Differential Toxicity of Alkylphenols in JEG-3 Human Placental Cells: Alteration of P450 Aromatase and Cell Lipid Composition

Abstract

Alkylphenols (APs) are a diverse class of chemicals that can cross the placental barrier and interfere with embryonic and fetal development. This work investigates the comparative toxicity, ability to inhibit aromatase activity, and to alter the lipid composition of 10 alkylphenols in the human placenta choriocarcinoma cell line JEG-3. Among the selected APs, 4-dodecylphenol (DP), 4-heptylphenol (HP), and 4-cumylphenol (CP) showed the highest cytotoxicity (EC 50: 18-65 μM). Aromatase inhibition was closely related to the hydrophobicity of APs. HP significantly induced the generation of reactive oxygen species (ROS) (43-fold), inhibited placental aromatase activity (IC 50: 41 μM), and induced a general dose-dependent depletion of polyunsaturated lipids (10-20 μM), which were attributed to high levels of oxidative stress. In contrast, 2,4,6-Tri-Tert-butylphenol (TTBP) significantly induced the intracellular accumulation of triacylglycerides (TGs), whereas DP increased the synthesis of phosphatidylcholines (PCs) and TGs at the expense of diacylglycerides (DGs). Overall, this study evidences the different modes of action of alkylphenols in human placental JEG-3 cells, describes differential lipidomic fingerprints, and highlights DP, HP, CP, and TTBP as the ones that caused the most harmful effects.