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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 Seminar

Thursday 2/25 11:00AM - 12:00PM

339 Bridgeside Point

EOH Journal Club Seminar - Spring 2016 Date: Thursday February 25, 2016 Time: 11am - 12pm Presenter: Cody Wolfe Paper: TREM2 sustains microglial expansion during aging and response to demyelination Authors: Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, Colonna M. Abstract: Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease. How TREM2 deficiency mediates demyelination and disease is unknown. Here, we addressed the basis for this genetic association using Trem2(-/-) mice. In WT mice, microglia expanded in the corpus callosum with age, whereas aged Trem2(-/-) mice had fewer microglia with an abnormal morphology. In the cuprizone model of oligodendrocyte degeneration and demyelination, Trem2(-/-) microglia failed to amplify transcripts indicative of activation, phagocytosis, and lipid catabolism in response to myelin damage. As a result, Trem2(-/-) mice exhibited impaired myelin debris clearance, axonal dystrophy, oligodendrocyte reduction, and persistent demyelination after prolonged cuprizone treatment. Moreover, myelin-associated lipids robustly triggered TREM2 signaling in vitro, suggesting that TREM2 may directly sense lipid components exposed during myelin damage. We conclude that TREM2 is required for promoting microglial expansion during aging and microglial response to insults of the white matter.

Last Updated On Monday, March 21, 2016 by GSPH Webmaster
Created On Monday, March 21, 2016

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