A TP53 Genotype Affects Mucin Gene Expression and Survival of Female Embryos

Rationale: We have reported that a genotype in the human TP53 gene that modifies the proline at codon 72 to arginine affects mucin gene expression in human airway cells. The present studies were designed to investigate the role of age and gender on mucin levels in these mice.

Methods: Lung homogenates were prepared from male and female p53WT and p53AXXA mice at the ages of 3 or 30 weeks (n=6, each group) and levels of MUC5AC, MUC5B and SPEDEF mRNAs and proteins were investigated by qPCR and Western blotting. Over a period of two years, the male to female ratio of the offsprings from these mice was documented. Further, the male to female ratio was determined at the embryonic stage in both colonies. Mouse airway epithelial cells (MAECs) from p53WT and p53AXXA mice were differentiated at air-liquid interface (ALI) to determine whether the observed sex-specific differences in mucin levels were independent of hormones.

Results: Overall, MUC5AC and MUC5B were 2-fold higher in the 30- compared with the 3-week-old mice on both the mRNA and protein levels. Specifically, female compared with male p53WT and p53AXXA male expressed 2.5-fold higher MUC5AC levels on the mRNA and protein levels. Female p53AXXA expressed higher level of MUC5AC than both p53WT and p53AXXA male mice. The ratio of male to female offsprings was 60%:40%, while at the embryonic stage the male/female ratio was 50%:50% in both p53WT and in p53AXXA mice. Paradoxically, MUC5AC and MUC5B mRNA levels were higher in male compared with female MAECs in p53AXXA mice.

Conclusions: Female hormones appear to affect mucin expression, especially in p53AXXA mice that express the highest levels in vivo. Further, higher levels of mucins obstructing the airways is a plausible cause of death for newborn female p53AXXA mice.