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EOH Departmental Calendar

Thu 11/14/2019 11:00AM - 12:00PM
EOH Journal Club
Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver EOH Journal Club
Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver
Thu 11/14/2019 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Jenna Kuhn

Paper: Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a Highthroughput Targeted Metabolomics Approach

Authors: Nanyang Yu, Si Wei, Meiying Li, Jingping Yang, Kan Li, Ling Jin, Yuwei Xie, John P. Giesy, Xiaowei Zhang & Hongxia Yu

Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.

4140 Public Health, Young Seminar Room
Fri 11/15/2019 1:00PM - 2:00PM
EOH Seminar Series
Public access to environ health data in Pennsylvania: What are the gaps? What is readily available? EOH Seminar Series
Public access to environ health data in Pennsylvania: What are the gaps? What is readily available?
Fri 11/15/2019 1:00PM - 2:00PM
A719 Public Health

A719 Public Health
Thu 11/21/2019 11:00AM - 12:00PM
EOH Journal Club
Association of Environmental Toxins With Amyotrophic Lateral Sclerosis EOH Journal Club
Association of Environmental Toxins With Amyotrophic Lateral Sclerosis
Thu 11/21/2019 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Fan Wu

Paper: Association of Environmental Toxins With Amyotrophic Lateral Sclerosis

Authors: Feng-Chiao Su,PhD; Stephen A. Goutman,MD; Sergey Chernyak,PhD; Bhramar Mukherjee,PhD; Brian C. Callaghan,MD; Stuart Batterman,PhD; Eva L. Feldman,MD,PhD

Persistent environmental pollutants may represent a modifiable risk factor involved in the gene-time-environment hypothesis in amyotrophic lateral sclerosis (ALS).

To evaluate the association of occupational exposures and environmental toxins on the odds of developing ALS in Michigan.

Case-control study conducted between 2011 and 2014
at a tertiary referral center for ALS. Cases were patients diagnosed as having definitive,
probable, probable with laboratory support, or possible ALS by revised El Escorial criteria;
controls were excluded if they were diagnosed as having ALS or another neurodegenerative
condition or if they had a family history of ALS in a first- or second-degree blood relative.
Participants completed a survey assessing occupational and residential exposures. Blood
concentrations of 122 persistent environmental pollutants, including organochlorine
pesticides (OCPs), polychlorinated biphenyls (PCBs), and brominated flame retardants
(BFRs), were measured using gas chromatography–mass spectrometry. Multivariable models
with self-reported occupational exposures in various exposure time windows and
environmental toxin blood concentrations were separately fit by logistic regression models.
Concordance between the survey data and pollutant measurements was assessed using the
nonparametric Kendall τ correlation coefficient.

Occupational and residential exposures to environmental toxins, and blood concentrations of 122 persistent environmental pollutants, including OCPs,
PCBs, and BFRs.

Participants included 156 cases (mean [SD] age, 60.5 [11.1] years; 61.5%male) and 128 controls (mean [SD] age, 60.4 [9.4] years; 57.8%male); among them, 101 cases and 110 controls had complete demographic and pollutant data. Survey data revealed that reported
pesticide exposure in the cumulative exposure windows was significantly associated with ALS
(odds ratio [OR] = 5.09; 95%CI, 1.85-13.99; P = .002). Military service was also associated
with ALS in 2 time windows (exposure ever happened in entire occupational history:
OR = 2.31; 95%CI, 1.02-5.25; P = .046; exposure ever happened 10-30 years ago: OR = 2.18;
95%CI, 1.01-4.73; P = .049). A multivariable model of measured persistent environmental
pollutants in the blood, representing cumulative occupational and residential exposure,
showed increased odds of ALS for 2 OCPs (pentachlorobenzene: OR = 2.57; 95%CI, 1.31-5.02;
P = .006; and cis-chlordane: OR = 6.51; 95%CI, 2.05-20.73; P = .002) and 1 PCB (PCB 151:
OR = 1.66; 95%CI, 1.03-2.67; P = .04. There was modest concordance between survey data
and the measurements of persistent environmental pollutants in blood; significant Kendall τ
correlation coefficients ranged from −0.18 (Dacthal and “use pesticides to treat home or
yard”) to 0.24 (trans-nonachlor and “store lawn care products in garage”).

In this study, persistent environmental pollutants measured in blood were significantly associated with ALS and may represent modifiable ALS disease risk

4140 Public Health, Young Seminar Room
Thu 12/5/2019 11:00AM - 12:00PM
EOH Journal Club
Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis EOH Journal Club
Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis
Thu 12/5/2019 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Rushikesh Deshpande

Paper: Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis

Authors: Yandong Lai, Xiuying Li, Tiao Li, Yan Chen, Chen Long, Toru Nyunoya, Kong Chen,Georgios D. Kitsios,Seyed Mehdi Nouraie,Yingze Zhang, Bryan J. McVerry, Janet S. Lee,Rama K. Mallampalli, and Chunbin Zou

Onehallmark of sepsis is a reduced number of lymphocytes, termed lymphopenia,that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by epigenetically modulating chromatin architecture, however, the role of these enzymes in lymphopenia remains elusive. In this study, we identified that a chromatin modulator Protein Arginine N-methyltransferase 4/Coactivator-Associated Arginine Methyltransferase 1 (PRMT4/ CARM1) that is elevated systemically inseptic patients and experimental sepsis, and is crucialfor inducing T-lymphocyte apoptosis.An E3 ubiquitin ligase SCFFBXO9 docks on PRMT4 via a phosphodegron to ubiquitinate the protein at K228 for ubiquitin proteasomal degradation.  High PRMT4 expression resulted from reduced levels of SCFFBXO9 that led to increased lymphocyte cell death after Escherichia coliorlipopolysaccharide(LPS) exposure. Ectopic expression of PRMT4 protein caused substantially mphocytedeathvia caspase 3 mediated cell death signaling, and knockout of PRMT4 abolished LPS mediated lymphocyte cell death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis. These findings demonstrate a previously uncharacterized role of a key chromatin modulator in lymphocytesurvival that may shed light on devising unique therapeutic modalities to lessen severity of septic immunosuppression.

4140 Public Health, Young Seminar Room

Recent Events

EOH Journal Club

EOH Journal Club - Spring 2017 - Shuo Cao

Thursday 3/30 11:00AM - 12:00PM
EOH Journal Club Seminar - Spring 2017

Date: Thursday March 30, 2017

Time: 11am - 12pm

Presenter: Shuo Cao

Paper: Structural and transcriptomic response to antenatal corticosteroids in an Erk3-null mouse model of respiratory distress

Authors: Pew BK, Harris RA, Sbrana E, Guaman MC, Shope C, Chen R, Meloche S, Aagaard K.

Neonatal respiratory distress syndrome in preterm infants is a leading cause of neonatal death. Pulmonary insufficiency-related infant mortality rates have improved with antenatal glucocorticoid treatment and neonatal surfactant replacement. However, the mechanism of glucocorticoid-promoted fetal lung maturation is not understood fully, despite decades of clinical use. We previously have shown that genetic deletion of Erk3 in mice results in growth restriction, cyanosis, and early neonatal lethality because of pulmonary immaturity and respiratory distress. Recently, we demonstrated that the addition of postnatal surfactant administration to antenatal dexamethasone treatment resulted in enhanced survival of neonatal Erk3-null mice.

To better understand the molecular underpinnings of corticosteroid-mediated lung maturation, we used high-throughput transcriptomic and high-resolution morphologic analysis of the murine fetal lung. We sought to examine the alterations in fetal lung structure and function that are associated with neonatal respiratory distress and antenatal glucocorticoid treatment.

Dexamethasone (0.4 mg/kg) or saline solution was administered to pregnant dams on embryonic days 16.5 and 17.5. Fetal lungs were collected and analyzed by microCT and RNA-seq for differential gene expression and pathway interactions with genotype and treatment. Results from transcriptomic analysis guided further investigation of candidate genes with the use of immunostaining in murine and human fetal lung tissue.

Erk3(-/-) mice exhibited atelectasis with decreased overall porosity and saccular space relative to wild type, which was ameliorated by glucocorticoid treatment. Of 596 differentially expressed genes (q < 0.05) that were detected by RNA-seq, pathway analysis revealed 36 genes (q < 0.05) interacting with dexamethasone, several with roles in lung development, which included corticotropin-releasing hormone and surfactant protein B. Corticotropin-releasing hormone protein was detected in wild-type and Erk3(-/-) lungs at E14.5, with significantly temporally altered expression through embryonic day 18.5. Antenatal dexamethasone attenuated corticotropin-releasing hormone at embryonic day 18.5 in both wild-type and Erk3(-/-) lungs (0.56-fold and 0.67-fold; P < .001). Wild type mice responded to glucocorticoid administration with increased pulmonary surfactant protein B (P = .003). In contrast, dexamethasone treatment in Erk3(-/-) mice resulted in decreased surfactant protein B (P = .012). In human validation studies, we confirmed that corticotropin-releasing hormone protein is present in the fetal lung at 18 weeks of gestation and increases in expression with progression towards viability (22 weeks of gestation; P < .01).

Characterization of whole transcriptome gene expression revealed glucocorticoid-mediated regulation of corticotropin-releasing hormone and surfactant protein B via Erk3-independent and -dependent mechanisms, respectively. We demonstrated for the first time the expression and temporal regulation of corticotropin-releasing hormone protein in midtrimester human fetal lung. This unique model allows the effects of corticosteroids on fetal pulmonary morphologic condition to be distinguished from functional gene pathway regulation. These findings implicate Erk3 as a potentially important molecular mediator of antenatal glucocorticoid action in promoting surfactant protein production in the preterm neonatal lung and expanding our understanding of key mechanisms of clinical therapy to improve neonatal survival

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Last Updated On Friday, February 24, 2017 by Orbell, Adam W
Created On Friday, January 20, 2017

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