Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution September 1999 ; New Bedford Harbor (NBH), MA, is contaminated with halogenated aromatic hydrocarbons HAH including some potent aryl hydrocarbon receptor AhR agonists. To determine if Fundulus heterocitus from NBH have developed resistance to HAll, we examined the inducibility of cytochrome P4501A1 CYP1A1 in fish from NBH and Scorton Creek SC, reference site. Despite higher PCB concentrations in NBH than in SC fish - -1 500-fold - CYP1A1 expression, in most tissues, was not higher in NBH fish than in SC fish. Glutathione S-transferase GST and UDP-glucuronosyltransferase UGT activities were higher in NBH fish than in SC fish, but only when fish were collected during different seasons. GST activity was higher in the intestines ofNBH fish than in any other tissue. 2,3,7,8-TetrachlorodibenzoftiranTCDF induced CYP1A1 expression, in all tissues examined, in SC fish. In contrast, NBH fish showed little CYP1A1 induction by any measure, in any tissue. Hepatic GST activity was induced only in male NBH fish. Hepatic UGT activity showed no relationship to treatment in fish from either site. 2,3,7,8-Tetrachlorodibenzo-p-dioxin TCDD and J3-naphthoflavone BNF induced CYP1A1 activity to the same level in primary cultures ofhepatocytes from either SC orNBH fish. However, hepatocytes from NBH fish were 14-fold less sensitive to TCDD and 3-fold less sensitive to BNF than hepatocytes from SC fish. To examine the heritability ofresistance, NBH and SC F1 fish were treated with 3HTCDD or BNF. 3H-TCDD induced CYP1A1 expression only in SC F1 fish. BNF induced CYP1A1 expression in both SC and NBH F1 fish. There was no significant difference in hepatic 3H-TCDD concentrations between SC and NBH F1 fish. Hepatic AhR content, as measured by photoaffinity labeling with 125I-N3Br2DD, was lower in NBH fish than in SC fish and lower in males than in females. After 90 days in captivity, the sex difference persisted, but the site difference did not. TCDF induced hepatic AIIR content in NBH F1 fish. These results indicate that NBH Fundulus have developed a pre-translational, systemic, heritable resistance to HAHs. These findings suggest that an alteration in the AIIR pathway is responsible for this resistance; this is the subject of continuing research. ; This work was supported by a National Science Foundation Graduate Fellowship Program and by a National Institute of Environmental Health and Safety grant P42 ES073 81 Superfund Basic Research Program at Boston University