Stress-Activated Pathways Mediate PFAS Effects on Human Placental Syncytiotrophoblast Cells

Clicks: 2
ID: 314716
2026
Free PDF
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal
Emerging

Ranked #112 of 123 articles by views in toxicological sciences : an official journal of the society of toxicology

Most read Least read

Bar heights use a square-root scale. Only the 120 most-read articles are drawn; the journal has 123 in total.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
Abstract Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants associated with placenta-mediated pregnancy complications, including preeclampsia, fetal growth restriction, and preterm birth. The syncytiotrophoblast (STB), which forms the placental barrier at the maternal-fetal interface and is directly exposed to maternal blood, is a primary site of PFAS exposure. Although PFAS induce STB apoptosis, the upstream stress-signaling pathways involved remain poorly defined. Here, we investigated stress-responsive signaling mechanisms mediating PFAS-induced STB cell death. STB differentiated from human trophoblast stem cells were exposed to vehicle or an environmentally relevant mixture of five PFAS (PFOA, PFOS, PFHxS, PFNA, and PFDA; 0.0138–34.5 µM) for 3 or 6 hours. Cytotoxicity, apoptosis, mitochondrial membrane potential, and stress-signaling pathway activation were assessed by lactate dehydrogenase release, immunoblotting, JC-10 assay, and RT-qPCR. PFAS mixtures did not induce cytotoxicity at 3 hours but significantly increased cytotoxicity at 6 hours at 34.5 µM, coinciding with induction of cleaved caspase-3, cleaved PARP, and NOXA. The pan-caspase inhibitor z-VAD-FMK prevented cytotoxicity, indicating caspase-dependent apoptosis. PFAS exposure reduced mitochondrial membrane potential and activated the integrated stress response (ISR), as evidenced by eIF2α phosphorylation, ATF4 induction, and increased ATF4 target gene expression. In parallel, c-Jun N-terminal kinase (JNK) signaling was activated, as evidenced by JNK phosphorylation and induction of immediate-early genes (JUN, FOS, EGR1). Pharmacologic inhibition of the ISR modestly attenuated PFAS-induced cytotoxicity, whereas pharmacologic inhibition of JNK rescued cytotoxicity and apoptotic signaling. Together, these findings identify JNK-driven stress signaling as the dominant mediator of PFAS-induced STB apoptosis, with a secondary contribution from the ISR.
Reference Key
openalex_W7162077908 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Keisuke Kozai, Kaela M. Varberg
Journal toxicological sciences : an official journal of the society of toxicology
Year 2026
DOI
10.1093/toxsci/kfag060
URL
https://doi.org/10.1093/toxsci/kfag060
Keywords Keywords not found

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.