ABSTRACT
Three possible scenarios are presented below and diagrammed in Figure 1. The mechanisms which TCDD upregulates transcription of a number of genes is very wellunderstood at the molecular level (Fig. 1; for review, see Schmidt and Bradfield, 1996). TCDD is very lipophilic and easily enters cells by passive diffusion. Once in the cytoplasm, TCDD binds to the AhR, a member of the basic-helix-loop-helix (bHLH) family of transcription factors (Burbach et al. , 1992). In its unliganded state, the AhR is bound in the cytoplasm to two 90 kDa heat shock proteins (hsp90). TCDD binding facilitates release of hsp90 and allows translocation of the liganded AhR to the nucleus, where it dimerizes with another bHLH protein, the AhR nuclear translocator (ARNT). This liganded AhR/ ARNT complex is a heterodimeric transcription factor that enhances transcription of a number of genes encoding xenobiotic metabolizing enzymes (CYP1A1, CYP1A2, glutathione-S-transferase-Ya, quinone reductase, and class 3 aldehyde dehydrogenase) by binding to enhancer elements (dioxin response elements, or DREs) in the 5' regulatory regions of these genes, achieving signaling via chromatin disruption as well as interaction with the basal cellular transcriptional machinery (Schmidt and Bradfit:ld, 1996, and references therein; Rowlands et al., 1996). However, although it is possible that activation of these xenobiotic metabolizing enzymes could lead to toxicity, for example by metabolizing an endogenous compound important in normal cell function, induction of these enzymes is generally considered to be more of a biomarker of TCDD exposure than a mechanism of toxicity. Other members of the Ahr gene battery that exhibit increases in mRNA abundance in response to TCDD exposure include CYP1B1, interleukin-1(3, plasminogen activator inhibitor-2 (Sutter et al., 1991) and transforming growth factor-a (Choi et al., 1991), although the mechanism by which these increases occur is unknown, as functional OREs have not yet been identified in these genes. But again, none of these or any other TCDD-responsive genes identified to date have been directly linked to toxicity. However, it remains possible that tissuespecific enhancement of transcription of as yet unidentified genes plays a key role in mediating the toxic effects of TCDD.
