L. S. Birnbaum

Bio: L. S. Birnbaum is an academic researcher from United States Environmental Protection Agency. The author has contributed to research in topics: Messenger RNA & Regulation of gene expression. The author has an hindex of 1, co-authored 1 publications receiving 182 citations.

Developmental expression of two members of a new class of transcription factors: I. Expression of aryl hydrocarbon receptor in the C57BL/6N mouse embryo

Abstract: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with a basic region/helix-loop-helix (bHLH) motif. AhR has been sequenced and the functional domains defined and there is information on the formation of complexes with other peptides and interactions with DNA, although these areas continue to be investigated. AhR mediates many biological effects such as developmental toxicity, including induction of cleft palate and hydronephrosis. This regulatory protein is expressed in embryonic liver and has been immunohistochemically localized in cells of human and mouse secondary palate. The expression of AhR in embryonic tissues and its ability to disrupt development suggests a significant role for this protein in development. The present study examines the pattern of AhR expression in the C57BL/6N mouse embryo from gestation days (GD) 10–16, using in situ hybridization and immunohistochemical analysis. AhR mRNA was localized with 35S-RNA antisense riboprobe (cAh1 probe, 1.8 Kb amino terminal DNA). AhR protein was localized with purified monoclonal antibody (RPT-9) raised against the N-terminal peptide sequence. AhR mRNA and protein were expressed in GD 10–13 neuroepithelium, and as development progressed the levels in brain decreased. GD 10–12 embryos also showed AhR in branchial arches, heart, somites, and liver. AhR protein and mRNA in heart were highest at GD 10–11 and decreased with age. In liver, AhR mRNA and protein levels increased and nuclear localization became more pronounced with gestational age. In GD 14–16 embryos levels in liver and adrenal were highest, but AhR was present in ectoderm, bone, and muscle. AhR expression was specific for both cell type, organ/tissue, and developmental stage, suggesting that this novel ligand-activated transcriptional regulator may be important in normal embryonic development. © 1995 wiley-Liss, Inc.1

Ah receptor signaling pathways

Abstract: The aryl hydrocarbon (Ah) receptor has occupied the attention of toxicologists for over two decades. Interest arose from the early observation that this soluble protein played key roles in the adaptive metabolic response to polycyclic aromatic hydrocarbons and in the toxic mechanism of halogenated dioxins and dibenzofurans. More recent investigations have provided a fairly clear picture of the primary adaptive signaling pathway, from agonist binding to the transcriptional activation of genes involved in the metabolism of xenobiotics. Structure-activity studies have provided an understanding of the pharmacology of this receptor; recombinant DNA approaches have identified the enhancer sequences through which this factor regulates gene expression; and functional analysis of cloned cDNAs has allowed the characterization of the major signaling components in this pathway. Our objective is to review the Ah receptor's role in regulation of xenobiotic metabolism and use this model as a framework for understanding the less well-characterized mechanism of dioxin toxicity. In addition, it is hoped that this information can serve as a model for future efforts to understand an emerging superfamily of related signaling pathways that control biological responses to an array of environmental stimuli.

Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor

Abstract: Background: The aryl hydrocarbon receptor (AhR or dioxin receptor) is a ligand-activated transcription factor that is considered to mediate pleiotropic biological responses such as teratogenesis, tumour promotion, epithelial hyperplasia and the induction of drug-metabolizing enzymes to environmental contaminants usually represented by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In contrast to the role of AhR in the regulatory mechanism of xenobiotic-metabolizing enzymes, there is no direct proof that the AhR is involved in the teratogenic effects of TCDD. Results: To gain insight into the physiological and teratogenic role of the AhR, we have used gene targeting in mice to disrupt the murine Ahr gene by homologous recombination. Ahr-null mice were viable and fertile and were apparently normal at birth, but displayed a slightly slower growth rate than wild-type mice for the first few weeks of life. When pregnant dams were administered with TCDD by gavage, at a dose of 40 μg/kg body weight at gestation day 12.5, none of the Ahr-null mutant foetuses were sensitive to the teratogenic effects of TCDD, although almost all wild-type foetuses suffered from cleft palate and hydronephrosis. In heterozygous Ahr+/− genotypes, nearly all foetuses suffered from hydronephrosis in response to TCDD treatment, while haplo-insufficiency was observed in the incidence of cleft palate. Conclusion: These results clearly show that the AhR is involved in the malformation of the palate and kidney in mouse embryos caused by TCDD and suggests that the mechanism of its involvement differs between the cleft palate and hydronephrosis.

Cancer and developmental exposure to endocrine disruptors.

Abstract: Developing organisms have increased susceptibility to cancer if they are exposed to environmental toxicants during rapid growth and differentiation. Human studies have demonstrated clear increases in cancer after prenatal exposure to ionizing radiation, and there is suggestive evidence that brain tumors and leukemia are associated with parental exposures to chemicals. Animal experiments have demonstrated increased tumor formation induced by prenatal or neonatal exposure to a variety of chemicals, including direct-acting carcinogens and drugs. Recently, natural estrogens have been classified as known human carcinogens. Prenatal exposure to natural and synthetic estrogens is associated with increases in breast and vaginal tumors in humans as well as uterine tumors in animals. Synthetic halogenated chemicals increase liver tumors after early life-stage exposure. Recently, a prototypical endocrine-disrupting compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin, has been shown to be a developmental toxicant of the mammary gland in rodents. Dioxin alters multiple endocrine systems, and its effects on the developing breast involve delayed proliferation and differentiation of the mammary gland, as well as an elongation of the window of sensitivity to potential carcinogens. Implications of these new findings suggest that causes of endocrine-related cancers or susceptibility to cancer may be a result of developmental exposures rather than exposures existing at or near the time of tumor detection.