RESUMEN
Rodents, mice and rats in particular, are the species of choice for evaluating chemical carcinogenesis. However, different species and strains often respond very differently, undermining the logic of extrapolation of animal results to humans and complicating risk assessment. Intracisternal A particles (IAPs), endogenous retroviral sequences, are an important class of transposable elements that induce genomic mutations and cell transformation by disrupting gene expression. Several lines of evidence support a role of IAPs as mouse-specific genetic factors in responses to toxicity and expression of disease phenotypes. Since multiple subtypes and copies of IAPs are present in the mouse genome, their activity and locations relative to functional genes are of critical importance. This study identified the major "active" subtypes of IAPs (subtype 1/1a) that are responsible for newly transposed IAP insertions described in the literature, and confirmed that (1) polymorphisms for IAP insertions exist among different mouse strains and (2) promoter activity of the LTRs can be modulated by chemicals. This study further identified all the genes in the C57BL/6 mouse genome with IAP subtype 1 and 1a sequences inserted in their proximity, and the major biofunctional categories and cellular signaling networks of those genes. Since many "IAP-associated genes" play important roles in the regulation of cell proliferation, cell cycle, and cell death, the associated IAPs, upon activation, can affect cellular responses to xenobiotics and disease processes, especially carcinogenesis. This systemic analysis provides a solid foundation for further investigations of the role of IAPs as species- and strain-specific disease susceptibility factors.
Asunto(s)
Genes de Partícula A Intracisternal/genética , Genoma/genética , Ratones/genética , Neoplasias/genética , Animales , Secuencia de Bases , Células COS , Línea Celular , Chlorocebus aethiops , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad/genética , Variación Genética , Genómica/métodos , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos , Datos de Secuencia Molecular , Mutagénesis Insercional , Filogenia , Polimorfismo Genético , Homología de Secuencia de Ácido Nucleico , Especificidad de la EspecieRESUMEN
Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.