Gestational Perfluorooctanoic Acid Exposure Inhibits Placental Development by Dysregulation of Labyrinth Vessels and uNK Cells and Apoptosis in Mice

Abstract

Perfluorooctanoic acid (PFOA) is a widely used perfluorinated compound and known to cause developmental toxicity which includes the increase of resorbed embryo, decrease of fetal survival, and fetal growth retardation. Nevertheless, whether it is associated with alteration of placental development remains unknown. Pregnant mice were gavaged with 0, 2.5, 5, 10 mg PFOA /kg/day from pregnancy day (PD) 1 to PD 13. Results showed that PFOA exposure markedly decreased the placental weight and caused interstitial edema of placenta. Laminin staining indicated that blood sinusoids area was shrunken in placenta of PFOA-exposed mice. Furthermore, PFOA treatment significantly reduced numbers of uNK cells. Western blot analysis revealed that levels of Bax and cleavedcaspase 3 proteins were markedly up-regulated in PFOA-treated groups. In addition, TEM examination showed that PFOA treatment caused rupture of nuclear membrane and nuclear pyknosis and fragmentation. Thus, our results suggested that gestational PFOA exposure significantly inhibited development of early placenta through shrinkage of labyrinth vessels and downregulation of uNK cells and apoptosis induction, which may result in adverse gestational outcomes.

Maternal Levels of Perfluoroalkyl Substances (PFAS) during Early Pregnancy in Relation to Preeclampsia Subtypes and Biomarkers of Preeclampsia Risk

“…Exposure to PFAS has also been shown to alter placental weight, disrupt its labyrinth structure, and induce congestion and clot formation ( Blake et al. 2020 ), as well as apoptosis ( Jiang et al. 2020 ), in in vivo studies.…”

“…However, it should be noted that existing toxicologic evidence indicates that PFAS may alter processes that are implicated in early-onset disease, including trophoblast migration and invasion (Szilagyi et al 2020) and angiogenic processes (Pham et al 2020;Poteser et al 2020). Exposure to PFAS has also been shown to alter placental weight, disrupt its labyrinth structure, and induce congestion and clot formation , as well as apoptosis (Jiang et al 2020), in in vivo studies. In light of this mechanistic evidence, further consideration of the relationship between PFAS and preeclampsia subtypes is warranted.…”

Gestational cholestasis induced intrauterine growth restriction through triggering IRE1α‐mediated apoptosis of placental trophoblast cells

“…46 Several animal studies also demonstrated that apoptosis of placental cells may be involved in the etiology of placental hypoplasia and dysfunction. 47,48 The current study found that the apoptosis of placental trophoblast was significantly elevated in mice with gestational cholestasis, and deoxycholic acid (DCA)-treated primary mouse placental trophoblast cell and human trophoblast cell lines. These results suggest that the apoptosis of placental trophoblast cell may be the main mechanism leading to placental insufficiency and IUGR during gestational cholestasis.…”

A High-Throughput Toxicity Screen of 42 Per- and Polyfluoroalkyl Substances (PFAS) and Functional Assessment of Migration and Gene Expression in Human Placental Trophoblast Cells

“…The placenta is involved in the etiology of these pregnancy conditions ( Pijnenborg et al, 1991 ) and PFAS pass from the maternal to fetal compartments through the placenta ( Chen et al, 2017 ; Zhao et al, 2017 ; Wang et al, 2019 ). Perfluorooctanoic acid (PFOA) and ammonium perfluoro-2-methyl-3-oxahexanoate (the ammonium carboxylate salt of the chemical compound hexafluoropropylene oxide-dimer acid, HFPO-DA, commonly referred to as GenX) have been shown to cause histopathological lesions in the mouse placenta ( Blake et al, 2020 ; Jiang et al, 2020 ). While it is not well understood how maternal exposure to a few PFAS may contribute to adverse pregnancy outcomes, their effect(s) on placental function is likely critical and may extend to other untested PFAS ( Blake and Fenton, 2020 ; Rickard et al, 2022 ).…”