Acetaminophen is one of the most common medications taken during pregnancy, considered safe for maternal health and fetal development. However, recent epidemiological studies have associated prenatal
acetaminophen use with several developmental disorders in offspring. As
acetaminophen can freely cross into and through the placenta, epidemiological associations with prenatal
acetaminophen use may reflect direct actions on the fetus and/or the impact of altered placental functions. In the absence of rigorous mechanistic studies, our understanding of how prenatal
acetaminophen exposure can cause long-term effects in offspring is limited. The objective of this study was to determine whether
acetaminophen can alter key functions of a major placental cell type by utilizing immortalized human first trimester trophoblast cells. This study employed a comparative analysis with the nonsteroidal, anti-inflammatory drug
aspirin, which has established effects in first trimester trophoblast cells. We report that immortalized trophoblast cells express the target
proteins of
acetaminophen and
aspirin:
cyclooxygenase (COX) -1 and -2. Unlike
aspirin,
acetaminophen significantly repressed the expression of angiogenesis and
vascular remodeling genes in HTR-8/SVneo cells. Moreover,
acetaminophen impaired trophoblast invasion by over 80%, while
aspirin had no effect on invasion.
Acetaminophen exposure reduced the expression of
matrix metalloproteinase (MMP)-2 and -9 and increased the expression of tissue inhibitors of
matrix metalloproteinases 2, leading to an imbalance in the ratio of
proteolytic enzymes. Finally, a bioinformatic approach identified novel
acetaminophen-responsive gene networks associated with key trophoblast functions and disease. Together these results suggest that prenatal
acetaminophen use may interfere with critical trophoblast functions early in gestation, which may subsequently impact fetal development.