Boston University Superfund Basic Research Program

Mark Hahn took a rather circuitous route to becoming a comparative toxicologist at an oceanographic institution. A music major for the first two years of college, he switched to biology and graduated with a bachelor's degree from Harpur College of the State University of New York at Binghamton. He then pursued doctoral research in mammalian toxicology at the University of Rochester School of Medicine and Dentistry. Having been fascinated by marine research as an eight year old during a visit to Woods Hole with his family in 1966, he was thrilled to return there 21 years later to pursue postdoctoral research in fish toxicology at the Woods Hole Oceanographic Institution (WHOI). Appointed to the WHOI scientific staff in 1991, Hahn established a research program to use molecular and evolutionary methods to investigate how species and populations of animals differ in their sensitivity to ubiquitous and highly toxic chemicals such as polychlorinated biphenyls (PCBs).

He currently works with a talented group of students, postdoctoral researchers, and senior technical staff conducting basic research on a variety of projects concerning mechanisms of chemical toxicity in fish, birds, whales, and marine invertebrates. His current research as part of the BU Superfund Basic Research program concerns mechanisms of adaptation and evolved resistance to PCBs in fish inhabiting a Superfund site in southeastern Massachusetts.

Research summary

A variety of industrial chemicals were released into the environment during the second half of the last century. Although their manufacture and use has been curtailed, many of them are very stable and persist in the environment. Thus, humans and wildlife continue to be exposed to these compounds. One group of persistent chemicals, the polychlorinated biphenyls (PCBs), was manufactured for a variety of uses, including in the electrical industry. PCBs are now distributed throughout the entire world, but especially high concentrations occur at some locations, including Superfund priority sites such as New Bedford Harbor, Massachusetts.

What happens to populations of animals that experience prolonged (multi-generational) exposure to these high PCB concentrations? This is a question being asked by Mark Hahn's research group in their SBRP project, which focuses on a common species of fish known as the mummichog or Atlantic killifish (Fundulus heteroclitus). Hahn and others have found that killifish living at PCB-contaminated sites develop resistance (reduced sensitivity) to certain types of PCBs, just as bacteria exposed to antibiotics and insects exposed to insecticides can evolve resistance to those chemicals. Hahn's research seeks to find out what biochemical changes have occurred in the New Bedford fish that make them resistant (the mechanism of resistance) as well as what the impacts of those changes are on the ability of these fish to withstand other environmental stresses, such as low oxygen (hypoxia-a common occurrence in the estuaries inhabited by killifish).

In their efforts to understand the mechanism of resistance, Hahn's research team has focused on two proteins that are the initial target for certain PCBs in the fish. These proteins, named aryl hydrocarbon receptor (AHR) 1 and 2, also are targets for the highly toxic chlorinated dioxins. (The specific PCBs and other chemicals that act through AHRs are thus sometimes known as "dioxin-like compounds".) The WHOI researchers have found that both AHR1 and AHR2 in killifish have polymorphisms-that is, they exist as different forms that differ slightly in their sequence of amino acids. Individual fish have one or two specific variants, which may differ from those in other individual fish. Protein polymorphisms are well known in humans and explain why, in any population, individuals exhibit different levels of sensitivity to drugs and other chemicals. The set of polymorphic variants of AHR1 and AHR2 found in the PCB-resistant New Bedford Harbor fish differs from that in PCB-sensitive killifish from less contaminated sites. Hahn's team is attempting to identify which specific AHR variants may be responsible for the resistance of New Bedford Harbor fish to PCBs. Through this research, they hope to gain insight not only into the response of fish populations to long-term PCB exposure, but also into the genetic differences among individuals that determine chemical sensitivity, a topic with potential application to the health of humans exposed to these chemicals.

Q. Why does your research focus on PCBs in particular?

A. We are focusing on PCBs because they are the main contaminants at the New Bedford Harbor Superfund site. The killifish at that site have become resistant to these chemicals, which normally are toxic to fish and many other kinds of animals. In addition, PCBs are important contaminants at many other sites, such as the Hudson River, so things that we learn at New Bedford Harbor may have application to other sites.

Q. Why would developing resistance to PCBs make fish respond differently to other environmental stressors?

A.There are at least two possible reasons why developing resistance to dioxin-like chemicals could affect responses to other stressors.

First, if at some point PCB exposure caused widespread mortality in NBH killifish, this could result in a genetic bottleneck, leading to reduced genetic diversity in this population of fish. With reduced genetic diversity, the fish population might be less able to adapt to other stressors. However, research by Diane Nacci at the US EPA lab in Narragansett and Sarah Cohen at Harvard (now at San Francisco State University) indicates that the NBH population is currently not less diverse than nearby populations.

The second reason why developing resistance to dioxin-like chemicals could affect the response to other stressors is that the biochemical pathways that the fish use to respond to various stressors often are interconnected. This means that changes in one pathway may affect the functioning of another pathway. A good example of this is the interaction between responses to dioxin-like chemicals (which occur through the aryl hydrocarbon receptor protein) and responses to low oxygen (hypoxia, which occur through a protein known as the hypoxia-inducible factor). The aryl hydrocarbon receptor and hypoxia-inducible factor share the same partner protein (called ARNT). Therefore, changes in the aryl hydrocarbon receptor pathway in dioxin-resistant fish might impact the sensitivity of the hypoxia response pathway.

Q. What can we learn from fish that would help us understand how PCBs may affect human health?

A. As vertebrate animals, fish share a close evolutionary relationship with humans. This means that fish and humans have genes that function similarly. For example, like fish, humans have an aryl hydrocarbon receptor protein that is involved in the response to dioxin-like chemicals as well as in the response to polycyclic aromatic hydrocarbons, the carcinogenic agents in cigarette smoke. Therefore, what we learn about the mechanisms by which fish populations differ in sensitivity to the toxic effects of dioxin-like chemicals may help us to understand how individual humans may differ in sensitivity to these compounds as well as to effects such as smoking-induced cancer.

It is also worth noting that certain drugs that are used therapeutically in humans are able to stimulate the aryl hydrocarbon receptor which may lead to their increased breakdown by enzymes in the liver and other organs. Thus, the knowledge gained by studying how fish differ in their response to PCBs could ultimately help us understand why individual humans differ in our response to therapeutic drugs.