A mutant Ahr allele protects the embryonic kidney from hydrocarbon-induced deficits in fetal programming

Adrian Nanez, Irma Ramos, Kenneth Ramos

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. Objectives: 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.

Original languageEnglish (US)
Pages (from-to)1745-1753
Number of pages9
JournalEnvironmental Health Perspectives
Volume119
Issue number12
StatePublished - Dec 2011
Externally publishedYes

Fingerprint

Fetal Development
Hydrocarbons
Alleles
Kidney
Inbred C57BL Mouse
Wilms' Tumor Genes
Syndecan-1
Developmental Genes
Somatomedin Receptors
Homeodomain Proteins
Forensic Anthropology
Messenger RNA
Benzo(a)pyrene
Kidney Diseases
Cadherins
Tumor Suppressor Genes
Morphogenesis
Epidermal Growth Factor Receptor
Theoretical Models
Down-Regulation

Keywords

  • Aryl hydrocarbon receptor
  • Benzo(a)pyrene
  • Fetal programming
  • Nephrogenesis
  • WT1

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Public Health, Environmental and Occupational Health

Cite this

A mutant Ahr allele protects the embryonic kidney from hydrocarbon-induced deficits in fetal programming. / Nanez, Adrian; Ramos, Irma; Ramos, Kenneth.

In: Environmental Health Perspectives, Vol. 119, No. 12, 12.2011, p. 1745-1753.

Research output: Contribution to journalArticle

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