Cyclooxygenase-2-driven oxylipin storm: A mechanistic link between prenatal DINP exposure and gestational chronic...

Chronic inflammation during pregnancy is a persistent, often subclinical condition strongly associated with adverse maternal and fetal outcomes. Its etiology is multifactorial, with exposure to exogenous environmental stressors emerging as major contributors, yet the underlying mechanisms remain unclear. Here, we report gestational chronic inflammation induced by exposure to realistic doses of phthalate replacement diisononyl phthalate (DINP), a ubiquitous environmental stressor, during pregnancy via drinking water using a murine model. We demonstrated for the first time that exposure provoked systemic and hepatic inflammation, evidenced by elevated circulating inflammatory cytokines and pronounced hepatic immune cell infiltration. Transcriptomic and oxidized lipidomic profiling further revealed disrupted polyunsaturated fatty acid metabolism and a storm of excessive arachidonic acid oxidation-derived proinflammatory oxylipins, particularly prostaglandins, produced by the liver as key mediators of environmental stress-induced inflammation. Specifically, exposure hyperactivated hepatic cyclooxygenase-2 (COX-2) without altering its protein abundance, which initiated excessive production of proinflammatory oxylipins in the liver. Notably, celecoxib, a selective COX-2 activity inhibitor, effectively suppressed oxylipin overproduction and mitigated both systemic and hepatic inflammation. These findings uncovered a previously unrecognized environmental stressor-COX-2-oxylipin pathway linking environmental exposure and maternal chronic inflammation, highlighting an emerging public health concern.