Diesel exhaust particle inhalation increases expression of mediators contributing to axonal growth cone collapse with sex-specific differences in a murine model

Friday, May 3, 2024

2:05 PM – 2:09 PM CT

Location: S401ab

Presenting Author(s)

Alexandra N. Demetriou, MA, BS

Medical Student
Department of Neurological Surgery, Keck School of Medicine, University of Southern California
Rancho Palos Verdes, CA, US

Co-Author(s)

SC

Selena Chen, B.S.

Student
University of Southern California, United States
CF

Caleb E. Finch, PhD

University Professor, ARCO/William F. Kieschnick Chair in the Neurobiology of Aging
Leonard Davis School of Gerontology, University of Southern California, United States
JG

Jose A. Godoy-Lugo, PhD

Postdoctoral Scholar
Leonard Davis School of Gerontology, University of Southern California, United States
RG

Rayudu Gopalakrishna, PhD

Professor of Integrative Anatomical Sciences
Department of Integrative Anatomical Sciences, University of Southern California, United States
WM

William Mack, MD, FAANS

Los Angeles, CA, US
KS

Kristina Shkirkova, PhD

Postdoctoral Scholar
Department of Neurological Surgery, Keck School of Medicine, University of Southern California, United States
CS

Constantinos Sioutas, ScD

Professor of Civil and Environmental Engineering and Aerospace and Mechanical Engineering
Viterbi School of Engineering, University of Southern California, United States
MT

Max A. Thorwald, PhD

Postdoctoral Scholar
Leonard Davis School of Gerontology, University of Southern California, United States
LZ

Lifu Zhao, MD

Laboratory Technician
Department of Neurological Surgery, Keck School of Medicine, University of Southern California, United States

Disclosure(s):

Alexandra N. Demetriou, MA, BS: No financial relationships to disclose

Introduction: Inhalation of traffic-associated pollutants such as diesel exhaust particles (DEP) is associated with neuroinflammation and white matter toxicity. We have previously demonstrated that DEP exposure exerts synergistic neurotoxicity when it occurs in the setting of cerebrovascular disease, though the underlying mechanisms are not fully understood. The Nogo receptor 1 (NgR1) pathway and its associated activators and downstream effectors, which are established mediators of axonal growth cone collapse, have been implicated in neurologic damage and impaired recovery following cerebrovascular disease. We hypothesized that DEP exposure increases NgR1 signaling as a mechanistic explanation of the synergistic neurotoxicity seen with DEP exposure and underlying cerebrovascular disease.

Methods: Eight-week male and female C57BL/6 mice were exposed to eight weeks (200 hours) of either aerosolized DEP or filtered air (FA). Following humane euthanasia, immunofluorescence was performed on corpus callosum sections to evaluate expression of injury-associated mediators of growth cone collapse including chondroitin sulfate proteoglycan (CSPG) and oligodendrocyte myelin glycoprotein (OMgp), as well as NgR1 and paired immunoglobulin-like receptor B (PirB), an alternate receptor for axonal growth inhibitors.

Results: DEP-exposed mice exhibited significant increases in CSPG (p < 0.005), OMgp (p=0.04), NgR1 (p < 0.001), and PirB (p=0.02) levels in the corpus callosum compared to FA mice. When analyzed by sex, female but not male DEP mice demonstrated significant increases in CSPG (p < 0.001), NgR1 (p < 0.0001), and OMgp (p < 0.01) in corpus callosum; both males and females separately exhibited significant increases in PirB expression (p=0.047 and 0.03, respectively).

Conclusion : Our results demonstrate DEP-mediated increases in NgR1 and associated signaling molecules implicated in axonal growth cone collapse, with sex-specific analyses indicating more pronounced effects in females. These results provide a potential mechanistic explanation, pending further study, of the synergistic neurotoxicity seen in DEP exposure with concurrent cerebrovascular disease, and they suggest that female humans may be more susceptible to this effect.