# Molecular Mechanisms of Marine Organohalogen Bioaccumulation and Neurotoxicity

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $117,612

## Abstract

ABSTRACT
There is urgent public health need to better understand the relative risks and benefits associated with
consumption of seafood. The overall mission of this project is to understand the toxicity of marine organohalogen
pollutants. We take a powerful approach to understanding and mitigating this risk by asking two questions, central
to future efforts to predict and minimize risk. Aim 1 of this project asks how these compounds bioaccumulate,
focusing on xenobiotic transporters, which are a key pathway for limiting accumulation of foreign chemicals. We
will determine the interactions of the four major human xenobiotic transporters (XTs) with environmentally
relevant natural and man-made marine organohalogens. The results will extend and expand the scope of our
previous work indicating that several of these compounds can act as potent inhibitors of transporter function. In
parallel, we will take advantage of recent progress with heterologous transporter-expression and CRISPR/CAS9
gene editing in sea urchins, to dissect the functional role of XTs in governing bioaccumulation in marine cells.
This will be supported by a structure guided approach to determine how evolutionary changes in transporter
structure modify interactions with TICs, following up on recent progress towards purification and crystallization
of marine XTs in complex with pollutants. Aim 2 of this project will determine the structure activity relationships
governing neurotoxicity of marine pollutants. These studies are motivated by preliminary data indicating that
naturally produced organohalogens are highly potent inhibitors of ryanodine sensitive Ca2+ channels (RyRs) and
Ca2+ ATPase transporters (SERCAs), which are arguably the most direct targets of environmentally relevant
organohalogens in the brain. We will use primary cultures of hippocampal neurons cultured from male and female
wild type mice to determine how activity at these molecular targets alter neuronal network Ca2+ dynamics and
morphology using real-time fluorescence cell imaging and morphometric approaches. In addition, we will determine
how hippocampal neurons that express mutation RyR1-R163C known to confer heat stress intolerance, alter
sensitivity to organohalogens, and ask whether these effects are gender-specific. These studies will address the
critical need to better understand the molecular mechanisms by which naturally occurring and man-made seafood
pollutants accumulate in target cells and perturb the Ca2+ dynamics essential for normal neuronal network
development.

## Key facts

- **NIH application ID:** 10172906
- **Project number:** 5R01ES030318-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** AMRO M HAMDOUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $117,612
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172906

## Citation

> US National Institutes of Health, RePORTER application 10172906, Molecular Mechanisms of Marine Organohalogen Bioaccumulation and Neurotoxicity (5R01ES030318-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10172906. Licensed CC0.

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