Organ specificity of beta‐carotene induced lung gene‐expression changes in Bcmo1^−/− mice

Abstract

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. Here, we explicitly questioned the lung specificity. Methods and results We show that BC supplementation resulted in an opposite direction of gene‐regulation in male compared to female Bcmo1−/− mice in lung, liver, and iWAT. This supports a systemic effect of BC on steroid hormone metabolism mediated responses. Lung, liver, and iWAT of female Bcmo1−/− mice showed an increased inflammatory response, which was counteracted by supplementation of BC. This supports a genotype dependent increased sensitivity of female mice for vitamin A deficiency. Finally, the effect of BC on Wnt signaling in male Bcmo1−/− mice was examined. Frizzled homolog 6 (Fzd6) downregulation was seen in all three tissues. Collagen triple helix containing 1 (Cthrc1) downregulation was seen in lung tissue only, suggesting specificity. Upregulation of genes involved in oxygen sensing was seen in lung and iWAT, while protocadherin upregulation was only seen in lung. Conclusion Our results demonstrate that effects of BC are strongly sex dependent. While effects of BC on hormone metabolism mediated responses and inflammation are systemic, effects on Wnt signaling may be lung specific.

β‐Carotene Bioavailability and Conversion Efficiency Are Significantly Affected by Sex in Rats

“…Conversely, it was shown that, in rodents, the concentration of VA in the liver was higher in females than in males 6 [26,28,29] . These differences in VA metabolism between males and females are also suggested by other observations: females have higher CRBP concentrations than males in certain tissues [30] , the effect of β-carotene supplementation is sex-dependent [31] and there is a female-specific mechanism for retinoic acid generation in some tissues [32] . We hypothesize that there may be other differences between males and females with respect to VA metabolism, such as differences in the bioavailability of β-carotene and in the efficiency of its conversion to VA.…”

Host‐related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans

“…This is exemplified by sex specific responses resulting from β‐carotene accumulation in white adipose tissue, which showed that 4970 genes were affected in WT female mice, while only 407 were affected in male mice , with the majority of the commonly affected genes (141 out of 144) showing a strong negative, rather than positive, correlation of expression between males and females. This negative correlation was also seen in BCO1 knockout mice, although the number of genes affected were more similar between the two sexes (1522 gene in females and 1202 in males, 33 overlapping) . In both WT and BCO1 knockout mice, only a minority of genes is commonly affected by β‐carotene in females and males.…”

“…Strikingly, the opposite regulation of genes in response to β‐carotene exposure was also prominent in the lung of BCO1 knockout mice, but this was not seen in WT mice in this tissue . On the other hand, WT liver showed a strong positive correlation of β‐carotene responsive genes between males and females .…”