Exposure to "Forever Chemical" perfluorooctanoic acid induces depression-like behaviors in mice by activating the HPA axis

Ya Wang; Yuning Chen; Houlin Chen; James N Samsom; Minfei Shu; Xuehui Gao; Qiyu Li; Kangmin Chen; Le Wang; Fang Liu

doi:10.1016/j.envint.2025.109631

Exposure to "Forever Chemical" perfluorooctanoic acid induces depression-like behaviors in mice by activating the HPA axis

Environ Int. 2025 Jun 23:202:109631. doi: 10.1016/j.envint.2025.109631. Online ahead of print.

Authors

Ya Wang¹, Yuning Chen¹, Houlin Chen¹, James N Samsom², Minfei Shu¹, Xuehui Gao¹, Qiyu Li¹, Kangmin Chen¹, Le Wang¹, Fang Liu³

Affiliations

¹ Institute of Mental Health and Drug Discovery, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Psychiatry, Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China.
² Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
³ Institute of Mental Health and Drug Discovery, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Psychiatry, Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Canada; Departments of Pharmacology and Toxicology, University of Toronto, Canada; Department of Psychiatry, University of Toronto, Canada; Department of Physiology, University of Toronto, Canada. Electronic address: fang.liu@camh.ca.

PMID: 40580708
DOI: 10.1016/j.envint.2025.109631

Abstract

Perfluorooctanoic acid (PFOA), an environmental endocrine disruptor, has been found to increase the expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN). In this study, adult male mice were given PFOA by oral gavage (p.o.) to evaluate whether it disrupts systems related to mood disorders. PFOA exposure (5 mg/kg) for 10 consecutive days caused depression-like behaviors in male mice. We measured increased corticosterone in serum and in the hippocampus of PFOA-exposed mice, which were linked to enhanced CRF expression measured in the PVN. Elevated corticosterone was associated with reductions in glucocorticoid receptor (GR) protein expression within the hippocampus. CRFR1 antagonist injected into the PVN and intracerebroventricular (i.c.v.) GR antagonist both reduced depression-like behaviors, respectively. In addition, NMDA-dependent Schaeffer collateral-CA3 synaptic transmission in PFOA-exposed mice was disrupted. Synaptic deficits could be corrected by either CRFR1 or GR antagonists. In summary, we found exposure of male mice to PFOA enhances CRF expression, which then activates the HPA axis to disrupt GR expression in the hippocampus, leading to depression-like behaviors. This data is relevant for understanding the potential harmful health effects of PFOA.

Keywords: Corticosterone; Depression-like behaviors; Glucocorticoid Receptors (GRs); Perfluorooctanoic acid (PFOA); corticotropin-releasing factor (CRF).