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Marine Models of Human Disease

In the second research core of the NIEHS center, the unifying theme is the use of marine and freshwater model systems for environmental health-related research. The use of model systems as surrogates for the study of pathological states related to the environment arises from several advantages that complement the direct use of mammalian systems:

Because aquatic species often have unique biological characteristics, many of them can offer the researcher a distinct experimental advantage over a mammalian system. Importantly, fish and invertebrates represent a vast phylogenetic diversity that far exceeds that of mammals. A comparative experimental approach drawing on this diversity ultimately can lead to the use of the "best" model species for a given pathology;

Since aquatic species often have different susceptibilities to environmental agents than mammals, these differences can be exploited to discover the underlying unifying mechanisms of toxicity and effect. Often the aquatic model is simpler and can give the scientist a "stripped-down" version of a more complicated mammalian system. Sometimes fish are more sensitive to critical toxins than mammals, and in particular may be more sensitive to the carcinogenic and less to the toxic effects;

In applying a comparative toxicological approach, aquatic species offer a simpler, natural, intensive exposure system because respiratory surfaces, skin, and fin surfaces (which lack keratinization) can be bathed directly in water with the toxicant of interest;

Since fish and invertebrates naturally experience body temperature changes, the effects of temperature on environmental-health related processes can be directly and realistically studied in these species;

Enhanced opportunities for genetic research and manipulations, where developing embryos can often be directly observed; and

Convenient models for sentinel species of environmental effects.

The following highlights advantages of some of the specific model systems currently used by NIEHS Center Investigators.

Toadfish Hyperammonemia

The gulf toadfish (Opsanus beta), a common bottom dweller in Biscayne Bay, is unique among marine bony fishes in North America in its ability to produce urea (instead of ammonia) for nitrogenous waste excretion via a fully functional hepatic ornithine-urea cycle. It also possesses an extreme ability (compared to both mammals and other fish) to tolerate ammonia exposure without apparent harm to the CNS.

This species is enabling studies of the basic mechanisms of CNS ammonia toxicity, including those induced by xenobiotic interference with liver function and urea synthesis. The toadfish's ability to make urea and its ability to tolerate ammonia and its aquatic mode of respiration allow rapid washout of ammonia to identify reversible biomarkers of hyperammonemia/hepatic encephalopathy, a line of research that has been impossible to date in mammalian systems.

Aplysia Neurobiology

The California sea hare, Aplysia californica is an established useful model for neurobiological investigations because of a relatively simple nervous system organization, with a small number of large re-identifiable neurons. It is mass cultured in our Fish and Shellfish Hatchery core and is available year-round in all developmental stages. Aplysia can also be used as a model for developmental neurotoxicology studies.

Zebrafish Transgenics

The zebrafish (Danio rerio) is an established model for vertebrate developmental genetics and the production of transgenic fishes. Its key features are that it is small, it can be stocked in high densities, it reaches sexual maturity in as little as 60 days, and females can lay several hundred eggs per day. Gametes can be stripped easily and non-invasively for in vitro fertilization where haploid, triploid or homozygous diploid fish can be produced. This model genetic species can be used directly in studies of gene interactions with environmental agents and also yield knowledge useful in making transgenic fish in other fish species.

The potential to produce altered specimens with specific traits such as genetically-linked enzyme induction and fluorescent proteins provides the raw system for high through-put toxicological assays which can be quantitatively graded by eye or spectrophotometer. It has the best mapped genome of any aquatic vertebrate and its complete genome will be completed by mid-2002 by the Sanger Institute in the UK.

Damselfish Neurofibromatosis

The bicolor damselfish (Stegastes [previously Pomacentrus] partitus) is one of the most common species of reef fish in coastal waters of South Florida, the Caribbean and the Bahamas. Damselfish on South Florida reefs develop a disease termed damselfish neurofibromatosis (DNF) which consists of neurofibromas and chromatophoromas.

The similarity of these neurofibromas to tumors observed in humans affected with neurofibromatosis type 1 has led us to propose this system as an animal model of pathogenesis of these tumors. Model systems involving peripheral nerve sheath tumors in any vertebrate animal are especially valuable because mammalian models of these tumors are rare. DNF is a transmissible disease caused by an unusual, virus-like agent. This appears to be the only naturally occurring, transmissible cancer affecting a neuroectodermal cell type (Schwann cells and chromatophores in the case of DNF). Thus damselfish provide a unique and important model for investigating carcinogenesis in these cell types. This model should be also be useful to NIEHS investigators for study of the synergistic effects of environmental factors on viral tumor initiation and promotion, as well as mechanisms of carcinogenesis in fishes in general.

Squirrelfish and Zinc Transport

Marine squirrelfish are active members of the reef community. They distinguish themselves from other vertebrates in that the females of this species sequester zinc in the highest concentrations ever reported for a vertebrate, exceeding even concentrations in the human retina.

In squirrelfish, both metallothionein, and a recently characterized female-specific zinc transport protein, are responsive to estrogen induction and appear to be involved in a shuttle that transfers zinc from the liver to the developing embryos.

Shark Immunology

The nurse shark (Ginglymostoma cirratum), another ubiquitous inhabitant of the Caribbean marine environment is an extremely useful model for studies of immunology. Sharks are the most primitive animals with documented aspects of both cellular and humoral immune components. Nurse sharks appear to have unique antigen-reactive molecules which may represent either a primitive antigen reactive system, or a primordial host defense mechanisms which has been overshadowed by more recently evolved and highly efficient T and B cell systems.

Thus, the work of McKinney and colleagues has shown that this species can serve as a simpler model for mammalian immune responses. It can also serve as a model for studies on the interaction between marine toxins and basic immune effector mechanisms. In this regard, the shark system is also a potential model for NIEHS initiatives in the area of the effects of environmental chemicals on the immune system.

Sentinel Species

Correlations between marine habitat degradation and the prevalence of abnormalities and diseases in populations can provide a starting point for understanding the effects of changes in environmental conditions on marine organisms. During the past five years, studies by Schmale et al. of effects of environmental contamination on health of fish and invertebrates in Biscayne Bay, Florida focused on field and laboratory studies of the most common abnormality seen in fishes in the Bay, scale disorientation, and the development of bioindicators of exposure in fishes from the Bay.

The two most important sentinel species in this regard have been the pinfish, Lagodon rhomboides and the gray snapper, Lutjanus griseus, with respect to exposure to red tide and other marine toxins. Notably, by examining the pathological effects in these organisms, there is great potential for developing biomarkers for human exposure.