Abstract

The developing brain is extremely sensitive to the environment, and is responsive to endocrine, nutritional and chemical cues. However, the fetal brain is also protected from factors present in the fetal and maternal circulation, by transporters at the blood-brain barrier and the placenta. As such, there are mechanisms in place that can regulate fetal brain exposure to both endogenous (hormones, nutrients) and exogenous factors (xenobiotics). My laboratory has been focused on understanding how the brain responds to certain endocrine cues, as well as how the protective transporters are regulated across gestation using both animal models and human tissues. Transporter function becomes critically important in babies that are born preterm and who are often exposed to drugs and other factors that can cross into the brain leading to neurotoxicity. Glucocorticoids (GC) are critical for normal brain development and are maintained at low levels in the fetus. However, GCs increase exponentially in late gestation, providing a critical trigger for lung and brain development. Maternal or fetal stress or maternal treatment with synthetic GCs can lead to increased fetal brain exposure to GC earlier in gestation. The latter occurs in cases of threatened preterm birth (>10% of all pregnancies). We have shown that premature exposure of the fetal brain to GC can lead to profound changes in the epigenetic and transcriptional landscapes in various brain regions critical to the regulation of hypothalamic-pituitary-adrenal (HPA) and stress-related behaviours. Furthermore, these effects can manifest across multiple generations. Our recent studies have also shown that GC exposure can lead to acute and long-term alterations in transporter function at the placenta and BBB . Our findings have significant implications for clinical practice, but also our fundamental understanding of the mechanisms by which the fetal endocrine environment impact the developing brain leading to life-long modification of endocrine function, behaviours and ongoing brain protection.

Our work is supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Council (NSERC).