Impact of extreme heat events on risk and mitigation of neural tube defects

Extreme heat events (EHE) increase risk of hyperthermia. Maternal hyperthermia is associated with a range of birth defects, particularly neural tube defects (NTDs). Maternal exposure to EHE during the critical period of pregnancy, when the embryo undergoes neurulation, may increase susceptibility to NTDs through additive interactions with nutritional and genetic risk factors. Highest rates of NTDs occur in low- and middle-income countries (LMIC), many of which are prone to EHE, and have a disproportionately higher prevalence of nutritional risk factors, including inadequate folate intake. The effect of increasingly frequent and severity of EHE on NTD frequency are likely to manifest most profoundly in LMIC. Improved understanding of the mechanisms underlying heat-induced NTDs and identification of potential protective interventions is crucial to mitigate effects of extreme climate. This project will use mouse genetic models of NTDs, in embryo culture and in vivo, to identify heat-sensitive components of neurulation and determine whether folate metabolism is impaired in heat-exposed embryos. We will interrogate three-way heat, genotype, maternal diet interactions and test whether supplemental nutrients, such as folic acid, can prevent hyperthermia-related NTDs. Identification of protective nutrients, as a modifiable variable in heat-induced NTDs, may be applicable to NTD prevention in ?at-risk? human populations