Effects of low level toxin

Epigenetic Mechanisms of Toxicity after Developmental Exposure to Marine Toxins

Project Lead: Dr. Mark E. Hahn
Project Co-Investigators: Drs. Neel Aluru and John Stegeman
Project Personnel: Dr. Juliette Smith, Dr. Sibel Karchner, Dr. Lilah Glazer, Ms. Jenny Panlilio

Harmful algal blooms (HABs) are a well known, persistent, and growing threat to public health in coastal areas of the U. S. and worldwide.   Among the toxins that are produced by dinoflagellates, diatoms, and other classes of algae are the agents responsible for paralytic shellfish poisoning (saxitoxins) and amnesic shellfish poisoning (domoic acid). Acute consequences of exposure to HAB toxins include respiratory effects, neurobehavioral and neurologic disorders, paralysis and death.

While acute effects to high-level exposure can be severe and immediate, the longer-term consequences of more modest exposure are poorly known.   In particular, the long-term effects of periodic acute exposure to moderate levels, chronic exposure to low levels, or short-term exposure during critical developmental stages are largely unknown.  Action levels for resource closure are based on risk analysis estimates to protect humans from acute toxicity, yet below such levels, resources will be harvested and sold, and thus some populations may experience frequent or chronic exposure to sub-acute levels, i.e. levels below those resulting in immediate clinical symptoms.  This project studies the implications of such exposure.

The goal of this project is to elucidate the molecular mechanisms by which short-term developmental exposure of embryos to HAB toxins and other marine toxicants (including anthropogenic contaminants such as polychlorinated biphenyls (PCBs)) may cause physiological and behavioral abnormalities later in life. The central hypothesis of this project is that early life exposure to chemicals alters epigenetic programming (involving DNA methylation and microRNAs) leading to altered gene expression and functional abnormalities in juveniles or adults. (“Epigenetics” refers to genetic effects that do not involve changes in the underlying DNA sequence of the genes involved, but rather occur through changes in how those genes are expressed.)  Using zebrafish as a model system, we are conducting studies to determine the effects of developmental exposure to toxins (saxitoxin and domoic acid) and chemical toxicants (selected PCB congeners) on gene expression and behavior in adults. We are testing the hypothesis that HAB toxins and toxicants cause persistent changes by epigenetic reprogramming of gene expression patterns, focusing on two key epigenetic mechanisms–DNA methylation and microRNA expression—that play critical roles in early development. In addition, we are using gene-specific knock-down in embryos to evaluate the roles of ion channels and receptors in the mechanisms leading to the long-term effects. This research will contribute to an improved understanding of the long-term health consequences of developmental exposure to marine toxins and toxicants.