TY - JOUR
T1 - A comprehensive assessment of associations between prenatal phthalate exposure and the placental transcriptomic landscape
AU - on behalf of program collaborators for Environmental influences on Child Health Outcomes
AU - Paquette, Alison G.
AU - Macdonald, James
AU - Lapehn, Samantha
AU - Bammler, Theo
AU - Kruger, Laken
AU - Day, Drew B.
AU - Price, Nathan D.
AU - Loftus, Christine
AU - Kannan, Kurunthachalam
AU - Marsit, Carmen
AU - Mason, W. Alex
AU - Bush, Nicole R.
AU - Lewinn, Kaja Z.
AU - Enquobahrie, Daniel A.
AU - Prasad, Bhagwat
AU - Karr, Catherine J.
AU - Sathyanarayana, Sheela
N1 - Funding Information:
This manuscript was submitted on behalf of program collaborators for Environmental influences on Child Health Outcomes. We also acknowledge the contribution of the following ECHO program collaborators: ECHO Components— Coordinating Center: Duke Clinical Research Institute, Durham, North Carolina: Smith PB, Newby KL, Benjamin DK. Research reported in this publication was supported by the ECHO program, Office of The Director, NIH, under award nos. U2COD023375 (Coordinating Center), U24OD023382 (Data Analysis Center), U24OD023319 (PRO Core), and 4UH3OD023271-03. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Funding Information:
ECHO PATHWAYS is funded by the National Institutes of Health (NIH; 1UG3OD023271-01, 4UH3OD023271-03). The University of Washington EDGE center is supported by the NIH (P30ES007033). The CANDLE study was funded by the Urban Child Institute and NIH (R01 HL109977). This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K99/R00HD096112) and an ECHO Opportunities and Infrastructure grant (ECHO OIF 35).
Publisher Copyright:
© 2021, Public Health Services, US Dept of Health and Human Services. All rights reserved.
PY - 2021/9
Y1 - 2021/9
N2 - BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. https://doi.org/10.1289/EHP8973.
AB - BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. https://doi.org/10.1289/EHP8973.
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U2 - 10.1289/EHP8973
DO - 10.1289/EHP8973
M3 - Article
C2 - 34478338
AN - SCOPUS:85114604825
SN - 0091-6765
VL - 129
JO - Environmental health perspectives
JF - Environmental health perspectives
IS - 9
M1 - 097003
ER -