored. Here, we detected that treating developing rats with DHA-enriched fish-oil caused dose-dependent GFAP augmentation. We investigated the mechanism promoting GFAP, hypothesizing the participation of fatty acid-binding protein-7 (FABP7), known to bind DHA.We identified that DHA stimulated FABP7 expression in astrocytes, and FABP7-silencing suppressed DHA-induced GFAP, indicating FABP7-mediated GFAP increase. Further investigation proved FABP7 expression to be phosphatidylinositide 3-kinases (PI3K)/AKT and nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARc)-dependent. We found that PI3K/AKT activated PPARc that triggered FABP7 expression via PPARc-responsive elements within its gene. Towards identifying FABP7-downstream pathways, we considered our previous report that demonstrated cyclin-dependent kinase-5 (CDK5)-PPARc-protein-protein Abbreviations used: BBB, blood-brain barrier; CDK5, cyclindependent kinase-5; CNS, central nervous system; DHA, docosahexaenoic acid; FABP7, fatty acid-binding protein-7; GFAP, glial fibrillary acidic protein; MKP3, MAP-kinase-phosphatase-3; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PPARc, peroxisome proliferatoractivated receptor-gamma. 96© complex to suppress GFAP. We found that the DHA-induced FABP7 underwent protein-protein interaction with PPARc, which impeded CDK5-PPARc formation. Hence, it appeared that enhanced FABP7-PPARc in lieu of CDK5-PPARc resulted in increased GFAP. PI3K/AKT not only stimulated formation of FABP7-PPARc protein-protein complex, but also up-regulated a FABP7-independent MAP-kinase-phosphatase-3 pathway that inactivated CDK5 and hence attenuated CDK5-PPARc. Overall, our data reveal that via the proximal PI3K/AKT, DHA induces FABP7-PPARc, through genomic and non-genomic mechanisms, and MAP-kinase-phosphatase-3 that converged at attenuated CDK5-PPARc and therefore, enhanced GFAP. Accordingly, our study demonstrates a DHA-mediated astroglial hyperactivation, pointing toward a probable injurious role of DHA in brain development.