An Investigation of the Single and Combined Phthalate Metabolite Effects on Human Chorionic Gonadotropin Expression in Placental Cells

Observational studies have reported associations between maternal phthalate levels and adverse outcomes at birth and in the health of the child. Effects on placental function have been suggested as a biologic basis for these findings. We evaluated the effects of phthalates on placental function by m...

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Bibliographic Details
Published in:	Environmental health perspectives Vol. 125; no. 10; p. 107010
Main Authors:	Adibi, Jennifer J, Zhao, Yaqi, Zhan, Lei V, Kapidzic, Mirhan, Larocque, Nicholas, Koistinen, Hannu, Huhtaniemi, Ilpo T, Stenman, Ulf-Håkan
Format:	Journal Article
Language:	English
Published:	United States National Institute of Environmental Health Sciences 31-10-2017 Environmental Health Perspectives
Subjects:	Biological effects Biopsy Cell culture Cells (biology) Cells, Cultured Chorionic gonadotropin Chorionic Gonadotropin - genetics Chorionic Gonadotropin - metabolism Conditioning Endocrinology Environmental Pollutants - adverse effects Experiments Female Females Fetus - chemistry Fetuses Gene expression Gene Expression - drug effects Gonadotropins Humans Male Males Metabolism Metabolites Molecular chains Peroxisome proliferator-activated receptors Phthalates Phthalic Acids - adverse effects Pituitary (anterior) Placenta Placenta - chemistry Placenta - drug effects Preeclampsia Pregnancy Progenitor cells Protein expression Proteins Sex Stem cells Stem Cells - chemistry Stem Cells - drug effects Studies Trophoblasts - chemistry Trophoblasts - drug effects Urine Womens health United States > US San Francisco California California
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Summary:	Observational studies have reported associations between maternal phthalate levels and adverse outcomes at birth and in the health of the child. Effects on placental function have been suggested as a biologic basis for these findings. We evaluated the effects of phthalates on placental function by measuring relevant candidate genes and proteins. Human trophoblast progenitor cells were isolated at 7-14 wk of pregnancy (two female and three male concepti), and villous cytotrophoblast cells (vCTBs) were isolated at 15-20 wk (three female and four male concepti). Cells were cultured with four phthalate metabolites and their combination at concentrations based on levels found previously in the urine of pregnant women: mono- -butyl (MnBP, 200 nM), monobenzyl (MBzP, 3μM), mono-2-ethylhexyl (MEHP, 700 nM), and monoethyl (MEP, 1.5μM) phthalates. mRNA levels of , , , , , and the intracellular β subunit of human chorionic gonadotropin (hCGβ) and peroxisome proliferator activated receptor γ (PPARγ) were measured in the cellular extracts, and protein levels for four forms of secreted hCG were measured in the conditioned media. Previously reported associations between maternal phthalates and placental gene expression were reproduced experimentally: MnBP with , MBzP with , and MEHP with . and hCGβ were up-regulated by MBzP. In some cases, there were marked, even opposite, differences in response by sex of the cells. There was evidence of agonism in female cells and antagonism in male cells of PPARγ by simultaneous exposure to multiple phthalates. Concentrations of MnBP, MBzP and MEHP similar to those found in the urine of pregnant women consistently altered hCG and PPARγ expression in primary placental cells. These findings provide evidence for the molecular basis by which phthalates may alter placental function, and they provide a preliminary mechanistic hypothesis for opposite responses by sex. https://doi.org/10.1289/EHP1539.
ISSN:	0091-6765 1552-9924
DOI:	10.1289/EHP1539