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.