Exposure to toxins from the environment has been linked to a rise in non-communicable diseases and behavioral deficits in adults. WHO data further indicate that deaths attributable to environmental factors are highest in children. Metabolic stress during embryonic development is also correlated with increased risk of type 2 diabetes, coronary artery disease and cancer as well as some psychiatric illnesses. Such findings lend support to the idea that disease predispositions are established in utero and are coalescing in to an emerging field that addresses the Fetal Origins of Adult Disease (FOAD). While many studies of cellular stress have been undertaken in cell cultures, it is important to investigate such stress in tissues and in the context of whole animal physiology. This project will use transgenic reporters for distinct cell stress pathways (McMahon et al. 2018) to uncover the effects of acute and chronic environmental stress on cell behaviour and differentiation in developing mouse embryo. Metabolic and pathogen-mediated stresses are known to trigger the integrated stress response (ISR)(Pakos-Zebrucka et al. 2016). This is initially adaptive and leads to attenuation of protein synthesis and upregulation of stress mitigating genes, but can ultimately lead to apoptosis. We will investigate here if stress factors from the environment induce the ISR in early embryos and whether distinct stresses summate through this regulatory pathway.
This project will identify embryonic tissues and cell states particularly vulnerable to environmental stress and begin to elucidate mechanistic links between cell stress pathways. Training will be provided in mammalian genetics and embryology as well as molecular biology and biochemical approaches.
McMahon M, Ding S, Acosta-Jimenez LP, Frangova TG, Henderson CJ, Wolf CR. 2018. Measuring in vivo responses to endogenous and exogenous oxidative stress using a novel haem oxygenase 1 reporter mouse. The Journal of physiology 596: 105-127.
Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. 2016. The integrated stress response. EMBO reports 17: 1374-1395.