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

• PFOA exposure increases CRF expression in the PVN of male mice. • Higher CRF in PFOA-exposed mice causes increased corticosterone levels. • Enhanced corticosterone disrupts glucocorticoid receptors in the hippocampus. • Disruption of glucocorticoid receptors leads to depression-like behaviors. 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.