Maternal Engineered Nanomaterial Inhalation During Gestation Drives Redox Dysregulation and Vascular Dysfunction Across Generations

Abstract Background Pregnancy is associated with many rapid biological adaptations that support healthy development of the growing fetus. One of which is critical to fetal health and development is the coordination between maternal liver derived substrates and vascular delivery. This crucial adaptation can be potentially derailed by inhalation of toxicants. Engineered nanomaterials (ENM) are commonly used in household and industrial products as well as in medicinal applications. As such, the potential risk of exposure remains a concern, especially during pregnancy. We have previously reported that ENM inhalation leads to upregulation in the production of oxidative species. Therefore, we aimed to determine if maternal nano-TiO2 inhalation exposure resulted in altered H2O2 production capacity and changes in downstream redox pathways. Additionally, we investigated whether this persisted into adulthood within the F1 generation and how this impacted F1 gestational outcomes and F2 fetal health and development. We hypothesized that maternal nano-TiO2 inhalation exposure during gestation would result in upregulated H2O2 in the F0 dams as well as her F1 offspring, resulting in gestational vascular dysfunction in the F1 dams yielding smaller F2 generation pups. Results Our results indicate upregulation of hepatic H2O2 production capacity in F0 dams, F1 offspring at 8 weeks and F1 females at gestational day 20. H2O2 production capacity was accompanied by a 2-fold increase in phosphorylation of the redox sensitive transcription factor NF-κB. In cell culture, naïve hepatocytes exposed to F1-nano-TiO2 plasma increased H2O2 production. Overnight exposure of these hepatocytes to F1 plasma increased H2O2 production capacity in a partially NF- κB dependent manner. Pregnant F1- nano-TiO2 females exhibited estrogen disruption (29.81 ± 8.8 pg/ml vs. 12.12 ± 3.1 pg/ml sham-control) and vascular dysfunction similar to their directly exposed mothers. F1-nano-TiO2 uterine artery H2O2 production capacity was also elevated 2-fold. Dysfunctional gestational outcomes in the F1-nano-TiO2 dams resulted in smaller F2 pups (4.93 ± 0.47 g vs. 5.78 ± 0.09 g sham-control pups). Conclusion In conclusion, this manuscript provides critical evidence of redox dysregulation across generations following maternal ENM inhalation. Furthermore, the dysfunctional gestational outcomes observed in the F1-nano-TiO2 generation impact the development of F2 offspring. In total, this data provides strong initial evidence that maternal ENM exposure has robust biological impacts that persists in at least two generations.