Effects of gestational perfluorohexanesulfonic acid exposure at human realistic dose on social communication deficit in mouse offspring

  • EBioMedicine. 2026 Mar:125:106160. doi: 10.1016/j.ebiom.2026.106160.
Shengmei Zhang  1 ,  Chang Gao  2 ,  Ruonan Li  1 ,  Jia Lv  1 ,  Jingjing Xu  1 ,  Maohua Miao  3 ,  Hong Liang  3 ,  De-Xiang Xu  4 ,  Bo Wang  5 ,  Yichao Huang  6
Affiliations
  • 1. School of Public Health and Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, 230031, China.
  • 2. School of Public Health and Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, 230031, China; Department of Pediatrics, Suzhou Hospital of Anhui Medical University, Anhui Medical University, Suzhou, 234099, China.
  • 3. Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, 200237, China.
  • 4. School of Public Health and Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, 230031, China. Electronic address: [email protected].
  • 5. School of Public Health and Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, 230031, China. Electronic address: [email protected].
  • 6. School of Public Health and Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, 230031, China; Department of Pediatrics, Suzhou Hospital of Anhui Medical University, Anhui Medical University, Suzhou, 234099, China. Electronic address: [email protected].
PMID: 41671867 DOI: 10.1016/j.ebiom.2026.106160
Abstract

Background: Early-life exposure to exogenous chemicals can disrupt neurodevelopment. Perfluorohexanesulfonic acid (PFHxS), a legacy PFAS widely used and detected globally, remains poorly studied for its neurotoxicity.

Methods: CD-1 mice (n = 90 dams) were exposed to human-relevant dose of PFHxS from gestational day (GD) 0-17. PFHxS levels were measured in maternal plasma and foetal/offspring medial prefrontal cortex (mPFC) (GD 18, postnatal weeks [PNW] 4 and 10) using liquid chromatography tandem mass-spectrometry (LC-MS/MS). Offspring social behaviour was assessed with the Three-Chamber social test. Neurotransmitters in mPFC of PNW 10 offspring were profiled by LC-MS/MS, transcriptomics was performed on GD 18 and PNW 4 mPFC, GABAergic neurons were quantified by immunofluorescence, and glutamate decarboxylase (GAD) expression by western blotting. PFHxS-GAD interactions were examined via molecular docking and microscale thermophoresis (MST).

Findings: Maternal plasma reached 5.1 ± 0.1 ng/mL, equivalent to human biomonitoring data, and PFHxS accumulated in foetal mPFC (68.1 ± 4.1 pg/g). PFHxS exposure induced social deficits at PNW 4 and 10, which were more pronounced in males. The mPFC of PFHxS exposed offspring exhibited an excitatory-tilted neurotransmitter profile, feature with reduced γ-aminobutyric acid (GABA, 90.6 ± 12.2 vs. 70.2 ± 4.3 μg/g, p = 0.008). The differentially expressed genes were enriched in GABAergic and synaptic signalling pathways. Despite unchanged percentage of GABAergic neuron and GAD expression, metabolite GABA/glutamate ratio was attenuated, suggesting impaired GAD function. Both molecular docking and MST suggested moderate-to-strong binding affinity between PFHxS and GAD, affecting GABA synthesis.

Interpretation: Gestational PFHxS exposure at human-relevant levels impairs offspring social behaviour, likely via disruption of GAD-mediated imbalance in excitation/inhibition.

Funding: This work was provided by grants from the National Natural Science Foundation of China (82404221 and 82373586), Anhui Provincial Natural Science Foundation (2308085Y50 and 2408085QH275), Education Department of Anhui Province for Excellent Young Scientist (2022AH030076), and funding from Center for Big Data and Population Health of IHM (JKS2022020).

Keywords
GABAergic signalling; Gestational chemical exposure; PFAS; Perfluorohexanesulfonic acid; Social communication deficits.
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