Project description:Rationale: Maternal immune responses can promote allergy development in offspring. Pilot data show that neonates of mother mice exposed during pregnancy to air pollution particles have increased allergic susceptibility. Objective: We investigated whether inflammatory response to titanium dioxide (TiO2) particles earlier considered immunologically ‘inert’ is enhanced during pregnancy. Methods: Pregnant BALB/c mice (or non-pregnant controls) received particle suspensions intranasally at day 14 of pregnancy. Lung inflammatory responses were evaluated 19 and 48 h after exposure. Results: Pregnant mice showed robust and persistent acute inflammatory responses after exposure to TiO2, while non-pregnant females had the expected minimal responses. Genomic profiling identified genes differentially expressed in pregnant lungs exposed to TiO2. Neonates of mothers exposed to TiO2 (but not PBS) developed increased susceptibility to allergens. Conclusion: Pregnancy enhances lung inflammatory responses to otherwise relatively innocuous inert particles. Keywords: Particles exposure, pregnancy vs normal
Project description:Rationale: Maternal immune responses can promote allergy development in offspring. Pilot data show that neonates of mother mice exposed during pregnancy to air pollution particles have increased allergic susceptibility. Objective: We investigated whether inflammatory response to titanium dioxide (TiO2) particles earlier considered immunologically âinertâ is enhanced during pregnancy. Methods: Pregnant BALB/c mice (or non-pregnant controls) received particle suspensions intranasally at day 14 of pregnancy. Lung inflammatory responses were evaluated 19 and 48 h after exposure. Results: Pregnant mice showed robust and persistent acute inflammatory responses after exposure to TiO2, while non-pregnant females had the expected minimal responses. Genomic profiling identified genes differentially expressed in pregnant lungs exposed to TiO2. Neonates of mothers exposed to TiO2 (but not PBS) developed increased susceptibility to allergens. Conclusion: Pregnancy enhances lung inflammatory responses to otherwise relatively innocuous inert particles. Experiment Overall Design: To test whether pregnancy alters the normally minimal inflammatory response to âinertâ particles, we have administered TiO2 and DEP suspensions (50 ug/mouse) or PBS solution by intranasal insufflation to normal or pregnant E14 mice (see Figure 1B). The mice were subjected to pathologic analysis 19 or 48 hrs later. Experiment Overall Design: Respirable-size TiO2 particles were generously provided by Dr. Ian Gilmour (US EPA). Particle samples were baked at 165 0C for 3 h to eliminate endotoxin, aliquoted and stored frozen at â 80 0C. Particle suspensions (50 ug in 50 uL) or PBS solution (vehicle) were administered by single intranasal insufflation of pregnant or normal Balb/c mice under light halothane anesthesia Experiment Overall Design: Total lung RNA extraction and isolation was performed 19 hrs after exposure using a Qiagen RNAeasy Mini kit according to manufacturerâs instructions (Qiagen, Valencia, CA). RNA purity and quality were analyzed by Agilent Bioanalyzer 2100 scan. The hybridization was carried out at the Harvard Partners Genomic Center Microarray facility (Cambridge, MA) using the Affymetrix GeneChip ® platform and Affymetrix mouse 430 2.0 chips (Affymetrix, Santa Clara, CA). Experiment Overall Design: 4 samples were analyzed in each of 4 groups: Normal PBS, Normal TiO2, Pregnant PBS and Pregnant TiO2, for a total of 16 samples.
Project description:Our objective was to investigate epigenomic and transcriptomic changes in J774 macrophages after incubation with talc and titanium dioxide particles. This dataset comprises the results of reduced representation bisulfite sequencing (RRBS) of the J774 cell DNA 24 hours after exposure to 10 ug/well of fine-sized talc or titanium dioxide particles in vitro with or without 2 ug/mL 17-b estradiol.
Project description:Chromic inhalation of poorly soluble low toxicity particles, like titanium dioxide or carbon black, at high exposure levels leading to particle overload in alveolar macrophages, can induce chronic inflammation and lung cancer in rats, but not in mice. Whether this rat adverse response is predictive for humans remains unsettled for more than 40 years. In order to clarify the human relevance of the adverse rat response to particle overload, primary rat, mouse and human alveolar macrophages were exposed in vitro to overload of titanium dioxide or carbon black particles, and their activation profile was analyzed by RNAseq. We report, here, a robust transcriptomic signature of poorly soluble low toxicity particle overload in rat alveolar macrophages in vitro ,which was not observed in mouse macrophages. A similar but markedly lower response was recorded in human macrophages.
Project description:Chromic inhalation of poorly soluble low toxicity particles, like titanium dioxide or carbon black, at high exposure levels leading to particle overload in alveolar macrophages, can induce chronic inflammation and lung cancer in rats, but not in mice. Whether this rat adverse response is predictive for humans remains unsettled for more than 40 years. In order to clarify the human relevance of the adverse rat response to particle overload, primary rat, mouse and human alveolar macrophages were exposed in vitro to overload of titanium dioxide or carbon black particles, and their activation profile was analyzed by RNAseq. We report, here, a robust transcriptomic signature of poorly soluble low toxicity particle overload in rat alveolar macrophages in vitro ,which was not observed in mouse macrophages. A similar but markedly lower response was recorded in human macrophages.
Project description:Chromic inhalation of poorly soluble low toxicity particles, like titanium dioxide or carbon black, at high exposure levels leading to particle overload in alveolar macrophages, can induce chronic inflammation and lung cancer in rats, but not in mice. Whether this rat adverse response is predictive for humans remains unsettled for more than 40 years. In order to clarify the human relevance of the adverse rat response to particle overload, primary rat, mouse and human alveolar macrophages were exposed in vitro to overload of titanium dioxide or carbon black particles, and their activation profile was analyzed by RNAseq. We report, here, a robust transcriptomic signature of poorly soluble low toxicity particle overload in rat alveolar macrophages in vitro ,which was not observed in mouse macrophages. A similar but markedly lower response was recorded in human macrophages.
Project description:Acute phase reactants serum amyloid A-1, 3 and micro RNA-135b, -449a, and -1 are induced in lungs of mice exposed to subtoxic doses of nano-titanium dioxide particles by inhalation In the present study we investigate pulmonary mRNA and miRNA profiles of mice exposed to subtoxic dose of nano-titanium dioxide particles by inhalation. We show dramatic induction of acute phase reactants, chemoattractants, immune and host defence related genes. We also demonstrate for the first time changes in miRNA profiles in the lungs in response to nanoTiO2. Keywords: Toxicology, disease state analysis, biomarkers of health effects
Project description:Background: N6-methyladenosine (m6A) is the most prominent epitranscriptomic modification to RNA in eukaryotes, but it’s role in adaptive changes within the gestational environment are poorly understood. Nano titanium dioxide (TiO2) exposure is common during pregnancy, though the impact fetal progeny is not entirely understood. We propose that gestational exposure to nano-TiO2 contributes to cardiac m6A methylation in fetal offspring and indirectly contributes to mitochondrial dysfunction.
Project description:Background: N6-methyladenosine (m6A) is the most prominent epitranscriptomic modification to RNA in eukaryotes, but it’s role in adaptive changes within the gestational environment are poorly understood. Nano titanium dioxide (TiO2) exposure is common during pregnancy, though the impact fetal progeny is not entirely understood. We propose that gestational exposure to nano-TiO2 contributes to cardiac m6A methylation in fetal offspring and indirectly contributes to mitochondrial dysfunction.