Environmentally relevant bis(2-ethylhexyl) phthalate exposure increases stress vulnerability, evoking depressive-like behaviors in male mice.

Chronic stress is a major risk factor for major depressive disorder, and accumulating evidence implicates environmental pollutants in depression-related pathophysiology. We previously showed that prolonged exposure to bis(2-ethylhexyl) phthalate (DEHP) induces depressive-like behaviors in male mice by dampening glutamatergic transmission in the medial prefrontal cortex (mPFC), resembling the effects shown in the chronic immobilization stress (CIS)-induced mouse model of depression. Here, we investigated whether chronic environmentally relevant (ER) DEHP exposure increases vulnerability to stress. Mice received DEHP (120-125 µg/kg body weight) for 42 days and were then subjected to a subthreshold immobilization stress (sIS) regimen that does not elicit overt depressive-like behaviors when administered alone. Notably, DEHP exposure rendered this otherwise subthreshold stress sufficient to unmask a robust depressive-like phenotype. Mice exposed to DEHP + sIS displayed anxiety-like, despair/helplessness-like, and anhedonia-like behaviors, along with elevated corticosterone and reactive oxygen/nitrogen species, recapitulating key features observed in mice with CIS-induced depression. Mechanistically, mice exposed to DEHP + sIS and to CIS both exhibited reduced glutamatergic signaling and decreased glutamine synthetase activity in the mPFC. Together, these findings indicate that sustained ER pollutant exposure can sensitize stress responses and lower the threshold for stress-evoked depressive-like behaviors, and that the underappreciated interaction between environmental pollutants and psychosocial stressors warrants closer attention in assessments of mental health risk.