PROJECT SUMMARY
Spontaneous preterm birth (sPTB) comprises the majority of preterm births (60%) and is a leading case of
newborn morbidity and death and a predictor of adverse health outcomes. Despite its high prevalence, there is
a limited understanding of how the in-utero environment contributes to the etiology of sPTB. Phthalates are
ubiquitous endocrine disrupting chemicals that induce gene expression and physiological changes within the
placenta. Epidemiological studies identify a consistent positive relationship between prenatal phthalate exposure
and preterm birth. The goal of this study is to develop placental molecular signatures that can be used to
mechanistically link prenatal phthalate exposure and sPTB. Placental molecular signatures can explain
functional differences related to sPTB and identify targets for clinical and therapeutic interventions, including
modifiable risk factors such as environmental exposures. Our research team has generated the largest placental
transcriptomics dataset to date (N=760 samples) and has used this to develop transcriptomic signatures of
prenatal phthalate exposure and sPTB. This study will expand our existing transcriptomic signatures to include
microRNAs, which are essential to a complete molecular signature because they are highly stable, have been
linked to a number of environmental exposures, and are secreted into maternal circulation where they may serve
as biomarkers. Candidate microRNA studies have identified correlations between prenatal phthalate exposure
and expression of placental microRNAs, but a comprehensive assessment is needed to fully understand the role
of placental microRNAs in phthalate mediated toxicity. Moreover, despite the potential importance of placental
microRNAs as a biomarker of sPTB, there has not been a comprehensive analysis. In this proposal, we seek to
fill these research gaps and apply innovative computational biology strategies with rigorous epidemiological
approaches to gain insight into the mechanistic links between prenatal phthalate exposure, placental function,
and sPTB. In aim 1, we will generate microRNA data on placental samples and use this to generate a signature
of prenatal phthalate exposure. We will use the matched microRNA-mRNA sequencing data to construct a global
placental microRNA-mRNA network, which we will apply to identify connections between microRNAs and genes
whose placenta expression is associated with different phthalate metabolites. In Aim two, we will develop a multi-
omic molecular signature of sPTB using our placental microRNA-mRNA network. In aim 3, we will examine the
role of the placenta as a mechanistic link between prenatal phthalate exposure and sPTB by interdisciplinary
strategies including an integrated pathway analysis and a formal mediation analysis. Findings from this study
will inform chemical toxicological risk assessment and policy to reduce health impacts due to phthalate exposure
in pregnancy. microRNA signatures of sPTB may serve as functional biomarkers of sPTB since they can be
secreted into maternal circulation and be targets for clinical and therapeutic intervention in the future.
