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\begin{document}

\title{Development of an Adverse Outcome Pathway for Deposition of Energy
Leading to Learning and Memory Impairment}



\author[1]{Ahmad Sleiman}%
\author[2]{Kathleen Miller}%
\author[3]{Danicia  Flores}%
\author[3]{Jaqueline  Kuan}%
\author[3]{Kaitlyn Altwasser}%
\author[3]{Benjamin Smith}%
\author[3]{Tatiana Kozbenko}%
\author[3]{Robyn Hocking}%
\author[4]{Scott Wood}%
\author[5]{Janice Huff}%
\author[1]{Christelle Adam-Guillermin}%
\author[6]{Nobuyuki Hamada}%
\author[7]{Carole Yauk}%
\author[3]{Ruth Wilkins}%
\author[3]{Vinita Chauhan}%
\affil[1]{Institut de radioprotection et de Sûreté Nucléaire}%
\affil[2]{National Institute of Aerospace}%
\affil[3]{Health Canada}%
\affil[4]{NASA Johnson Space Center}%
\affil[5]{NASA Langley Research Center}%
\affil[6]{Central Research Institute of Electric Power Industry}%
\affil[7]{University of Ottawa}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
The understanding of radiation-induced non-cancer effects on the central
nervous system (CNS) is essential for the medical setting (e.g.,
radiotherapy), and occupational exposures, such as nuclear workers or
astronauts. Herein, the adverse outcome pathway (AOP) approach was used
to consolidate relevant studies in the area of cognitive decline for
identification of research gaps, countermeasure development, and for
eventual use in risk assessments. AOPs are an analytical construct
describing critical events to an adverse outcome (AO) in a simplified
form beginning with a molecular initiating event (MIE). An AOP was
constructed utilizing mechanistic information to build empirical support
for the key event relationships (KERs) between the MIE of deposition of
energy to the AO of learning and memory impairment through multiple key
events (KEs). The evidence for the AOP was developed through a scoping
review of the literature. In this AOP, the MIE is connected to the AO
via six KEs of increased oxidative stress, increased deoxyribonucleic
acid (DNA) strand breaks, altered signaling pathways, tissue resident
cell activation, increased pro-inflammatory mediators and neural
remodeling. Deposition of energy directly leads to oxidative stress,
increased DNA strand breaks, an increase of pro-inflammatory mediators
and tissue resident cell activation. These KEs, which are themselves
interconnected, converge through increased DNA strand breaks, altered
signaling pathways and pro-inflammatory routes and directly lead to
neural remodeling. Broadly, it is envisioned that the outcome of these
efforts could be applied to other cognitive disorders and support
ongoing work by international authorities to review the system of
radiological protection.%
\end{abstract}%



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\textbf{Hosted file}

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