Maternal and Placental Inflammation Influence Formation of Neural Tube Defects in Quaternary Ammonium Compound Exposed Mice.

BACKGROUND: Quaternary ammonium compounds (QACs) are common chemicals used for their antimicrobial, antistatic, and surfactant properties. Two common QACs, alkyldimethylbenzyl ammonium chloride (ADBAC or BAC) and didecyldimethyl ammonium chloride (DDAC), cause neural tube defects (NTDs) in mice and are proinflammatory in both mice and humans. The maternal immune system plays an integral role in normal fetal development with cytokine mediators in the placenta directing both placental and fetal development. This study was conducted to determine whether maternal systemic or placental inflammation was involved in QAC-induced NTDs.

METHODS: Pregnant CD-1 mice received either a single gavage dose on gestational day (GD) 8.5; two gavage doses, one on GD 7.5 and the other on GD 8.5; or were dosed in the feed prior to mating and throughout breeding and gestation. Maternal whole blood, maternal bone marrow-derived macrophages, placentas, GD 10.5 embryos, and GD 17.5 fetuses were collected for NTD, cytokine and QAC analysis. Cytokines IL-6, IL-10, IL-12, PlGF, and TNF-α were determined by ELISA. ADBAC and DDAC concentrations were determined by UPLC-MS/MS.

RESULTS: ADBAC and DDAC concentrated in placental tissue. Placentas from exposed pregnancies demonstrated increased production of inflammatory IL-10, IL-6, and TNF-α in embryo-placental units with NTDs. Inflammatory IL-10, anti-inflammatory IL-10, IL-6, and TNF-α were increased in macrophages isolated from QAC-exposed mothers, and plasma IL-6, and TNF-α were correlated with NTDs.

CONCLUSION: The placenta is the target tissue for ADBAC and DDAC-induced teratogenicity. Both placental inflammation and maternal systemic inflammation are likely involved in QAC-induced NTD formation in mice.