Prenatal PFOS impairs offspring cognition via HDAC and translational repression
- 1Department of Environmental Health and Toxicology, School of Public Health, Dalian Medical University, Dalian, 116044, China
- 2Corresponding authors.
Abstract
Perfluorooctane sulfonate (PFOS) is a persistent environmental pollutant widely detected in human cord blood and breast milk, raising concerns about its neurodevelopmental toxicity. While epidemiological and animal studies have linked prenatal PFOS exposure to cognitive deficits, the molecular mechanisms—particularly those involving translational regulation—remain unclear. The present study tested whether prenatal PFOS exposure induces hippocampal-dependent cognitive deficits through histone deacetylase (HDAC) overactivation and eukaryotic initiation factor 2α (eIF2α)-mediated translational repression. Pregnant Wistar rats received vehicle or PFOS (0.5 or 2 mg/kg/day) from gestation day 1–21. Offspring cognitive function was assessed using the Morris water maze on postnatal day 28; hippocampal tissue was collected for histopathology, apoptosis, HDAC activity, and expression of phosphorylated PKR-like endoplasmic reticulum kinase (p-PERK), phosphorylated eIF2α (p-eIF2α), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), small ubiquitin-like modifier 1/2 (SUMO1/2), brain-derived neurotrophic factor (BDNF), and protein phosphatase 1 (PP1). Maternal PFOS exposure impaired learning and memory, reduced normal neuron density, and increased neuronal apoptosis. PFOS elevated HDAC activity and activated the PERK–eIF2α–ATF4–CHOP integrated stress response (ISR) pathway, while reduced protein levels of SUMO1/2, BDNF, and PP1—despite elevated mRNA levels, suggesting translational repression. To test whether HDAC overactivation directly contributes to these changes, we pretreated PC12 cells with trichostatin A (TSA), a pan-HDAC inhibitor. TSA partially reversed PFOS-induced apoptosis, suppressed HDAC overactivation, attenuated ISR activation, and restored SUMO1/2, BDNF, and PP1 expression. Collectively, these findings demonstrate that prenatal PFOS exposure causes hippocampal-dependent cognitive deficits through HDAC overactivation and eIF2α-mediated translational repression, shifting the focus from transcriptional to translational control and identifying HDACs as a potential target in PFOS developmental neurotoxicity.
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BibTeX
@article{niu2026prenatal,
title = {{Prenatal PFOS impairs offspring cognition via HDAC and translational repression}},
author = {Xiaoying Niu and Ruru Xi and Yufeng Tan and Jing Shao and Xiaohui Liu},
journal = {Ecotoxicology and Environmental Safety},
year = {2026},
month = oct,
doi = {10.1016/j.ecoenv.2026.120958},
url = {https://doi.org/10.1016/j.ecoenv.2026.120958},
note = {CC BY},
}
RIS
TY - JOUR
TI - Prenatal PFOS impairs offspring cognition via HDAC and translational repression
AU - Xiaoying Niu
AU - Ruru Xi
AU - Yufeng Tan
AU - Jing Shao
AU - Xiaohui Liu
PY - 2026
DA - 2026/10/25
JO - Ecotoxicology and Environmental Safety
DO - 10.1016/j.ecoenv.2026.120958
UR - https://doi.org/10.1016/j.ecoenv.2026.120958
AB - Perfluorooctane sulfonate (PFOS) is a persistent environmental pollutant widely detected in human cord blood and breast milk, raising concerns about its neurodevelopmental toxicity. While epidemiological and animal studies have linked prenatal PFOS exposure to cognitive deficits, the molecular mechanisms—particularly those involving translational regulation—remain unclear. The present study tested whether prenatal PFOS exposure induces hippocampal-dependent cognitive deficits through histone deacetylase (HDAC) overactivation and eukaryotic initiation factor 2α (eIF2α)-mediated translational repression. Pregnant Wistar rats received vehicle or PFOS (0.5 or 2 mg/kg/day) from gestation day 1–21. Offspring cognitive function was assessed using the Morris water maze on postnatal day 28; hippocampal tissue was collected for histopathology, apoptosis, HDAC activity, and expression of phosphorylated PKR-like endoplasmic reticulum kinase (p-PERK), phosphorylated eIF2α (p-eIF2α), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), small ubiquitin-like modifier 1/2 (SUMO1/2), brain-derived neurotrophic factor (BDNF), and protein phosphatase 1 (PP1). Maternal PFOS exposure impaired learning and memory, reduced normal neuron density, and increased neuronal apoptosis. PFOS elevated HDAC activity and activated the PERK–eIF2α–ATF4–CHOP integrated stress response (ISR) pathway, while reduced protein levels of SUMO1/2, BDNF, and PP1—despite elevated mRNA levels, suggesting translational repression. To test whether HDAC overactivation directly contributes to these changes, we pretreated PC12 cells with trichostatin A (TSA), a pan-HDAC inhibitor. TSA partially reversed PFOS-induced apoptosis, suppressed HDAC overactivation, attenuated ISR activation, and restored SUMO1/2, BDNF, and PP1 expression. Collectively, these findings demonstrate that prenatal PFOS exposure causes hippocampal-dependent cognitive deficits through HDAC overactivation and eIF2α-mediated translational repression, shifting the focus from transcriptional to translational control and identifying HDACs as a potential target in PFOS developmental neurotoxicity.
SN - 0147-6513
SN - 1090-2414
ER -