Numerous studies have shown that species, strains, sexes, and developmental stages of animals differ in their sensitivity to effects of toxic chemicals. In addition to this innate differential chemical sensitivity, some natural populations chronically exposed to environmental contaminants can acquire increased resistance or tolerance to those contaminants through genetic adaptation or physiological acclimation. Differential sensitivity of experimental animals to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related planar halogenated aromatic hydrocarbons (PHAH) is well known, but a clear understanding of the underlying mechanisms is lacking. In fish and wildlife, both innate differential sensitivity to dioxins and acquired dioxin resistance have been observed. Most of the biological activity of PHAH is mediated through the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and member of the bHLH-PAS gene family. The expression and function of the AHR and other components of the AHR-dependent signal transduction pathway are likely to be key factors determining sensitivity of species, populations, and subpopulations to PHAH effects. Similarly, alterations in AHR signaling might be responsible for acquired dioxin resistance.

This review begins with an overview of general mechanisms underlying differential chemical sensitivity and acquired tolerance, followed by a summary of our current understanding of mechanisms underlying dioxin sensitivity and resistance in laboratory mammals and mammalian cell lines, in which alterations in certain "control points" in the AHR signaling pathway have been shown to be responsible for reduced dioxin sensitivity. Differential dioxin sensitivity in aquatic animals is then reviewed, including case histories of adaptation following chronic exposure to dioxin-like compounds. Knowledge from mammalian cellular and organismal models can help guide the investigation of mechanisms underlying dioxin resistance in aquatic species.
 
 

I. Introduction

    A. Adaptation, resistance, tolerance

    B. Mechanisms of Resistance

II. Molecular Mechanisms of Dioxin Sensitivity and Resistance in Mammals

    A. Mechanisms of dioxin toxicity

        1. The Ah receptor/ARNT signal transduction pathway

        2. Alternative pathways of dioxin action

    B. Species- and strain-differences in dioxin sensitivity

    C. Cell and tissue models for dioxin resistance and negative regulation of AHR signaling

    D. Potential and demonstrated molecular sites of dioxin resistance ("control points")

III. Dioxin sensitivity in fish and wildlife - species differences

    A. Vertebrates

    B. Invertebrates

IV. Adaptation to Aromatic Hydrocarbons in Aquatic Species - Case Histories and Possible Mechanisms

    A. Dioxin-resistant killifish in Newark, NJ

    B. PCB-resistant killifish in the Acushnet River Estuary, New Bedford, MA

    C. PAH-resistant killifish in the Elizabeth River, VA

    D. PCB-resistant Perch in Lake Jarnsjon, Sweden

    E. PCB-resistant tomcod in the Hudson River

    F. Other cases of adaptation or acquired resistance to PHAH

V. Conclusions and Future Directions