Age-dependent variability in gene expression in male Fischer 344 rat retina.
Ontology highlight
ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC4796736 | biostudies-literature | 2009 Jan
REPOSITORIES: biostudies-literature
Publications
Age-dependent variability in gene expression in male Fischer 344 rat retina.
Li Zhen Z Wright Fred A FA Royland Joyce J
Toxicological sciences : an official journal of the Society of Toxicology 20081020 1
Recent evidence suggests that older adults may be a sensitive population with regard to environmental exposure to toxic compounds. One source of this sensitivity could be an enhanced variability in response. Studies on phenotypic differences have suggested that variation in response does increase with age. However, few reports address the question of variation in gene expression as an underlying cause for increased variability of phenotypic response in the aged. In this study, we utilized global ...[more]
Similar Datasets
Project description:To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week). Results: Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. Conclusions: These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mg Ni/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 µg Ni/g lung, for immune/inflammatory signaling. Implications: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity.
2014-07-19 | GSE59593 | GEO
Project description:BackgroundBisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to development of obesity and metabolic disorders. Humans are constantly exposed to low concentrations of BPA, and studies support that the developmental period is particularly sensitive.ObjectivesThe aim was to investigate the effects of low-dose developmental BPA exposure on metabolic parameters in male and female Fischer 344 (F344) rat offspring.MethodsPregnant F344 rats were exposed to BPA via their drinking water, corresponding to 0.5 ?g/kg BW/d (BPA0.5; n=21) or 50 ?g/kg?BW/d (BPA50; n=16), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (n=26). Body weight (BW), adipose tissue, liver (weight, histology, and gene expression), heart weight, and lipid profile were investigated in the 5-wk-old offspring.ResultsMales and females exhibited differential susceptibility to the different doses of BPA. Developmental BPA exposure increased plasma triglyceride levels (0.81±0.10 mmol/L compared with 0.57±0.03 mmol/L, females BPA50 p=0.04; 0.81±0.05 mmol/L compared with 0.61±0.04 mmol/L, males BPA0.5 p=0.005) in F344 rat offspring compared with controls. BPA exposure also increased adipocyte cell density by 122% in inguinal white adipose tissue (iWAT) of female offspring exposed to BPA0.5 compared with controls (68.2±4.4 number of adipocytes/HPF compared with 55.9±1.5 number of adipocytes/HPF; p=0.03) and by 123% in BPA0.5 females compared with BPA50 animals (68.2±4.4 number of adipocytes/high power field (HPF) compared with 55.3±2.9 number of adipocytes/HPF; p=0.04). In iWAT of male offspring, adipocyte cell density was increased by 129% in BPA50-exposed animals compared with BPA0.5-exposed animals (69.9±5.1 number of adipocytes/HPF compared with 54.0±3.4 number of adipocytes/HPF; p=0.03). Furthermore, the expression of genes involved in lipid and adipocyte homeostasis was significantly different between exposed animals and controls depending on the tissue, dose, and sex.ConclusionsDevelopmental exposure to 0.5 ?g/kg?BW/d of BPA, which is 8-10 times lower than the current preliminary EFSA (European Food Safety Authority) tolerable daily intake (TDI) of 4 ?g/kg?BW/d and is within the range of environmentally relevant levels, was associated with sex-specific differences in the expression of genes in adipose tissue plasma triglyceride levels in males and adipocyte cell density in females when F344 rat offspring of dams exposed to BPA at 0.5 ?g/kg?BW/d were compared with the offspring of unexposed controls. https://doi.org/10.1289/EHP505.
| S-EPMC5743697 | biostudies-literature
Project description:To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week). Results: Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. Conclusions: These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mg Ni/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 M-BM-5g Ni/g lung, for immune/inflammatory signaling. Implications: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week).
2014-07-19 | E-GEOD-59593 | biostudies-arrayexpress
Project description:This paper reports the development of a high-resolution 3-D MRI atlas of the Fischer 344 adult rat brain. The atlas is a 60 ?m isotropic image volume composed of 256 coronal slices with 71 manually delineated structures and substructures. The atlas was developed using Pydpiper image registration pipeline to create an average brain image of 41 four-month-old male and female Fischer 344 rats. Slices in the average brain image were then manually segmented, individually and bilaterally, on the basis of image contrast in conjunction with Paxinos and Watson's (2007) stereotaxic rat brain atlas. Summary statistics (mean and standard deviation of regional volumes) are reported for each brain region across the sample used to generate the atlas, and a statistical comparison of a chosen subset of regional brain volumes between male and female rats is presented. On average, the coefficient of variation of regional brain volumes across all rats in our sample was 4%, with no individual brain region having a coefficient of variation greater than 13%. A full description of methods used, as well as the atlas, the template that the atlas was derived from, and a masking file, can be found on Zenodo at www.zenodo.org/record/3700210. To our knowledge, this is the first MRI atlas created using Fischer 344 rats and will thus provide an appropriate neuroanatomical model for researchers working with this strain.
| S-EPMC7181609 | biostudies-literature
Project description:Here, the role of methylation in regulation of rat Oct4 gene was evaluated during embryonic development, in adult tissues and in embryo-derived cells. First, the region 3.1 kb upstream to the rat Oct4 ATG site was cloned and sequenced. The rat Oct4 upstream sequence was similar to that in bovine, mouse and human with two upstream elements: proximal (PE) and distal enhancers (DE) and four homology conserved regions (CR1-4). The conserved regions in the rat have 69% - 96% homology with bovine, human, mouse sequences. Next, the methylation pattern in the promoter was determined during embryonic development, in adult tissues, in rat embryonic stem cell (ESC)-like cells and umbilical cord-derived cells (the feeder for ESC-like cells) using the bisulfite method and DNA sequencing. The promoter was methylated in adult and fetal tissues, and in days post coitus (DPC) 10.5 and 12.5 embryos and hypomethylated in DPC4.5 embryos and in rat ESC-like cells. The expression of Oct4 was evaluated by qRT-PCR. DPC4.5 embryos and rat ESC-like cells had higher expression of the Oct4 gene compared to DPC10.5 and 12.5 embryos, adult tissues and embryoid bodies derived from rat ESC-like cells. Thus, the methylation status correlated with the qRT-PCR results. These results indicate that the rat Oct4 3.1kb promoter region is organized and contains transcription binding and regulatory sites similar to those described for bovine, mouse and human. The rat Oct4 promoter is methylated during embryonic development after 4.5 DPC and during differentiation of rat ESC-like cells to embryoid bodies.
| S-EPMC3280817 | biostudies-literature
Project description:In addition to the loss in bone volume that occurs with age, there is a decline in material properties. To test new therapies or diagnostic tools that target such properties as material strength and toughness, a pre-clinical model of aging would be useful in which changes in bone are similar to those that occur with aging in humans. Toward that end, we hypothesized that similar to human bone, the estimated toughness and material strength of cortical bone at the apparent-level decreases with age in the male Fischer F344 rat. In addition, we tested whether the known decline in trabecular architecture in rats translated to an age-related decrease in vertebra (VB) strength and whether non-X-ray techniques could quantify tissue changes at micron and sub-micron length scales. Bones were harvested from 6-, 12-, and 24-month (mo.) old rats (n=12 per age). Despite a loss in trabecular bone with age, VB compressive strength was similar among the age groups. Similarly, whole-bone strength (peak force) in bending was maintained (femur) or increased (radius) with aging. There was though an age-related decrease in post-yield toughness (radius) and bending strength (femur). The ability to resist crack initiation was actually higher for the 12-mo. and 24-mo. than for 6-mo. rats (notch femur), but the estimated work to propagate the crack was less for the aged bone. For the femur diaphysis region, porosity increased while bound water decreased with age. For the radius diaphysis, there was an age-related increase in non-enzymatic and mature enzymatic collagen crosslinks. Raman spectroscopy analysis of embedded cross-sections of the tibia mid-shaft detected an increase in carbonate subsitution with advanced aging for both inner and outer tissue.
| S-EPMC4724327 | biostudies-literature
Project description:The biological mechanisms that give rise to age-related hearing loss (ARHL) are still poorly understood. However, there is growing recognition that oxidative stress may be an important factor. To address this issue, we measured the changes in the expression of cochlear oxidative stress and antioxidant defense-related genes in young (2 months old), middle-aged (12 months old), and old (21-25 months old) Fischer 344/NHsd (F344/NHsd) rats and compared gene expression changes with ARHL. A quantitative real-time reverse transcription polymerase chain reaction array revealed a significant age-related downregulation of only 1 gene, stearoyl-coenzyme A desaturase 1, and upregulation of 12 genes: 24-dehydrocholesterol reductase; aminoadipate-semialdehyde synthase; cytoglobin; dual oxidase 2; glutathione peroxidase 3; glutathione peroxidase 6; glutathione S-transferase, kappa 1; glutathione reductase; nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase, quinone 1; solute carrier Family 38, Member 5; thioredoxin interacting protein; and vimentin. Statistical analyses revealed significant correlations between gene expression and auditory function in 8 genes. Our results identified specific subsets of oxidative stress genes that appear to play an important role in ARHL in the Fischer 344/NHsd rat.
| S-EPMC4077169 | biostudies-literature
Project description:The rostral ventrolateral medulla (RVLM), a part of the medullary reticular formation, plays a major role in several physiological responses, including cardiovascular and sympathetic nervous system functions. Although aging causes disturbances in the responses of these physiological systems, RVLM involvement in these age-related changes is not clear. Previous work using high-throughput gene expression analysis of the RVLM in aged animals suggested that chemical neurotransmission-related genes might be downregulated with advancing age. Since the RVLM function involves a balance of inhibitory and excitatory inputs, which is largely mediated by gamma-aminobutyric acid (GABA) and excitatory amino acid (EAA) neurotransmission, we hypothesized that aging is associated with altered excitatory and/or inhibitory neurotransmission-related gene expression in the RVLM. To test this hypothesis, we micropunched an RVLM-containing area from young (3–5 months), middle-aged (12–14 months), and aged (22–26 months) Fischer 344 male rats. RNA purified from these micropunches was analyzed using GABA and Glutamate RT2 Profiler PCR arrays (n= 8–10). In addition, the expression of selected genes was validated at the RNA level using TaqMan® based- qPCR and at the protein level using western blotting. All the genes that displayed significant differential expression (1.5-fold, p < .05, FDR < .05) were identified to be downregulated in the RVLM of aged and middle-aged rats compared to young rats. Among the downregulated genes, the percentage of glutamate neurotransmission-related genes was higher than GABA neurotransmission-related genes. Solute carrier family 1 member 6 (Slc1a6) gene showed the highest fold downregulation at the RNA level in the RVLM of aged compared to young rats, and its protein product, Excitatory amino acid transporter 4 (EAAT4), showed a downregulatory trend in the RVLM of aged and middle-aged rats. These results suggest that molecular constituents of both GABA and glutamate neurotransmission might be altered in the RVLM of aged and middle-aged rats, and the changes in glutamate neurotransmission might be more prominent. Investigating age-associated anatomical and functional changes in RVLM GABA and glutamate neurotransmission might provide a foundation for understanding the effects of aging on physiological function.
2022-12-07 | GSE220296 | GEO
Project description:BackgroundMembers of the mammalian nucleotide binding domain, leucine-rich repeat (LRR)-containing receptor (NLR) family of proteins are key modulators of innate immunity regulating inflammation. Our previous work has shown that among the members of this family, NLRP1/NALP1, present in neurons, plays a crucial role in inflammasome formation and the production of the inflammatory cytokines interleukin (IL) -1? and IL-18 after various types of central nervous system injury.ResultsWe investigated whether age-related cognitive decline may involve a heightened inflammatory response associated with activation of the NLRP1 inflammasome in the hippocampus. Young (3 months) and aged (18 months) male Fischer 344 rats were tested in a spatial acquisition task via Morris water maze. Following behavioral testing, hippocampal lysates were assayed for expression of NLRP1 inflammasome components and inflammatory cytokines. Hippocampal lysates from aged rats showed significantly higher levels of NLRP1 inflammasome constituents, caspase-1, caspase-11, the purinergic receptor P2X7, pannexin-1 and X-linked inhibitor of apoptosis (XIAP) than lysates from younger animals. Following treatment with probenecid, an inhibitor or pannexin-1, aged animals demonstrated reduction in inflammasome activation and improvement in spatial learning performance.ConclusionsOur behavioral findings are consistent with increases in IL-1? and IL-18 that have been previously shown to correlate with spatial learning deficits. Probenecid reduced activated caspase-1 and ameliorated spatial learning deficits in aged rats. Thus, aging processes stimulate activation of the NLRP1 inflammasome and secretion of IL-1? and IL-18 that may contribute to age-related cognitive decline in the growing elderly population. Moreover, probenecid may be potentially useful as a therapy to improve cognitive outcomes in the aging population.
| S-EPMC3259063 | biostudies-literature
Project description:The age dependence of the oval cell response and bile duct carcinomas of male F344 rats exposed to a cyclic choline deficiency-ethionine (CDE) diet (2 weeks on, 1 week off) supports the concept of loss of potential of liver stem cells to form cancers with aging. Livers of rats exposed at 3 weeks of age demonstrated a robust and widespread oval cell proliferation followed by cholangiofibrosis and bile duct metaplasia with extensive mucinous cysts throughout all lobes, and induction of cholangiocarcinomas (CCAs) in seven of eight rats. Livers of rats exposed beginning at 8 weeks of age had much less oval cell response and cholangiofibrosis with only 1 of 15 rats developing a CCA. Livers in old (10-12 months when started) rats remained virtually unaffected, with minimal oval cell proliferation, only occasional and small foci of ductular dysplasia, and none of 16 rats developed CCAs. In contrast to most published studies using uninterrupted choline deficiency plus a carcinogen, hepatocellular carcinoma (HCC) was not observed under the conditions of this study.With aging, male F344 rats exposed to cyclic CDE diet display a diminished oval cell response and fewer CCAs. The absence of HCC is possibly due to the fact that during cyclic CDE, the week off may allow putative liver stem cells to avoid death or differentiation and survive to give rise to CCAs, whereas with continuous CDE exposure, the stem cells are forced to differentiate and develop into HCCs with relatively few CCAs.
| S-EPMC2967670 | biostudies-literature