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

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

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

DESIGN, SETTING, AND PARTICIPANTS
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.

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

RESULTS
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”).

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

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

Abstract:
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.