title: A mutant Ahr allele protects the embryonic kidney from hydrocarbon-induced deficits in fetal programming.
abstract: BACKGROUND
  The use of experimental model systems has expedited the elucidation of pathogenetic mechanisms of renal developmental disease in humans and the identification of genes that orchestrate developmental programming during nephrogenesis.
  
  
  OBJECTIVE
  We conducted studies to evaluate the role of AHR polymorphisms in the disruption of renal developmental programming by benzo(a)pyrene (BaP).
  
  
  METHODS
  We used metanephric cultures of C57BL/6J (C57) mice expressing the Ahr(b-1) allele and B6.D2N-Ahr(d)/J (D2N) mice expressing a mutant allele deficient in ligand binding (Ahr(d)) to investigate molecular mechanisms of renal development. Deficits in fetal programming were evaluated in the offspring of pregnant mice treated with BaP during nephrogenesis.
  
  
  RESULTS
  Hydrocarbon challenge of metanephri from C57 mice altered Wilms' tumor suppressor gene (Wt1) mRNA splice variant ratios and reduced mRNAs of the Wt1 transcriptional targets syndecan-1 (Sdc1) paired box gene 2 (Pax2), epidermal growth factor receptor (Egfr), and retinoic acid receptor, alpha (Rarα). These changes correlated with down-regulation of effectors of differentiation [secreted frizzled-related sequence protein 1 (Sfrp1), insulin-like growth factor 1 receptor (Igf1r), wingless-related MMTV-integration site 4 (Wnt4), Lim homeobox protein 1 (Lhx1), E-cadherin]. In contrast, metanephri from D2N mice were spared hydrocarbon-induced changes in Wt1 splice variant ratios and deficits of differentiation. We observed similar patterns of dysmorphogenesis and progressive loss of renal function at postnatal weeks 7 and 52 in the offspring of pregnant C57 but not D2N mice gavaged with 0.1 or 0.5 mg/kg BaP on gestation days 10-13.
  
  
  CONCLUSIONS
  These findings support a functional link between AHR and WT1 in the regulation of renal morphogenesis and raise important questions about the contribution of human AHR polymorphisms to the fetal origins of adult-onset kidney disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky 40292, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Nanez
authors.forename: Irma N
authors.initials: IN
authors.lastname: Ramos
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Ramos
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D015153:Blotting, Western; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006652:Histological Techniques; D007150:Immunohistochemistry; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000187:drug effects*; D051762:PAX2 Transcription Factor / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D053668:Syndecan-1 / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D017931:DNA Primers; D066246:ErbB Receptors; D051762:PAX2 Transcription Factor; D020033:Protein Isoforms; D018336:Receptors, Aryl Hydrocarbon; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D053668:Syndecan-1; D025721:WT1 Proteins; C484722:Ahr protein, mouse; C497319:Pax2 protein, mouse; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C508242:Sdc1 protein, mouse