Organ specificity of beta-carotene induced lung gene-expression changes in Bcmo1-/- mice.

Scope: Whole genome transcriptome analysis of male and female beta-carotene 15,15'-monooxygenase knockout (Bcmo1(-/-) ) and Bcmo1(+/+) (wild-type) mice with or without 14 wk of BC supplementation was done. We previously showed that only 1.8% of the genes regulated by BC in lung were also regulated in liver and inguinal white adipose tissue (iWAT), suggesting lung specific responses.

Gene expression response of mouse lung, liver and white adipose tissue to β-carotene supplementation, knockout of Bcmo1 and sex.

Scope: Little information is available on differences, commonalities and especially interactions in overall gene expression responses as a result of diet, differences in sex (male and female) and effects induced by differences in metabolism. Moreover, it is unknown whether such effects are tissue specific.

Methods And Results: We investigated the gene expression effects induced by β-carotene (BC) supplementation, knockout of β-carotene 15,15'-monooxygenase 1 (Bcmo1) and differences between male and female mice in lung, liver and inguinal white adipose tissue (iWAT).

Beta-carotene reduces body adiposity of mice via BCMO1.

Evidence from cell culture studies indicates that β-carotene-(BC)-derived apocarotenoid signaling molecules can modulate the activities of nuclear receptors that regulate many aspects of adipocyte physiology. Two BC metabolizing enzymes, the BC-15,15'-oxygenase (Bcmo1) and the BC-9',10'-oxygenase (Bcdo2) are expressed in adipocytes. Bcmo1 catalyzes the conversion of BC into retinaldehyde and Bcdo2 into β-10'-apocarotenal and β-ionone.

Beta-carotene affects gene expression in lungs of male and female Bcmo1 (-/-) mice in opposite directions.

Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15'-monooxygenase 1 knockout (Bcmo1 (-/-)) mice, which are-like humans-able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1 (-/-) mice by BC.

Downregulation of Fzd6 and Cthrc1 and upregulation of olfactory receptors and protocadherins by dietary beta-carotene in lungs of Bcmo1-/- mice.

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.

Knockout of the Bcmo1 gene results in an inflammatory response in female lung, which is suppressed by dietary beta-carotene.

Beta-carotene 15,15'-monooxygenase 1 knockout (Bcmo1 (-/-)) mice accumulate beta-carotene (BC) similarly to humans, whereas wild-type (Bcmo1 (+/+)) mice efficiently cleave BC. Bcmo1 (-/-) mice are therefore suitable to investigate BC-induced alterations in gene expression in lung, assessed by microarray analysis. Bcmo1 (-/-) mice receiving control diet had increased expression of inflammatory genes as compared to BC-supplemented Bcmo1 (-/-) mice and Bcmo1 (+/+) mice that received either control or BC-supplemented diets.

Transcriptome analysis in benefit-risk assessment of micronutrients and bioactive food components.

The establishment of functional effects due to variation in concentrations of micronutrients in our diet is difficult since they are often not immediately recognized as being healthy or unhealthy. Indeed, effects induced by micronutrients are hard to identify and therefore the establishment of the recommended daily intake, the optimal intake and the upper limit pose a challenge. For bioactive food components this is even more complicated.

Beta-carotene affects oxidative stress-related DNA damage in lung epithelial cells and in ferret lung.

Beta-carotene (BC) was found to enhance lung cancer risk in smokers. This adverse effect was unexpected because BC was thought to act as an anti-oxidant against cigarette smoke-derived radicals. These radicals can directly or indirectly damage DNA, leading to the formation of pro-mutagenic DNA lesions such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 3-(2-deoxy-beta-D-erythro-pentafuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one deoxyguanosine (M(1)dG).

Beta-carotene metabolites enhance inflammation-induced oxidative DNA damage in lung epithelial cells.

beta-Carotene (BC) intake has been shown to enhance lung cancer risk in smokers and asbestos-exposed subjects (according to the ATBC and CARET studies), but the mechanism behind this procarcinogenic effect of BC is unclear. Both smoking and asbestos exposure induce an influx of inflammatory neutrophils into the airways, which results in an increased production of reactive oxygen species and formation of promutagenic DNA lesions. Therefore, the aim of our study was to investigate the effects of BC and its metabolites (BCM) on neutrophil-induced genotoxicity.