which include polychlorinated biphenyls (PCBs), dibenzofuSpecies-Specific Recombinant Cell Lines as Bioassay Systems rans (PCDFs), and dibenzo-p-dioxins (PCDDs) as well as for the Detection of 2,3,7,8-Tetrachlorodibenzo-p-dioxin-like many other subclasses of PCDHs (Giesy et al., 1994a). These known to bioaccumulate and biomagnify in the food chain Exposure to specific polychlorinated diaromatic hydrocarbons (Ballschmitter et al., 1989; Tanabe et al., 1987; Webster and (PCDH), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, di- Commoner, 1994; Giesy et al., 1994a,b). Exposure to and oxin), produces a wide variety of species-and tissue-specific toxic bioaccumulation of PCDHs has been observed to produce a and biological effects. Many of these responses are mediated by variety of species-and tissue-specific effects, such as tumor of PCDHs involve costly and time-consuming traditional instrumental analysis methods, such as gas chromatography Polychlorinated diaromatic hydrocarbons (PCDHs) 2 are a (GC) separation and mass spectrometry (MS). The identifidiverse group of widespread environmental contaminants, cation and quantification of these compounds is complicated by the fact that techniques and standards for identifying many of the congeners and isomers do not exist. In addition,
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of a variety of hydrophobic natural and synthetic chemicals, including the environmental contaminant 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). A variety of indole-containing chemicals, such as indole-3-carbinol, indolo[3, 2-b]carbazole, and UV photoproducts of tryptophan (TRP), have previously been identified as ligands for AhR. Here we have examined the ability of endogenous metabolites of tryptophan (TRP) to bind to and activate AhR in vitro and in cells in culture. Although hydroxylated TRP metabolites were inactive, two metabolites, namely tryptamine (TA) and indole acetic acid (IAA), were shown to be AhR agonists. Not only do TA and IAA bind competitively to AhR, but they also can stimulate AhR transformation and DNA binding and induce expression of an AhR-dependent reporter gene in cells. In addition to being an AhR ligand, TA is also a competitive substrate for cytochrome P4501A1, a well-characterized AhR- and TCDD-inducible gene product. Although these compounds are relatively weak ligands, compared to TCDD, they represent some of the first endogenous hydrophilic AhR agonists identified to date.
Sexually dimorphic expression of a broad array of liver proteins involved in reproduction and xenobiotic metabolism is induced at puberty by sex-specific growth hormone patterns. An additional control of sex-dependent gene expression is conferred by Regulator of sex-limitation (Rsl) alleles. In variant rsl mice, females inappropriately express the male Sex-limited protein, Slp. We recently showed that a panel of male-specific liver genes is repressed by Rsl, accentuating sex differences in a hormone-independent manner. Here we map rsl to a region on Chromosome 13 comprised exclusively of KRAB (Kruppel-associated box) zinc-finger protein (ZFP) genes. Among eight Rsl candidate (Rslcan) genes within the critical genetic interval, the recent duplicates Rslcan-4 and Rslcan-9 both harbor mutations in rsl mice (partial deletion and splice-site inactivation, respectively). Transgenesis with bacterial artificial chromosome (BAC) clones encompassing Rslcan-4 restores male-specific MUP (major urinary protein) expression to rsl mice, whereas a BAC containing Rslcan-9 rescues sex-specific expression of Slp and cytochrome P450 Cyp2d9. Thus, the Rslcan-4 and Rslcan-9 paralogs partitioned regulation of their target genes during evolution. This demonstrates the first biological role for a set of KRAB zinc-finger repressor proteins and reveals the molecular basis of a gene-silencing pathway critical for sexual dimorphism.
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