Acetaminophen overdose suppresses human extravillous trophoblast invasion by downregulating SP1-mediated MMP2 expression.

In brief statement: Acetaminophen (APAP) overdose impairs extravillous trophoblast (EVT) cell invasion by inhibiting AKT signaling, leading to downregulation of SP1 and reduced MMP2 expression. These findings highlight a potential mechanism by which excessive APAP use may compromise early placental development and pregnancy outcomes.

Abstract: Extravillous trophoblast (EVT) cell invasion is crucial for the establishment of proper maternal-fetal circulation and successful pregnancy outcomes. Acetaminophen (APAP) is commonly used as the first-line analgesic during pregnancy, yet its potential effects on placental function are not well understood. In this study, we investigated the effects of APAP at therapeutic (0.1 and 0.5 mM) and overdose (1, 2, and 5 mM) concentrations on the expression of matrix metalloproteinase 2 (MMP2), a key enzyme involved in extracellular matrix degradation and EVT cell invasion, and explored the underlying molecular mechanisms in human EVT cells. Our results showed that therapeutic doses of APAP did not alter MMP2 expression, whereas overdose concentrations significantly suppressed EVT cell invasion by downregulating MMP2. We further demonstrated that this suppression of MMP2 was mediated by the inhibition of AKT signaling, leading to reduced expression of SP1, a transcription factor critical for MMP2 regulation. Given the critical role of EVT cell invasion in early placental development, our findings provide new insights into how APAP overdose may disrupt EVT function and potentially impact pregnancy outcomes.