Breast cancer 1 (BRCA1)-deficient embryos develop normally but are more susceptible to ethanol-initiated DNA damage and embryopathies

Redox Biol. 2016 Apr:7:30-38. doi: 10.1016/j.redox.2015.11.005. Epub 2015 Nov 18.

Abstract

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, our results show 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.

Keywords: Breast cancer 1 (BRCA1); DNA repair; Embryo culture; Embryopathies; Ethanol; Oxidatively damaged DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein
  • DNA Damage
  • Embryonic Development* / drug effects
  • Ethanol / adverse effects*
  • Female
  • Male
  • Mice
  • Oxidative Stress
  • SOXB1 Transcription Factors / metabolism*
  • Teratogenesis
  • Tumor Suppressor Proteins / deficiency*

Substances

  • BRCA1 Protein
  • Brca1 protein, mouse
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Tumor Suppressor Proteins
  • Ethanol