Organophosphate Flame Retardants, Highly Fluorinated Chemicals, and Biomarkers of Placental Development and Disease During Mid-Gestation

Abstract

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) and organophosphate flame retardants (OPFRs) are chemicals that may contribute to placenta-mediated complications and adverse maternal-fetal health risks. Few studies have investigated these chemicals in relation to biomarkers of effect during pregnancy. We measured 12 PFASs and four urinary OPFR metabolites in 132 healthy pregnant women during mid-gestation and examined a subset with biomarkers of placental development and disease (n = 62). Molecular biomarkers included integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and matrix metalloproteinase-1 (MMP1). Morphological endpoints included potential indicators of placental stress and the extent of cytotrophoblast (CTB)-mediated uterine artery remodeling. Serum PFASs and urinary OPFR metabolites were detected in ∼50–100% of samples. The most prevalent PFASs were perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS), with geometric mean (GM) levels of ∼1.3–2.8 (95% confidence limits from 1.2–3.1) ng/mL compared to ≤ 0.5 ng/mL for other PFASs. Diphenyl phosphate (DPhP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were the most prevalent OPFR metabolites, with GMs of 2.9 (95% CI: 2.5–3.4) and 3.6 (95% CI: 2.2–3.1) ng/mL, respectively, compared to < 1 ng/mL for bis(2-chloroethyl) phosphate (BCEP) and bis(1-chloro-2-propyl) phosphate (BCIPP). We found inverse associations of PFASs or OPFRs with ITGA1 or CDH5 immunoreactivity and positive associations with indicators of placental stress in multiple basal plate regions, indicating these chemicals may contribute to abnormal placentation and future health risks. Associations with blood pressure and lipid concentrations warrant further examination. This is the first study of these chemicals with placental biomarkers measured directly in human tissues and suggests specific biomarkers are sensitive indicators of exposure during a vulnerable developmental period.

Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program

“… 43 , 53 , 55 , 56 Finally, similar to other endocrine disrupting chemicals, OPEs could also contribute to abnormal placental development and functions in sex-dependent manners. 99 , 100 …”

The effect of endocrine-disrupting chemicals on placental development

“…At levels greater than 10 mM (BDE-47 and BDE-99), PBDE exposure is cytotoxic in first-trimester human EVTs, substantially lowering cell viability and inducing apoptosis. The same dose of BDE-47 also changed the metabolism of lipids and cholesterol while decreasing EVTs migration and invasion ( 76 ).…”

Prenatal exposures to organophosphate ester metabolite mixtures and children’s neurobehavioral outcomes in the MADRES pregnancy cohort

“…As a result, common OPE exposure routes include dermal contact, inhalation, and ingestion of air and dust particles, as well as dietary ingestion of OPE-contaminated food and drinking water [7,15]. OPEs have been found in the placenta and cord blood, suggesting in utero transfer to the fetus, and resulting in growing concern, particularly regarding early neurodevelopment, given the structural similarity between OPEs and organophosphate pesticides which have been previously found to be neurotoxic [25][26][27][28][29][30]. The two most frequently detected OPE metabolites among people in the U.S are diphenyl phosphate (DPHP; parent compound, triphenyl phosphate (TPHP)) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP; parent compound, tris(1,3-dichloropropyl) (TDCIPP)), with greater than 95% detection frequencies in the 2013 to 2014 National Health and Nutrition Examination Survey [31,32].…”