Foetal alcohol spectrum disorder (FASD) can be caused by prenatal alcohol exposure (PAE) during gastrulation, which occurs at 3 weeks after fertilization in humans and on embryonic day 7 (E7) in mice. FASD affects ∼5% of live births in the USA and is characterised by craniofacial and central nervous system malformations. However, some children exposed prenatally to alcohol are developmentally unaffected, and there is evidence that genetics orchestrate increased sensitivity to PAE.

In their recent study, Scott Parnell and colleagues (Boschen et al., 2021) investigate differences in the transcriptome of two closely related mouse substrains that are known to respond differently to PAE during gastrulation: C57BL/6J (6J) and C57BL/6NHsd (6N) mice have two known genetic mutations differing between them. One of which, in the 6J strain, is a mutation in Nnt, which encodes an enzyme that prevents accumulation of reactive oxygen species (ROS) and has been linked to increased susceptibility to PAE-induced malformations in these mice. The authors developed a web-based tool to compare the dynamic transcriptional changes during gastrulation. They found that, during gastrulation, on E7, 6J mice have a higher baseline expression of inflammatory signalling genes compared to 6N mice. Overall, the 6J strain displays more pronounced transcriptional changes compared to the 6N strain following PAE. Furthermore, the authors identified novel genes associated with increased alcohol sensitivity in the 6J strain, and many of the differentially expressed genes relate to apoptosis, cell proliferation, and craniofacial and brain development. By contrast, the 6J strain exhibits notable downregulation of genes in the sonic hedgehog (Shh) pathway, as well as ciliary pathways, which is less apparent in the 6N strain. Interestingly, deleting genes in each of these pathways has previously been shown to exacerbate PAE effects.

Based on these findings, the authors propose that the known Nnt mutation in 6J mice impairs ROS resolution, leading to a higher inflammatory state and incapability to cope with stressors such as alcohol. This study thus unveils a novel pathogenic mechanism underlying PAE sensitivity and also provides valuable resources that can be used to inform future studies of FASD. With advances in single-cell and spatial sequencing, studies such as these can be expanded to investigate gene expression patterns that contribute to tissue morphology during gastrulation.

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