title: Downregulation of Fzd6 and Cthrc1 and upregulation of olfactory receptors and protocadherins by dietary beta-carotene in lungs of Bcmo1-/- mice.
abstract: An ongoing controversy exists on beneficial versus harmful effects of high beta-carotene (BC) intake, especially for the lung. To elucidate potential mechanisms, we studied effects of BC on lung gene expression. We used a beta-carotene 15,15'-monooxygenase 1 (Bcmo1) knockout mouse (Bcmo1(-/-)) model, unable to convert BC to retinoids, and wild-type mice (Bcmo1(+/+)) mice to dissect the effects of intact BC from effects of BC metabolites. As expected, BC supplementation resulted in a higher BC accumulation in lungs of Bcmo1(-/-) mice than in lungs of Bcmo1(+/+) mice. Whole mouse genome transcriptome analysis on lung tissue revealed that more genes were regulated in Bcmo1(-/-) mice than Bcmo1(+/+) mice upon BC supplementation. Frizzled homolog 6 (Fzd6) and collagen triple helix repeat containing 1 (Cthrc1) were significantly downregulated (fold changes -2.99 and -2.60, respectively, false discovery rate < 0.05) by BC in Bcmo1(-/-). Moreover, many olfactory receptors and many members of the protocadherin family were upregulated. Since both olfactory receptors and protocadherins have an important function in sensory nerves and Fzd6 and Cthrc1 are important in stem cell development, we hypothesize that BC might have an effect on the highly innervated pulmonary neuroendocrine cell (PNEC) cluster. PNECs are highly associated with sensory nerves and are important cells in the control of stem cells. A role for BC in the innervated PNEC cluster might be of particular importance in smoke-induced carcinogenesis since PNEC-derived lung cancer is highly associated with tobacco smoke.
authors.affiliation: Wageningen University, The Netherlands.
authors.forename: Yvonne G J
authors.initials: YG
authors.lastname: van Helden
authors.forename: Roger W
authors.initials: RW
authors.lastname: Godschalk
authors.forename: Sandra G
authors.initials: SG
authors.lastname: Heil
authors.forename: Annelies
authors.initials: A
authors.lastname: Bunschoten
authors.forename: Susanne
authors.initials: S
authors.lastname: Hessel
authors.forename: Jaume
authors.initials: J
authors.lastname: Amengual
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Bonet
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
authors.forename: Jaap
authors.initials: J
authors.lastname: Keijer
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics*; D002338:Carotenoids / Q000302:isolation & purification; D017931:DNA Primers; D004032:Diet; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D051157:Frizzled Receptors / Q000235:genetics*; D005784:Gene Amplification; D016678:Genome; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D018035:Receptors, Odorant / Q000235:genetics*; D012176:Retinoids / Q000302:isolation & purification; D015854:Up-Regulation; D019207:beta Carotene / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D050559:beta-Carotene 15,15'-Monooxygenase / Q000172:deficiency*
chemical_list: D015820:Cadherins; C530500:Cthrc1 protein, mouse; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D051157:Frizzled Receptors; C111048:Fzd6 protein, mouse; D043562:Receptors, G-Protein-Coupled; D018035:Receptors, Odorant; D012176:Retinoids; D019207:beta Carotene; D002338:Carotenoids; D012313:RNA; C493359:Bco1 protein, mouse; D050559:beta-Carotene 15,15'-Monooxygenase