Grant: Project Grant

The breast cancer 1 (BRCA1) protein is known to protect against breast cancer. However, we have discovered that during pregnancy BRCA1 also protects fetal mice from DNA damage that can cause birth defects and disorders in brain function after birth. The DNA damage is caused by reactive oxygen species (ROS), which are normal forms of activated oxygen essential for fetal development. However, when the fetus lacks proteins like BRCA1 that prevent and repair DNA damage, or when ROS production is enhanced by drugs like alcohol (ethanol, EtOH), the damage accumulates and causes abnormal fetal development. The developmental disorders in BRCA1-deficient mice may be relevant to children with autism spectrum disorders (ASD), and the exacerbated disorders with fetal EtOH exposure may be relevant to children with fetal alcohol spectrum disorders (FASD). To elucidate the role of BRCA1 in these disorders, we have developed a genetically altered mouse model lacking only 1 of their 2 copies (+/-) of the Brca1 gene, with a small decrease in BRCA1 protein. The progeny exhibit increased DNA damage and postnatal learning and memory deficits, which are worsened by a single low-level fetal EtOH exposure. We will use this mouse model to determine how both normal and EtOH-enhanced ROS levels and prenatal DNA damage cause birth defects and postnatal behavioural differences, and how BRCA1 protects the fetus from DNA damage. Our studies will establish a biological role for BRCA1 beyond cancer, in protecting the developing fetus from normal and chemically-enhanced ROS levels. This developmentally protective role of BRCA1 is likely important, since both copies of the Brca1 gene must be lost to increase the risk of cancer, whereas the loss of only 1 copy increases the risk of developmental disorders. Our results may identify new mechanisms and risk factors relevant to ASD and FASD, which could help in developing novel predictive and therapeutic strategies for high-risk pregnancies.