Mechanisms of Immunological Adaptation to a Harsh Chemical Environment
Creosote is an especially toxic distillate of coal tar containing primarily polycyclic aromatic hydrocarbons (PAHs). Creosote has been used almost exclusively as a means to preserve wood, therefore large scale production has taken place with several instances of high level environmental contamination. The Atlantic Wood (AW) Superfund site on the southern branch of the Elizabeth River in Virginia contains some of the highest levels of PAHs in the United States, with total PAHs reaching 2200 mg/kg dry weight of sediment. Despite such high levels of PAHs at the AW site, a population of estuarine killifish (the mummichog, Fundulus heteroclitus) survives and thrives, while mummichogs from a reference site quickly die when exposed to sediments and water from the AW site. Through adaptation, AW mummichogs are recalcitrant to further CYP1A induction by classical Ahr-binding PAHs like BAP and 3-MC. P-glycoprotein (MDR-1), a multi-drug resistance protein is elevated in livers of the resident AW mummichog, yet the majority of adults are burdened with liver and other tumors. Moreover, CYP1A is expressed in and around these tumors. Until recently, the status of immune function in the AW population was unknown, but work by the PI's lab showed that both total and specific antibody responses were very low compared to reference fish, and in some AW fish there were little to no circulating immunoglobulins. On the other hand, lymphoid COX-2 and lysozyme were greatly elevated compared to the reference population, indicating a state of macrophage/phagocyte activation. In chronic inflammation, macrophages differentiate along a phenotypic spectrum to produce growth factors and cytokines that aid and abet a newly form group of cancerous cells. It is not known whether chemically-induced tumors can grow in this manner, but the Atlantic Wood mummichog offers a timely and simple model for understanding how enhanced macrophage function and chemically-induced neoplasia may conspire. The proposal described herein seeks to develop the AW mummichog as a model for understanding how the developing immune system responds to harsh chemicals at the AW site, and how (or if) a correlation between high PAHs, "inflammation-like" conditions, expression of multi-drug resistance proteins, recalcitrant CYP1A induction, altered antibody responses and neoplasia develops. This model will offer novel insights into how resistance can develop and gained knowledge can be applied to human systems. PUBLIC HEALTH RELEVANCE: The proposal described herein seeks to develop a lower vertebrate model for understanding how the developing immune system responds to harsh environmental chemicals, and how (or if) a correlation between high levels of environmental PAHs, altered antibody responses, "inflammation-like" conditions, expression of multi-drug resistance proteins, recalcitrant CYP1A induction, and neoplasia develops in adults. This model will offer novel insights into how resistance or adaptation to environmental contaminants can develop.