Maternal nano-titanium dioxide inhalation exposure alters placental cyclooxygenase and oxidant balance in a sexually dimorphic manner

Abstract

The placenta plays a critical role in nutrient-waste exchange between the maternal and fetal circulation, and thus impacts fetal growth and development. We have previously shown that nano-titanium dioxide (nano-TiO₂) inhalation exposure during gestation decreased fetal female pup and placenta mass [1], which persists in the following generation [2]. In utero exposed females, once mated, their offspring's placentas had increased capacity for H₂O₂ production. Generation of oxidants such as hydrogen peroxide (H₂O₂), have been shown to impact cyclooxygenase activity, specifically metabolites such as prostacyclin (PGI₂) or thromboxane (TXA₂). Therefore, we hypothesized that maternal nano-TiO₂ inhalation exposure during gestation results in alterations in placental production of prostacyclin and thromboxane mediated by enhanced H₂O₂ production in a sexually dimorphic manner. Pregnant Sprague-Dawley rats were exposed to nano-TiO₂ aerosols or filtered air (sham-control) from gestational day (GD) 10–19. Dams were euthanized on GD 20, and fetal serum and placental tissue were collected based on fetal sex. Fetal placental zones (junctional zone (JZ) and labyrinth zone (LZ)) were assessed for xanthine oxidoreductase (XOR) activity, H₂O₂, and catalase activity, as well as 6-keto-PGF_1α and TXB₂ levels. Nano-TiO₂ exposed fetal female LZ demonstrated significantly greater XOR activity compared to exposed males. Exposed fetal female LZ also demonstrated significantly diminished catalase activity compared to sham-control females. Exposed fetal female LZ had significantly increased abundance of 6-keto-PGF_1α compared to sham-control females and increased TXB₂ compared to exposed males. In the aggregate these data indicate that maternal nano-TiO₂ inhalation exposure has a greater impact on redox homeostasis and PGI₂/TXA₂ balance in the fetal female LZ. Future studies need to address if treatment with an XO inhibitor during gestation can prevent diminished fetal female growth during maternal nano-TiO₂ inhalation exposure.