COVID-related stress during pregnancy may leave epigenetic footprints in newborns epigenome

A few months ago, in December 2020, Bennet and other colleagues published a paper in Quaternary Science Reviews reporting on a set of footprints from Pleistocene retrieved in New Mexico. The footprints were probably those of two adult individuals, walking or escaping from mammoths or giant sloths. What is most interesting about these footprints is that another set also appears: smaller footprints of a young child. So, that was a family, wondering in what we now call White Sands National Park. One of the adults was probably bearing the child and he/she just let the child step on his/her feet, probably adjusting while escaping. Mimicking Forrest Gump on the bench - "There's an awful lot you can tell about a person by their shoes" - we can say that footprints tell us who we are and they tell us that we are animals who care for each other, who care for babies.

Back in our days, we know very well how the present pandemic is challenging our ability to care for others and to do that by investing in social relationships and affective exchanges. The COVID-19 healthcare emergency has impacted every area of our daily life, resulting in a real collective trauma with no similar antecedents in human history. Such an adverse environment may affect the health and development of human beings who are living specific time windows of heightened plasticity or sensitivity to environmental exposures. Pregnancy is such a period of dramatic openness of our neurobiology to external stimulations, which may leave long-lasting biomarkers at least through epigenetic mechanisms. DNA methylation is an epigenetic mechanism that is especially sensitive to environmental adversities and that may occur in mothers and infants' stress-related genes during pregnancy, with short- and long-term consequences for health and development.

We continuously learn from our experience, storing memories of adverse and protective events in our epigenome. The issue is: how are we going to use these memories to guide our future behavior?

Thanks to a multi-center and longitudinal project we have launched in May 2020 - which was independently funded by the Italian Ministry of Health and by Fondazione Roche - we are now able to provide the first evidence of altered methylation status in the newborn epigenome as a consequence of maternal pandemic-related stress during pregnancy. In a recent paper published in Scientific Reports, indeed, we have documented how pregnant women who reported greater stress due to the pandemic also had newborn infants with higher levels of methylation of a specific gene that is critically involved in behavioral, emotional, and socio-cognitive development: the SLC6A4 gene, encoding for the serotonin transporter. Notably, this neonatal biomarker of prenatal exposure to adversities was in turn significantly associated with infants' behavioral development at 3 months. On these premises, one can speculate that the stress induced by the COVID-19 healthcare emergency may embed into maternal-fetal biology, altering infants' epigenome, and ultimately resulting in an altered developmental trajectory.

As the vaccine campaign slowly proceeds and we try to learn living in a pandemic world, the risk of a hidden stressful pandemic should not be underestimated. By investing in developmental psychobiology research we may be able to chase the footprints of pandemic-related stress impact and to identify potential markers of risk and resilience in mothers and infants. This research is also highlighting that our biology never stops learning from the environment, even from adverse conditions. Where these footprints will lead us is unknown; nonetheless, it is of paramount importance that we learn from the pandemic by empowering actions of preventive and therapeutic support for mothers and infants at risk.

Full citation: Provenzi, L., Mambretti, F., Villa, M. et al. Hidden pandemic: COVID-19-related stress, SLC6A4 methylation, and infants’ temperament at 3 months. Sci Rep 11, 15658 (2021).

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