The long-term health outcome of prenatal exposure to arsenic has been associated with increased mortality in human populations. In this study, the extent to which maternal arsenic exposure impacts gene expression in the newborn was addressed. We monitored gene expression profiles in a population of newborns whose mothers experienced varying levels of arsenic exposure during pregnancy. Through the application of machine learning–based two-class prediction algorithms, we identified expression signatures from babies born to arsenic-unexposed and -exposed mothers that were highly predictive of prenatal arsenic exposure in a subsequent test population. Furthermore, 11 transcripts were identified that captured the maximal predictive capacity to classify prenatal arsenic exposure. Network analysis of the arsenic-modulated transcripts identified the activation of extensive molecular networks that are indicative of stress, inflammation, metal exposure, and apoptosis in the newborn. Exposure to arsenic is an important health hazard both in the United States and around the world, and is associated with increased risk for several types of cancer and other chronic diseases. These studies clearly demonstrate the robust impact of a mother's arsenic consumption on fetal gene expression as evidenced by transcript levels in newborn cord blood.

Human lymphoblastoid cells derived from different healthy individuals display considerable variation in their transcription profiles.Here we show that such variation in gene expression underlies interindividual susceptibility to DNA damaging agents. The results demonstrate the massive differences in sensitivity across a diverse cell line panel exposed to an alkylating agent. Computational models identified 48 genes with basal expression that predicts susceptibility with 94% accuracy. Modulating transcript levels for two member genes, MYH and C21ORF56, confirmed that their expression does indeed influence alkylation sensitivity. Many proteins encoded by these genes are interconnected in cellular networks related to human cancer and tumorigenesis. The interindividual differences in disease susceptibility, responsiveness to chemotherapeutics, and susceptibility to environmental exposures across human populations are influenced by a combination of gene-environment interactions. Over the past few years, studies aimed at dissecting the genetic basis underlying human phenotypic variation have built off of the dense genotyping established by the HapMap Consortium. A wealth of genome-wide association studies (GWAS) have described how human genetic variation, at the level of single nucleotide differences, is linked to such complex diseases as diabetes and breast cancer (Hunter et al. 2007;Zeggini and McCarthy 2007). In addition, GWAS have also linked DNA polymorphic variants to gene expression variation across populations (Cheung et al. 2005;Stranger et al. 2005Stranger et al. , 2007Dixon et al. 2007).However, while it is known that human lymphoblastoid cells derived from different healthy individuals display considerable variation in their transcription profiles (Cheung et al. 2003(Cheung et al. , 2005Stranger et al. 2005Stranger et al. , 2007Dixon et al. 2007), the influence this variation has on the response to environmental and chemotherapeutic agents is unknown. In this study, a panel of 24 cell lines previously derived from unrelated, healthy individuals with diverse ancestry (Collins et al. 1998) was tested for variation in sensitivity to the DNA damaging agent, N-methyl-NЈ-nitro-N-nitrosoguanidine (MNNG). MNNG induces a variety of alkylated DNA bases, among which O 6 -methylguanine (O 6 MeG) is known to be particularly toxic as well as mutagenic because it pairs with thymine during replication. O 6 MeG can be repaired by the MGMT DNA repair methyltransferase (Pegg 1990(Pegg , 2000, but left unrepaired, the ensuing O 6 MeG:T base pair can be processed by the DNA mismatch repair (MMR) pathway, and such processing actually triggers apoptotic cell death and cytotoxicity (Kaina et al. 1997; Samson 1999, 2004). Therefore, cells deficient in MGMT but proficient for MMR are extremely sensitive to MNNG-induced killing, whereas cells deficient in both MGMT and MMR are extremely resistant or tolerant to MNNG, but at the cost of increased mutation (Karran 2001). While MGMT and MMR status are thus known to be associated w...

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Stress is implicated in the development of AD since oxidative stress has been linked to cognitive impairment. Epigallocatechin-3-gallate (EGCG) is the most abundant catechin in green tea and has antioxidant, anti-inflammatory and anti-atherogenic effects, while Diazepam is an anxiolytic with promising neuroprotective properties. Methods: Seven groups (8 rats/ group) were daily IP injected for six week either with saline for control (2 groups) or with 70 mg/kg ALCL3 for AD-induced model (5 groups). Stress was induced for all groups except one control and one ALCL3 group by exposing rats 6 times during six weeks to Stress-induced box paradigm (1time/ week for 30 minute). Three groups of AD-induced model were also daily received either EGCG (10mg/kg, IP), Diazepam (0.1mg/kg, IP) or their combination. All rats were examined in two behavioral experiments; Morris water maze task and Conditioned-avoidance learning test. Histological examination was achieved in different brain regions and biochemical measurements as brain cholinergic markers (ACHE); oxidative stress markers (SOD, GSH-Px, MDA, TAC) and inflammatory mediators (TNF-a, IL-1b) were also assayed for all groups. Results: Rats exposed to ALCL3 together with stress showed marked decline in learning and memory abilities. Stress also induced significant elevation in hippocampus TNF-a, IL-1b and MDA level as well as in ACHE activity accompanied by reduction in GSH-Px, TAC and SOD activities. Marked histopathological brain degenerations were also shown in AD-model group exposed to stress. EGCG showed more marked protective effect than Diazepam from stress-potentiated the deleterious effect of ALCL3 on the brain, however Co-administration of both resulted in more pronounced protection as regarding all measured parameters. Conclusions:Exposure to stress represents a risk factor in induction and progression of AD. The deleterious effect of stress on the brain and hippocampus can be counteracted by Co-administration of both EGCG and Diazepam.

We describe a rapid method to accurately measure the cytotoxicity of mammalian cells upon exposure to various drugs. Using this assay, we obtain survival data in a fraction of the time required to perform the traditional clonogenic survival assay, considered the gold standard. The dynamic range of the assay allows sensitivity measurements on a multi-log scale allowing better resolution of comparative sensitivities. Moreover, the results obtained contain additional information on cell cycle effects of the drug treatment. Cell survival is obtained from a quantitative comparison of proliferation between drug-treated and untreated cells. During the assay, cells are treated with a drug and, following a recovery period, allowed to proliferate in the presence of BrdU. Cells that synthesize DNA in the presence of bromodeoxyuridine (BrdU) exhibit quenched Hoechst fluorescence easily detected by flow cytometry; quenching is used to determine relative proliferation in treated versus untreated cells. Finally, the multi-well setup of this assay allows the simultaneous screening of multiple cell lines, multiple doses, or multiple drugs to accurately measure cell survival and cell cycle changes after drug treatment.