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A Comprehensive Assessment of Associations between Prenatal Phthalate Exposure and the Placental Transcriptomic Landscape

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  • A Comprehensive Assessment of Associations between Prenatal Phthalate Exposure and the Placental Transcriptomic Landscape

    Alison G. Paquette, James MacDonald, Samantha Lapehn, Theo Bammler, Laken Kruger, Drew B. Day, Nathan D. Price, Christine Loftus, Kurunthachalam Kannan, Carmen Marsit, W. Alex Mason, Nicole R. Bush, Kaja Z. LeWinn, Daniel A. Enquobahrie, Bhagwat Prasad, Catherine J. Karr, and Sheela Sathyanarayana, on behalf of program collaborators for Environmental influences on Child Health Outcomes
    A Comprehensive Assessment of Associations between Prenatal Phthalate Exposure and the Placental Transcriptomic Landscape

    Environmental Health Perspectives 129:9 CID: 097003


    Phthalates are commonly used endocrine-disrupting chemicals that are ubiquitous in the general population. Prenatal phthalate exposure may alter placental physiology and fetal development, leading to adverse perinatal and childhood health outcomes.


    We examined associations between prenatal phthalate exposure in the second and third trimesters and the placental transcriptome at birth, including genes and long noncoding RNAs (lncRNAs), to gain insight into potential mechanisms of action during fetal development.


    The ECHO PATHWAYs consortium quantified 21 urinary phthalate metabolites from 760 women enrolled in the CANDLE study (Shelby County, TN) using high-performance liquid chromatography–tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate separate associations between maternal urinary phthalate metabolite concentration during the second and third trimester and placental gene expression at birth, adjusted for confounding variables. Genes were considered differentially expressed at a Benjamini-Hochberg false discovery rate (FDR) p<0.05

    Associations between phthalate metabolites and biological pathways were identified using self-contained gene set testing and considered significantly altered with an FDR-adjusted p<0.2


    We observed significant associations between second-trimester phthalate metabolites mono (carboxyisooctyl) phthalate (MCIOP), mono-2-ethyl-5-carboxypentyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate and 18 genes in total, including four lncRNAs. Specifically, placental expression of NEAT1 was associated with multiple phthalate metabolites. Third-trimester MCIOP and mono-isobutyl phthalate concentrations were significantly associated with placental expression of 18 genes and two genes, respectively. Expression of genes within 27 biological pathways was associated with mono-methyl phthalate, MCIOP, and monoethyl phthalate concentrations.


    To our knowledge, this is the first genome-wide assessment of the relationship between the placental transcriptome at birth and prenatal phthalate exposure in a large and diverse birth cohort. We identified numerous genes and lncRNAs associated with prenatal phthalate exposure. These associations mirror findings from other epidemiological and in vitro analyses and may provide insight into biological pathways affected in utero by phthalate exposure.


    Phthalates are ubiquitous chemicals used as plasticizers in numerous consumer products, leading to pervasive human exposure (Ferguson et al. 2014; Sathyanarayana 2008). Parent phthalate compounds undergo hydrolysis to monoesters, which are then are transformed into secondary metabolites depending upon on their chemical structure and molecular weight, overall resulting in a variety of different metabolites that the fetus and placenta are exposed to during pregnancy and are detectable in urine (Domínguez-Romero and Scheringer 2019). Prenatal phthalate exposure is associated with adverse perinatal outcomes and pregnancy complications (Martínez-Razo et al. 2021), including decreased gestational length (Boss et al. 2018; Wolff et al. 2008), decreased anogenital distance, and hydrocoele (Sathyanarayana et al. 2017; Swan et al. 2005). Recent studies also suggest increased odds of negative childhood outcomes, including eczema development, asthma development in males (Adgent et al. 2020), decreased mental and motor development scores and increased internalizing behaviors (Whyatt et al. 2012), social impairment characteristics (Day et al. 2021), and deficits in intellectual development (Factor-Litvak et al. 2014) in relation to prenatal phthalate exposure. In combination, these observational studies suggest that phthalate exposure during the prenatal period may program alterations in the in utero environment that have lasting effects on developing children from infancy into middle childhood....

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