Transplacental transfer of p-phenylenediamine antioxidants: Insights from human gestational exposure and an optimized BeWo cell monolayer model.

p-Phenylenediamine antioxidants (PPDs) have recently garnered significant attention due to their potential human toxicity. There is still a lack of research investigating their fetal exposure patterns and transplacental transfer behaviors during pregnancy. This study analyzed nine PPDs in 148 paired samples of maternal plasma, cord plasma, and placenta from China, and investigated the transcellular transfer dynamics of six PPDs using an optimized BeWo cell monolayer model. N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), N, N'-bis(1,4-dimethylpentyl)-p-phenylenediamine (77PD), and N-isopropyl-N'-phenyl-1,4-phenylenediamine (IPPD) were always the most abundant PPDs in maternal (detection frequencies 63-76 %, mean 0.055-0.26 ng/mL) and cord plasma (58-80 %, mean 0.029-0.15 ng/mL), as well as the placental tissue (66-81 %, mean 0.072-0.34 ng/g ww). Mean transplacental transfer efficiency (TTE) values of PPDs followed the decreasing order of N, N'-di-sec-butyl-1,4-phenylenediamine (44PD; 0.89 ± 0.21) > IPPD (0.79 ± 0.20) > N, N'-diphenyl-p-phenylenediamine (DPPD; 0.74 ± 0.17) > N-phenyl-N'-cyclohexyl-p-phenylenediamine (CPPD; 0.65 ± 0.16). The highest mean placental retention extent value was observed for CPPD (3.1 ± 0.44), followed by 44PD (2.3 ± 0.15) and 77PD (1.8 ± 0.40). Results from the TTE analysis and the optimized BeWo model suggest that passive diffusion and active transport mechanisms, influenced by physicochemical properties such as lipophilicity, govern the transplacental transfer of PPDs. These findings contribute to a deeper understanding of intrauterine exposure to PPDs and the mechanisms of maternal-fetal chemical exchange.