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

Abstract

Background: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.Objective:We evaluated the effects of phthalates on placental function in vitro by measuring relevant candidate genes and proteins.Materials and Methods: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 in vitro with four phthalate metabolites and their combination at concentrations based on levels found previously in the urine of pregnant women: mono-n-butyl (MnBP, 200 nM), monobenzyl (MBzP, 3μM), mono-2-ethylhexyl (MEHP, 700 nM), and monoethyl (MEP, 1.5μM) phthalates. mRNA levels of CGA, CGB, PPARG, CYP19A1, CYP11A1, PTGS2, EREG, and the intracellular normalβ subunit of human chorionic gonadotropin (hCGβ) and peroxisome proliferator activated receptor normalγ (PPARγ) were measured in the cellular extracts, and protein levels for four forms of secreted hCG were measured in the conditioned media.Results:Previously reported associations between maternal phthalates and placental gene expression were reproduced experimentally: MnBP with CGA, MBzP with CYP11A1, and MEHP with PTGS2. CGB 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.Conclusions: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

The Role of Peroxisome Proliferator–Activated Receptor Gamma (PPARγ) in Mono(2-ethylhexyl) Phthalate (MEHP)-Mediated Cytotrophoblast Differentiation

“…To our knowledge, we are the first to report an impact of environmentally relevant concentrations of MEHP on human ST formation, which is essential for a fully functional placenta (Mayhew 2014). However, it is necessary to remember that organs are exposed to several phthalates that can accumulate and have additive or opposite effects, as recently described by Adibi et al. 2017b.…”

“…In these studies, a relatively high dose of MEHP was used (100μM and 50μM, respectively). A more recent study performed on primary VCTs showed that after 40 h of treatment with 0.7μM MEHP, hCG secretion decreased significantly in a sex-independent manner (Adibi et al. 2017b).…”

“…Recent in vitro studies have reported that MEHP inhibits human EVCT invasion (Gao et al. 2017a) and hCG secretion by the villous trophoblast (Adibi et al. 2017b).…”

Ovarian Metabolism of an Environmentally Relevant Phthalate Mixture

“…Perinatal exposure in rats to a mixture of environmental chemicals, including phthalates, resulted in irregular estrous cycles, reduced ovary weights, and reduced follicle numbers (Johansson et al, 2016). Human placental trophoblast progenitor cells cultured with 4 phthalate metabolites exhibited altered PPARc expression and human chorionic gonatropin levels (Adibi et al, 2017). Previously, we have cultured mouse adult antral follicles with a mixture of 6 phthalates and found alterations in gene expression as well as decreased hormone levels and increased oocyte fragmentation (Zhou and Flaws, 2016).…”

A pathway level analysis of PFAS exposure and risk of gestational diabetes mellitus

“…PBDEs are negatively associated with total T3 and T4 in cord serum and with altered birth outcomes, including lower IQ [ 123 – 125 ]. Furthermore, endocrine disruptors in plastics and personal care items, including phthalates and bisphenol A, have been shown to affect TH regulation including impairment of iodine uptake and inhibition of TH homeostasis [ 126 ] and phthalates have been found to be associated with hCG, glucose intolerance, and GDM [ 127 – 129 ].…”