NRF2-Dependent Placental Effects Vary by Sex and Dose following Gestational Exposure to Ultrafine Particles

Abstract

Exposure to ultrafine particles (UFPs, PM0.1) during pregnancy triggers placental oxidative stress and inflammation, similar to fine PM (PM2.5). The Nrf2 gene encodes a redox-sensitive transcription factor that is a major regulator of antioxidant and anti-inflammatory responses. Disruption of NRF2 is known to substantially enhance PM2.5-driven oxidant and inflammatory responses; however, specific responses to UFP exposure, especially during critical windows of susceptibility such as pregnancy, are not fully characterized; To investigate the role of NRF2 in regulating maternal antioxidant defenses and placental responses to UFP exposure, wildtype (WT) and Nrf2−/− pregnant mice were exposed to either low dose (LD, 100 µg/m3) or high dose (HD, 500 µg/m3) UFP mixture or filtered air (FA, control) throughout gestation; Nrf2−/− HD-exposed female offspring exhibited significantly reduced fetal and placental weights. Placental morphology changes appeared most pronounced in Nrf2−/− LD-exposed offspring of both sexes. Glutathione (GSH) redox analysis revealed significant increases in the GSH/GSSG ratio (reduced/oxidized) in WT female placental tissue exposed to HD in comparison with Nrf2−/− HD-exposed mice. The expression of inflammatory cytokine genes (Il1β, Tnfα) was significantly increased in Nrf2−/− placentas from male and female offspring across all exposure groups. Genes related to bile acid metabolism and transport were differentially altered in Nrf2−/− mice across sex and exposure groups. Notably, the group with the most marked phenotypic effects (Nrf2−/− HD-exposed females) corresponded to significantly higher placental Apoa1 and Apob expression suggesting a link between placental lipid transport and NRF2 in response to high dose UFP exposure; Disruption of NRF2 exacerbates adverse developmental outcomes in response to high dose UFP exposure in female offspring. Morphological effects in placenta from male and female offspring exposed to low dose UFPs also signify the importance of NRF2 in maternal–fetal response to UFPs.

Maternal exposure to ultrafine particles enhances influenza infection during pregnancy

“…PM exposure was carried out as previously described in Behlen et al and Lau et al [ 12 , 27 , 53 ]. Mice ( n = 18 for FA; n = 18 for UFPs) were exposed from GD0.5 to 13.5 for 6 h/day in whole-body inhalation chambers.…”

“…The UFP chamber was monitored, and the flow of HEPA-filtered air adjusted accordingly to maintain particle concentrations of ~ 100 g /m 3 throughout the study. This dose was based on previously observed effects on offspring health [ 12 , 27 , 53 ]. Moreover, this dose was equivalent to a 24-h average exposure 25 g /m 3 , just under the EPA PM 2.5 regulatory level (35 g /m 3 ).…”

Melatonin Supplementation during the Late Gestational Stage Enhances Reproductive Performance of Sows by Regulating Fluid Shear Stress and Improving Placental Antioxidant Capacity

“…For example, the placental malfunction associated abnormal intrauterine environment during the embryonic period not only inhibits the fetus’ development and growth but also increases the risk of diabetes, hypertension and cardiovascular diseases after birth [ 2 ]. Even though multiple risk factors are attributed to placental dysfunctions, one of them is oxidative stress [ 3 , 4 ]. It has been reported that maternal exposure to high levels of reactive oxygen species (ROS) during pregnancy impairs placental function and leads to poor outcomes in pregnancy [ 5 ].…”