, 2008, Fernandez-Salguero et al , 1995, Lin et al , 2002, Mimura

, 2008, Fernandez-Salguero et al., 1995, Lin et al., 2002, Mimura and Fujii-Kuriyama, 2003, Nishimura et al., 2005, Schmidt et al., 1996 and Vorderstrasse et al., 2001). They are find more also refractory to transcriptional responses (Boutros et al., 2009 and Tijet et al., 2006). Second, mice with mutations in the AHR that prevent nuclear translocation (Bunger et al., 2003) or binding to AHREs (Bunger et al., 2008) were non-responsive to all impacts of TCDD examined including hepatomegaly and thymic

atrophy. Finally, mice hypomorphic for ARNT exhibited attenuated thymic atrophy and hepatotoxicity but unaffected Cyp1a1 induction ( Walisser et al., 2004). Taken together, these data suggest that DNA-binding of the ligand-activated AHR:ARNT complex is essential for major toxic outcomes of TCDD. Beyond transgenic mice, several other model systems have been used to study dioxin toxicity. Of particular importance, Long-Evans (Turku A/B) (L-E) and Han/Wistar (Kuopio) (H/W) rats have been extensively exploited in mechanistic studies because of their striking differential susceptibilities to TCDD toxicity. L-E rats are sensitive to TCDD, with an LD50 of 10–20 μg/kg ( Pohjanvirta et al., 1993). In contrast, a large deletion in the AHR transactivation domain ( Pohjanvirta Roxadustat cost et al., 1998) induces remarkable resistance to TCDD

(LD50 > 10,000 μg/kg) in H/W rats ( Unkila et al., 1994). However, in spite of this mutation, H/W rats remain responsive to TCDD treatment: for example, thymic

atrophy occurs in both L-E and H/W rats after TCDD-exposure ( Pohjanvirta et al., 1989, Tuomisto et al., 1999 and Viluksela et al., 2000). Responses that are similar in sensitive and resistant strains are termed “Type-I” responses, while those that differ, such as acute lethality, are known as “Type-II” responses ( Pohjanvirta et al., 2011, Simanainen et al., 2002 and Simanainen et al., 2003). These pathologic Lenvatinib differences are also evident at the molecular level: many AHR-regulated genes such as Cyp1a1, Cyp1a2, and Nqo1 respond equally in sensitive and resistant rats ( Boutros et al., 2011 and Moffat et al., 2010). Previously, we identified transcriptional changes that are concurrent with the onset of dioxin toxicities by contrasting mRNA abundances in mice and rats treated with TCDD (Boutros et al., 2008). We found very dramatic inter-species heterogeneity, with approximately 90% of dioxin-responsive genes being species-specific. Similarly, when we compared dioxin-sensitive L-E versus dioxin-resistant H/W rats 19, 96, and 240 h following exposure to TCDD (Boutros et al., 2011 and Moffat et al., 2010), we found that the vast majority of genes exhibited altered mRNA abundances in only one rat strain (Boutros et al., 2011 and Moffat et al., 2010).

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