# Project 3: Cellular and molecular mechanisms underlying effects from early life exposure to HAB toxins

> **NIH NIH P01** · WOODS HOLE OCEANOGRAPHIC INSTITUTION · 2024 · $150,139

## Abstract

The overall objective of the proposed research is to elucidate the cellular and molecular mechanisms of toxicity
from developmental exposure to harmful algal bloom (HAB) toxins. The HAB toxins domoic acid (DA), saxitoxin
(STX), and anatoxin-a (ATX-a) occur in marine and coastal water bodies as well as in food sources and pose a
significant threat to public health. Current regulatory guidelines for HAB toxins in seafood are designed to
protect against acute exposure to adults. However, seafood with HAB toxins below the regulatory limits is
regularly harvested and the consequences of exposure to low levels of HAB toxins particularly to children and
young adults are not well understood. It is well known that the early life environment can profoundly influence
health throughout the life course (the developmental origins of health and disease concept). The central
hypothesis of the proposed research is that exposure to HAB toxins during early development alters various
neuronal and glial cell types independently, leading to cell-type specific transcriptional changes, ultimately
contributing to altered neurobehavioral outcomes. We propose to test this hypothesis using two
complementary model systems: zebrafish, an established model organism for characterizing molecular,
cellular, and behavioral changes in vivo, and human iPSC-derived 3D brain systems in vitro for elucidating the
effects of toxins on differentiating human neural cells. In Aim 1, we will use transgenic zebrafish embryos and
single-cell RNA sequencing to investigate the cellular and molecular mechanisms underlying the
neurodevelopmental toxicity of DA, STX, and ATX-a. Building on our previous studies, in Aim 1.1 we will test
the hypothesis that DA exposure of zebrafish embryos affects oligodendrocyte-neuron interactions in part by
targeting oligodendrocytes that are necessary for the maturation and survival of axons. In Aim 1.2, we will test
the hypothesis that STX exposure during development alters extracellular matrix at the synapses in the brain,
with impacts on neural circuit formation in larvae. In Aim 1.3, we will test the hypothesis that developmental
exposure of zebrafish embryos to ATX-a causes nervous system deficits by activating nicotinic acetylcholine
receptors. In Aim 2, using human iPSC-derived neuronal cultures, we will investigate the effects on exposure
to HAB toxins on mechanisms of neuronal and glial cell differentiation. In Aim 3, we will test the hypothesis that
combined early life and preconceptional exposure to low levels of PCBs influences the responses to HAB
toxins. In Aim 4, we will use probabilistic models to assess human exposure to DA during susceptible windows
of development and collaborate with Project 1, 2 and CEC to use coupled HAB biophysical models and
exposure models to predict the impact of climate change on human exposure to STX and DA. Overall, the
results from this research will contribute to improved understanding of the potential health conseque...

## Key facts

- **NIH application ID:** 10732091
- **Project number:** 2P01ES028938-06
- **Recipient organization:** WOODS HOLE OCEANOGRAPHIC INSTITUTION
- **Principal Investigator:** NEELAKANTESWAR Aluru
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $150,139
- **Award type:** 2
- **Project period:** 2018-09-30 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10732091

## Citation

> US National Institutes of Health, RePORTER application 10732091, Project 3: Cellular and molecular mechanisms underlying effects from early life exposure to HAB toxins (2P01ES028938-06). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10732091. Licensed CC0.

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