Project description:There is substantial evidence for intergenerational health effects of trauma. The biological mechanisms linking traumatic exposures with intergenerational health effects remain unclear, but epigenetics represent a candidate mechanism. We measured DNA methyation to test for intergenerational epigenetic signatures of exposure to violence during pregnancy. Participating families were recruited based on generational exposure to violence trauma. There were four groups: unexposed controls, directly exposed to violence, prenatally exposed to violence, and germline exposed to violence. Three separate epigenome-wide association studies compared direct, prenatal, and germline exposure to unexposed controls to test for differentially methylated positions.
Project description:Despite lower rates and intensity of smoking, Black men experience a higher incidence of lung cancer compared to White men. The racial disparity in lung cancer is particularly pronounced in Chicago, a highly segregated urban city. Neighborhood conditions, particularly social stress, may play a role in lung tumorigenesis. Preliminary studies indicate that Black men residing in neighborhoods with higher rates of violent crime have significantly higher levels of hair cortisol, an indicator of stress response. To examine the relationship between social stress exposure and gene expression in lung tumors, we investigated glucocorticoid receptor (GR) binding in lung tumor samples in relation to GR target gene expression levels and zip code level residential neighborhood violence. Spatial transcriptomics and a version of ChIP-sequencing known as CUT & RUN were used. GR recruitment to chromatin was correlated with neighborhood violent crime rate and overall GR binding increased with increasing neighborhood violent crime rates. Among patients residing in high-violence neighborhoods, tumor samples, compared to normal neighboring lung tissue, had fewer GR binding sites. The opposite was seen in patients residing in low-violence neighborhoods, with tumor samples having more GR binding sites when compared to normal lung tissue. Tumor samples from patients living in high-violence neighborhoods exhibited increased GR recruitment to genes associated with greater tumor aggressiveness. Our findings suggest that exposure to neighborhood violence may influence tumor biology via reprogramming GR recruitment. Prioritizing lung cancer screening in neighborhoods with increased social stress, such as high violence, may reduce racial disparities in lung cancer.
Project description:Despite lower rates and intensity of smoking, Black men experience a higher incidence of lung cancer compared to White men. The racial disparity in lung cancer is particularly pronounced in Chicago, a highly segregated urban city. Neighborhood conditions, particularly social stress, may play a role in lung tumorigenesis. Preliminary studies indicate that Black men residing in neighborhoods with higher rates of violent crime have significantly higher levels of hair cortisol, an indicator of stress response. To examine the relationship between social stress exposure and gene expression in lung tumors, we investigated glucocorticoid receptor (GR) binding in lung tumor samples in relation to GR target gene expression levels and zip code level residential neighborhood violence. Spatial transcriptomics and a version of ChIP-sequencing known as CUT & RUN were used. GR recruitment to chromatin was correlated with neighborhood violent crime rate and overall GR binding increased with increasing neighborhood violent crime rates. Among patients residing in high-violence neighborhoods, tumor samples, compared to normal neighboring lung tissue, had fewer GR binding sites. The opposite was seen in patients residing in low-violence neighborhoods, with tumor samples having more GR binding sites when compared to normal lung tissue. Tumor samples from patients living in high-violence neighborhoods exhibited increased GR recruitment to genes associated with greater tumor aggressiveness. Our findings suggest that exposure to neighborhood violence may influence tumor biology via reprogramming GR recruitment. Prioritizing lung cancer screening in neighborhoods with increased social stress, such as high violence, may reduce racial disparities in lung cancer.
Project description:These data demonstrate that parental exposure to bacterial infection and osmotic stress intergenerational changes in offspring gene expression in C. elegans, C. kamaaina, C. briggsae and C. tropicalis. Many of these intergenerational changes in gene expression are observed in multiple species and this data identified >250 genes that exhibit intergenerational changes in expression in all species tested.
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:Female fish are known to be sensitive to temperature during reproduction, but the long-term consequences on offspring adaptive behaviour and their underlying intergenerational mechanisms remain unknown. We studied the intergenerational consequences of female rainbow trout (Oncorhynchus mykiss) exposure to high (17°C) or normal temperature (12°C) on offspring behavioural phenotypes. We also analysed genome-wide gene expression in eggs and embryos to elucidate the mechanisms by which thermal maternal exposure impacts offspring behaviour. Here we show that a thermal maternal stress induces emotional and cognitive disorders in offspring. Fear responses to a novel environment were inhibited in 17°C offspring indicating global emotional blunting. Thermal stress in mothers also decreased spatial learning abilities in progeny. Behavioural phenotypes were associated with the dysregulation of several genes known to play major roles in neurodevelopment. This is especially true for auts2, a key gene for neurodevelopment in fish and mammals, more specifically neuronal migration and neurite extension, and critical for the acquisition of neurocognitive function in fish and mammals. In addition to auts2, our analysis revealed the dysregulation of another neurodevelopment gene (dpysl5) as well as genes associated with human cognitive disorders (arv1, plp2). Our study also revealed major differences in maternal mRNA abundance in the eggs following maternal exposure to high temperature indicating that some of the observed intergenerational effects are mediated by maternally-inherited mRNAs accumulated in the egg. Together, our observations shed new light on the intergenerational determinism of fish behaviour and associated underlying mechanisms. They also stress the importance of maternal history on fish adaptive capacities in a context of global climate changes.
Project description:Passive smoke intake by pregnant women may have detrimental effects such as spontaneous abortion, lower birth weight, stillbirth, and reduced infant lung function. To extend our knowledge on molecular effects of tobacco smoke exposure in pregnancy, we analyzed transcriptome alterations in passive smokers (PS) and compared them to those in active smokers (AS). Using Illumina Expression Beadchip with 24,526 transcript probes, gene expression patterns were assayed in placentas from PS (N=25) exposed to environmental tobacco smoke (ETS) throughout pregnancy and non-exposed (NS) counterparts (N=35), and in cord blood cells from their newborns. The ETS exposure was evaluated by questionnaire disclosure and cotinine measurement in maternal and cord bloods. A total of 196 genes were significantly deregulated in placentas of PS compared to NS. These genes were primary associated with extracellular matrix, apoptosis, blood clotting, response to stress, embryonic morphogenesis, and lipid metabolism. Cord blood of newborns of PS displayed differential expression of 116 genes encoding mainly neuronal factors, regulators of immunologic response, and protooncogenes. Gene ontology analyses highlighted some important biological processes that might be associated with placental insufficiency and fetal growth restriction in PS, such as fatty acid catabolism, coagulation, regulation of growth, and response to steroid hormone stimulus. The study demonstrates that even low dose exposure to ETS during pregnancy leads to the significant deregulation of transcriptional regulation in placental and fetal cells. The data suggest the effect of ETS on the fetus is primary indirect, mediated via deregulation of placental functions. Comparison of PS and AS indicated that ETS exposure and active smoking in pregnancy partly employ the same molecular mechanisms. A total of 60 women who gave birth to a baby in the Faculty Hospital Motol (Czech Republic) were enrolled into the study approved by the local Institutional Review Board. The participants signed written informed consent and self-reported information on tobacco smoke exposure (type of exposure, number of cigarettes per day, exposure period) and life style during pregnancy (alcohol drinking, diet, area of residency etc.). Further, the women completed the questionnaire on pregnancy/delivery course (complications, diseases, medication, and delivery mode) and newborn characteristics (physical parameters, Apgar score) with the assistance of gynecologist. Only women without any health complications during pregnancy and their newborns without manifestation of pathological abnormalities were included in the study. Based on self-reported tobacco smoke exposure, the women were divided into two groups, non-smokers (NS, N=35) and passive smokers (PS, N=25). Former and active smokers were excluded from the study. Exposure to tobacco smoke was further evaluated by measurement of plasma cotinine levels in maternal peripheral blood and newborn cord blood using radioimmunoassay.