1. Introduction
The developmental origins of the health and disease hypothesis state that exposure during the intrauterine period of life modulates the risk of disease later in life. In particular, low birth weight has been associated to an increased risk of hypertension, diabetes, and cardiovascular disease (1). Therefore, investigations on how environmental exposure, such as air pollution, affects fetal growth and the duration of pregnancy represent a crucial step in defining pathways that link prenatal exposure, intrauterine stress, and future outcomes.
The possible link between exposure to air pollutants and fetal growth has been investigated by a growing number of studies (2, 3). The effects of air pollutants, particularly fine particulate matter (PM) and nitrogen dioxide (NO2), mostly contribute towards restricting in utero growth (4-10) or adverse neonatal outcomes, such as reduced birthweight and prematurity (11-17). Although many methodological issues exist, such as small sample size and the large variety of approaches used to determine pollutant exposure, collectively these studies support the association between increased maternal exposure and reduced fetal growth.
A key requirement of fetal growth is the maternal supply of cholesterol, the uptake of which is largely mediated by the LDL receptor (LDL-R) which is expressed abundantly in the placenta but expressed at low levels, if at all, in the yolk sac (18). However, the mechanisms by which placental endothelial cells transport cholesterol to the fetal microcirculation, the regulation of efflux, and their ability to deliver substantial quantities of cholesterol are still unknown (19).
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a major modulator of LDL metabolism, as well as being a marker of cardiovascular risk. We previously reported increased levels of PCSK9 after short term PM exposure, with this phenomenon being particularly significant in individuals with a lower inflammatory burden,based on an assessment of plasma interferon levels (20). These individuals represent hypersusceptible subjects, who are more sensitive to the damaging effects of exposure to environmental PM.
PCSK9 was initially discovered as an anti-apoptotic mediator in the brain (21). PCSK9 levels in pregnant women might provide important information on the potential use of the currently available PCSK9 monoclonal antibodies in these subjects. Reduced PCSK9 levels in rat embryos was associated with the occurrence of neural tube defects (22), indicating the sensitivity of this biomarker in pregnancy. Consequently, it was hypothesized that the potential reduction of neuronal inflammation and amyloid -aggregation is antagonized by PCSK9 (23).
The present study aimed to characterize how air pollutants (i.e.,particulate matter, PM10 and PM2.5) and NO2 influence the PCSK9 levels of Italian women during early pregnancy (11–12 weeks of gestational age). Within this framework, we also investigated how these changes were correlated with fetal growth (i.e. birth weight and gestational age at birth). Pregnant women are of particular interest because they have generally healthy life habits, particularly in the Western world. In this region of the world, the decline in the number of pregnancies has led to the greater care of child-bearing women, who are encouraged to follow a healthy diet and maintain physical exercise to not gain excess weight (24). This population, thus, provides a unique opportunity to evaluate the damage exerted by ambient pollution on both women and their fetuses.