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How does exposure to air pollution affect the proper course of pregnancy and the development of the unborn child? A research team from Inserm and Université Grenoble Alpes investigated the potential effects on placental DNA of exposure to three major airborne pollutants. When comparing the data obtained from around 1 500 pregnant women, it observed that exposure to these pollutants during pregnancy was associated with epigenetic changes[1] liable to alter the development of the foetus, particularly at the metabolic, immune and neurological levels. Its findings, to be published in The Lancet Planetary Health, also show that the periods of susceptibility to air pollutants differ according to the sex of the foetus, thereby impacting the development of girls and boys in different ways.

Exposure to outdoor air pollution presents a major risk for the proper course of pregnancy. It is particularly suspected of causing cardiometabolic, respiratory and neuropsychological pathologies in unborn children. However, while its physiological effects have been studied, the molecular mechanisms involved remain poorly understood.

The placenta is an organ that plays a key role in foetal development. Particularly vulnerable to many chemical compounds, it can be likened to an ‘archive’ that reflects the child’s prenatal environment: the epigenetic changes occurring in its cells partially reflect the mother’s environmental exposures during pregnancy. To study these changes, we usually measure the level of DNA methylation, one of the best known epigenetic mechanisms involved in gene control and expression.

A team led by Inserm researcher Johanna Lepeule at the Institute for Advanced Biosciences (Inserm/CNRS/Université Grenoble Alpes) investigated the impact of three air pollutants – nitrogen dioxide (NO₂) and particulate matter (PM_2.5 and PM₁₀) – on placental DNA methylation. Thanks to data from three French mother-child cohorts[2], it was able to compare exposure to these pollutants and methylation levels in over 1 500 participants during their pregnancy.

Its findings show a significant impact of exposure to the three airborne pollutants on placental DNA methylation levels concerning genes involved in foetal development. One third of these changes were directly associated with indicators of child development (birthweight, birth length, head circumference, duration of pregnancy, etc.).

Other placental changes concerned genes involved in the development of the nervous system, immune system and the metabolism – including genes involved in the onset of neonatal diabetes or obesity. 

While these alterations in methylation are present in both sexes, the scientists also identified changes that have an additional impact and affect different genes depending on the sex of the unborn child. Two different gestation periods that are particularly vulnerable to epigenetic changes under the effect of the pollutants have emerged from this research: the start of pregnancy (1st trimester) in boys and the end of pregnancy (3rd trimester) in girls.

‘Our findings show that exposure to air pollution during pregnancy induces changes in placental DNA methylation specific to each of the two sexes, says Lepeule. This differentiated impact could contribute to alterations in the development and course of pregnancy that differ according to the sex of the unborn child.’

Thus in boys, significant alterations in methylation have been detected in genes that are critically involved in the development of the nervous system and intellect.

‘These observations support the growing number of studies linking exposure to air pollution during pregnancy with impaired neurodevelopment and/or reduced cognitive capacities, with greater vulnerability among male children,’ explains Lucile Broséus, Inserm researcher and first author of the publication.

In girls, the methylation affected genes involved in foetal development and the regulation of oxidative stress. It could therefore be associated with developmental defects liable to increase the risk of developing chronic metabolic diseases (hypertension, diabetes, obesity, etc.) later in life, but also with the occurrence of miscarriage or pre-eclampsia in the mother[3].

This research therefore provides new data on the epigenetic mechanisms involved in the deregulation of foetal growth under the effect of air pollution and which could cause long-term changes in the metabolism. 

‘Future studies may investigate whether placental epigenetic changes caused by exposure to air pollution during pregnancy persist after childbirth and how they could influence development during childhood, adds Lepeule. In addition, as this research has been carried out on French cohorts, its findings will have to be verified in populations from other geographical regions and with different genetic profiles,’ concludes the researcher.

[1] Epigenetic changes are materialised by biochemical marks present on DNA. Reversible, they do not lead to changes in DNA sequence but do induce changes in gene expression. They are induced by the wider environment: the cell receives signals informing it about its environment, and specialises itself accordingly, or adjusts its activity.

[2]EDEN, led by Inserm, Poitiers University Hospital and Nancy University Hospital; PELAGIE, led by Inserm; and SEPAGES, led by Inserm and Grenoble Alpes University Hospital.

[3]Pre-eclampsia is a complication of pregnancy characterised by elevated blood pressure and increased protein in the urine. It can occur in the middle of the second trimester or later, shortly before delivery or sometimes even after. Responsible for one third of the births of very preterm infants in France, this syndrome is a major cause of intrauterine growth retardation. If left untreated, it can lead to the death of the mother, child, or both.

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