PCB IMMUNOTOXICITY

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The primary function of the immune system is the recognition and elimination of cellular and noncellular entities which are non-self (bacteria, viruses, protozoa) or altered self (transformed malignant cells) which would otherwise compromise health. It has been established that some environmental contaminants, including the halogenated aromatic hydrocarbons, polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause immune dysfunction, however, the mechanisms are unresolved. Recent progress in this area has demonstrated that the immunotoxicity of TCDD and of certain PCB congeners is mediated through a cytoplasmic/nuclear receptor protein (the aromatic hydrocarbon (Ah) receptor) which binds certain halogenated aromatic hydrocarbons with high affinity. The formation of this ligand-Ah receptor complex leads to the activation of the Ah gene complex and results in the synthesis of a number of proteins, many of which are enzymes such as aryl hydrocarbon hydroxylase (AHH), and several toxic effects including cleft-palate formation, thymic atrophy, and immune dysfunction, but the mechanisms by which activation of this complex results in these effects remains unclear. Since it has been established that the Ah receptor protein is expressed in lymphoid tissue and that Ah receptor ligands can induce lymphoid AHH activity, it is proposed that: 1) lymphoid tissue possesses all the necessary cellular apparatus to be functionally impaired by activation of its Ah gene complex, 2) only specific subpopulations of T and B lymphocytes are sensitive to Ah gene activation, 3) only lymphocytes at certain stages of differentiation are sensitive to Ah gene activation, and 4) that activation of this complex in lymphoid tissue leads to the synthesis of products which directly or indirectly result in impairment of immune function. These hypotheses will be tested using in vivo and in vitro methods of toxicology and immunology to evaluate several parameters of humoral and cellular immunity in mice which are either Ah responsive or nonresponsive and whose lymphoid tissues have been experimentally exchanged or forced to cooperate with those of the opposite Ah genotype. These studies will further elucidate the mechanisms by which halogenated aromatic hydrocarbons interact with mammalian systems and will aid in the human health risk assessments of these pollutants.