Nanomaterial Inhalation During Pregnancy Alters Systemic Vascular Function in a Cyclooxygenase-Dependent Manner

Abstract

Pregnancy requires rapid adaptations in the uterine microcirculation to support fetal development. Nanomaterial inhalation is associated with cardiovascular dysfunction, which may impair gestation. We have shown that maternal nano-titanium dioxide (nano-TiO2) inhalation impairs microvascular endothelial function in response to arachidonic acid (AA) and thromboxane (TXA2) mimetics. However, the mechanisms underpinning this process are unknown. Therefore, we hypothesize that maternal nano-TiO2 inhalation during gestation results in uterine microvascular prostacyclin (PGI2) and TXA2 dysfunction. Pregnant Sprague-Dawley rats were exposed from gestational day (GD) 10-19 to nano-TiO2 aerosols (12.17 mg/m3 ± 1.67) or filtered air (sham-control). Dams were euthanized on GD20, and serum, uterine radial arterioles, implantation sites and lungs were collected. Serum was assessed for PGI2 and TXA2 metabolites. TXB2, the stable TXA2 metabolite, was significantly decreased in nano-TiO2 exposed dams (597.3 ± 84.4 pg/mL vs 667.6 ± 45.6 pg/mL), whereas no difference was observed for 6-keto-PGF1α, the stable PGI2 metabolite. Radial arteriole pressure myography revealed that nano-TiO2 exposure caused increased vasoconstriction to the TXA2 mimetic, U46619, compared to sham-controls (-41.3 ± 4.3% vs -16.8 ± 3.4%). Nano-TiO2 exposure diminished endothelium-dependent vasodilation to carbaprostacyclin, a PGI2 receptor agonist, compared to sham-controls (30.0 ± 9.0% vs 53.7 ± 6.0%). Maternal nano-TiO2 inhalation during gestation decreased nano-TiO2 female pup weight when compared to sham-control males (3.633 ± 0.064 g vs 3.995 ± 0.124 g). Augmented TXA2 vasoconstriction and decreased PGI2 vasodilation may lead to decreased placental blood flow and compromise maternofetal exchange of waste and nutrients, which could ultimately impact fetal health outcomes.

Maternal nano-titanium dioxide inhalation alters fetoplacental outcomes in a sexually dimorphic manner

“…This transporter may lead to increased movement of arsenic across the female placenta and elicit the expression of a subset of genes that are female-specific in response to arsenic exposure ( Winterbottom et al, 2017 ). Maternal inhalation of nano-titanium dioxide, a nanomaterial used in building materials and water/air filters ( Bowdridge et al, 2019 ), during gestation has caused decreased female pup mass ( Griffith et al, 2022 ) and decreased male: female sex ratios in early and mid-gestation ( Garner et al, 2022b ). This exposure paradigm our laboratory has utilized for nano-titanium dioxide (nano-TiO 2 ) inhalation exposure is a model for pregnant women working in an occupational setting would experience.…”

“…This exposure paradigm our laboratory has utilized for nano-titanium dioxide (nano-TiO 2 ) inhalation exposure is a model for pregnant women working in an occupational setting would experience. This encompasses the time periods when women may not realize they are pregnant through late gestation ( Griffith et al, 2022 ). These studies indicate that maternal environmental exposures affect offspring in a sexually dimorphic manner that appears to be paradigm specific.…”

“…A rat gestational hypoxia model demonstrated that vasoactivity can change in both the uterine circulation and umbilical vein ( Aljunaidy et al, 2016 ). Our lab has demonstrated that maternal nano-titanium dioxide (nano-TiO 2 ) inhalation alters the uterine microcirculation and results in increased sensitivity to the vasoconstrictive actions of U46619 ( Griffith et al, 2022 ). Maternal inhalation of nano-TiO 2 also reduced vasodilation in response to the stable PGI 2 analog, carbaprostacyclin ( Griffith et al, 2022 ).…”

“…Our lab has demonstrated that maternal nano-titanium dioxide (nano-TiO 2 ) inhalation alters the uterine microcirculation and results in increased sensitivity to the vasoconstrictive actions of U46619 ( Griffith et al, 2022 ). Maternal inhalation of nano-TiO 2 also reduced vasodilation in response to the stable PGI 2 analog, carbaprostacyclin ( Griffith et al, 2022 ). In conjunction with this, we have also found that maternal nano-TiO 2 inhalation during gestation results in litter decreased fetal mass ( Bowdridge et al, 2019 ), increased placental mass ( Bowdridge et al, 2019 ), and decreased male: female ratio in early and mid-gestational exposures ( Garner et al, 2022b ).…”

“…In conjunction with this, we have also found that maternal nano-TiO 2 inhalation during gestation results in litter decreased fetal mass ( Bowdridge et al, 2019 ), increased placental mass ( Bowdridge et al, 2019 ), and decreased male: female ratio in early and mid-gestational exposures ( Garner et al, 2022b ). Further studies expanded on the fetal mass and determined that maternal nano-TiO 2 inhalation during gestation specifically decreased female pup mass ( Griffith et al, 2022 ). This has led us to hypothesize herein that maternal nano-TiO 2 inhalation exposure during gestation alters placental hemodynamics and therefore influences fetal health outcomes in a sexually dimorphic manner.…”