According to the “Developmental Origins of Health and Disease” (DOHaD) concept, the early-life environment is a critical period for fetal programming. Given the epidemiological evidence that air pollution exposure during pregnancy adversely affects newborn outcomes such as birth weight and preterm birth, there is a need to pay attention to underlying modes of action to better understand not only these air pollution-induced early health effects but also its later-life consequences. In this review, we give an overview of air pollution-induced placental molecular alterations observed in the ENVIRONAGE birth cohort and evaluate the existing evidence. In general, we showed that prenatal exposure to air pollution is associated with nitrosative stress and epigenetic alterations in the placenta. Adversely affected CpG targets were involved in cellular processes including DNA repair, circadian rhythm, and energy metabolism. For miRNA expression, specific air pollution exposure windows were associated with altered miR-20a, miR-21, miR-146a, and miR-222 expression. Early-life aging markers including telomere length and mitochondrial DNA content are associated with air pollution exposure during pregnancy. Previously, we proposed the air pollution-induced telomere-mitochondrial aging hypothesis with a direct link between telomeres and mitochondria. Here, we extend this view with a potential co-interaction of different biological mechanisms on the level of placental oxidative stress, epigenetics, aging, and energy metabolism. Investigating the placenta is an opportunity for future research as it may help to understand the fundamental biology underpinning the DOHaD concept through the interactions between the underlying modes of action, prenatal environment, and disease risk in later life. To prevent lasting consequences from early-life exposures of air pollution, policy makers should get a basic understanding of biomolecular consequences and transgenerational risks.

Telomeres are nucleoprotein structures that cap the end of chromosomes. They can consist of several thousands of tandem-repeated TTAGGG sequences.^1,2 With each cellular division, telomeres shorten. Telomere length (TL) has been associated with age-related diseases and mortality and is considered a marker of biological aging.^3-8 Telomere length is also associated with environmental and lifestyle factors that influence the oxidative stress and inflammatory status in humans, such as smoking,⁹ obesity,¹⁰ Mediterranean diet,¹¹ exposure to violence,¹² and life stress,¹³ which underscores the vulnerability of telomeres to reactive oxygen species (ROS). In a 2015 update of the Global Burden of Disease study, ambient particulate matter (PM) was ranked as the sixth most leading risk factor influencing public health worldwide.¹⁴ Increased oxidative stress and inflammation are proposed as underlying mechanisms through which PM may influence human health.^15,16 Exposure to air pollution during in utero life may have adverse effects on the fetus and neonate.^17-19 The ability of PM air pollution to generate ROS has led to the hypothesis that telomere attrition is influenced by air pollution exposure.²⁰ Occupational and population-based studies have described both positive and negative associations between different types of air pollution and TL in adults.^21-27 In general, long-term exposure to PM²⁵ and black carbon (BC)^24,26 are associated with shorter TL in adults. Because TL is highly variable at birth,^28,29 potential determinants, such as newborn sex,²⁸ paternal age,²⁸ maternal prepregnancy body mass index (BMI),²⁰ maternal stress,³⁰ maternal educational level,³¹ maternal smoking during pregnancy,³² and maternal residential proximity to a major road,³³ have recently been explored for explaining this phenomenon. In this regard, we hypothesized that exposure to PM air pollution during pregnancy may contribute to telomere setting at birth. Because in utero life is believed to be a critical time window in the early programming of diseases later in life,³⁴ unravelling the connection between prenatal air pollution exposure and TL at birth may help to gain new insights in the causes of diseases linked with telomere biological characteristics. In this study, we assessed the association between prenatal exposure to PM_2.5 (particulate matter with an aerodynamic diameter ≤2.5 μm) and TL at birth.

Background: There is evidence that altered DNA methylation is an important epigenetic mechanism in prenatal programming and that developmental periods are sensitive to environmental stressors. We hypothesized that exposure to fine particles (PM_2.5) during pregnancy could influence DNA methylation patterns of the placenta. Methods: In the ENVIRON AGE birth cohort, levels of 5’-methyl-deoxycytidine (5-mdC) and deoxycytidine (dC) were quantified in placental DNA from 240 newborns. Multiple regression models were used to study placental global DNA methylation and in utero exposure to PM_2.5 over various time windows during pregnancy. Results: PM_2.5 exposure during pregnancy averaged (25^th-75^th percentile) 17.4 (15.4-19.3) μg/m³. Placental global DNA methylation was inversely associated with PM_2.5 exposures during whole pregnancy and relatively decreased by 2.19% (95% confidence interval [CI]: -3.65, -0.73%, p = 0.004) for each 5 μg/m³ increase in exposure to PM_2.5. In a multi-lag model in which all three trimester exposures were fitted as independent variables in the same regression model, only exposure to PM_2.5 during trimester 1 was significantly associated with lower global DNA methylation (-2.13% per 5 μg/m³ increase, 95% CI: -3.71, -0.54%, p = 0.009). When we analyzed shorter time windows of exposure within trimester 1, we observed a lower placental DNA methylation at birth during all implantation stages but exposure during the implantation range (6-21d) was strongest associated (-1.08% per 5 μg/m³ increase, 95% CI: -1.80, -0.36%, p = 0.004). Conclusions: We observed a lower degree of placental global DNA methylation in association with exposure to particulate air pollution in early pregnancy, including the critical stages of implantation. Future studies should elucidate genome-wide and gene-specific methylation patterns in placental tissue that could link particulate exposure during in utero life and early epigenetic modulations.