The breast cancer 1 (brca1) gene is associated with breast and ovarian cancers, and heterozygous (+/−) brca1 knockout progeny develop normally, suggesting a negligible developmental impact. However, a study has shown that BRCA1 plays a broader biological role in protecting the embryo from oxidative stress.
Sox2-promoted Cre-expressing hemizygous males were mated with floxed brca1 females, and gestational day 8 +/− brca1 conditional knockout embryos with a 28% reduction in protein expression were exposed in culture to the reactive oxygen species (ROS)-initiating drug ethanol (EtOH). Untreated +/− brca1-deficient embryos developed normally, but when exposed to EtOH exhibited increased levels of oxidatively damaged DNA, measured as 8-oxo-2’- deoxyguanosine, γH2AX, which is a marker of DNA double strand breaks that can result from 8-oxo-2’- deoxyguanosine, formation, and embryopathies at EtOH concentrations that did not affect their brca1- normal littermates.
These results reveal that even modest BRCA1 deficiencies render the embryo more susceptible to drug-enhanced ROS formation, and corroborate a role for DNA oxidation in the mechanism of EtOH teratogenesis.
Source: Breast cancer 1 (BRCA1)-deficient embryos develop normally but are more susceptible to ethanolinitiated DNA damage and embryopathies Aaron M. Shapiro, Lutfiya Miller-Pinsler Peter G. Wells Redox Biol. 2015 Nov 18