Abstract
Fetal growth restriction (FGR) is a condition with several underlying etiologies including gestational disease (e.g., preeclampsia, gestational diabetes) and xenobiotic exposure (e.g., environmental contaminants, pharmaceuticals, recreational drugs). Rodent models allow study of FGR pathogenesis. However, given the multiparous rodent pregnancy, fetal growth variability within uterine horns may arise. To ascertain whether intrauterine position is a determinant of fetal growth, we redesigned fetal weight analysis to include litter size and maternal weight. Our FGR model is produced by exposing pregnant Sprague Dawley rats to aerosolized titanium dioxide nanoparticles at 9.44 ± 0.26 mg/m3 on gestational day (GD) 4, GD 12 or GD 17 or 9.53 ± 1.01 mg/m3 between GD 4-GD 19. In this study fetal weight data was reorganized by intrauterine location (i.e., right/left uterine horn and ovarian/middle/vaginal position) and normalized by maternal weight and number of feti per uterine horn. A significant difference in fetal weight in the middle location in controls (0.061 g ± 0.001 vs. 0.055 g ± 0.002), GD 4 (0.033 g ± 0.003 vs. 0.049 g ± 0.004), and GD 17 (0.047 g ± 0.002 vs. 0.038 g ± 0.002) exposed animals was identified. Additionally, GD 4 exposure produced significantly smaller feti in the right uterine horn at the ovarian end (0.052 g ± 0.003 vs. 0.029 g ± 0.003) and middle of the right uterine horn (0.060 g ± 0.001 vs. 0.033 g ± 0.003). GD 17 exposure produced significantly smaller feti in the left uterine horn middle location (0.055g ± 0.002 vs. 0.033 ± 0.002). Placental weights were unaffected, and placental efficiency was reduced in the right uterine horn middle location after GD 17 exposure (5.74 g ± 0.16 vs. 5.09 g ± 0.14). These findings identified: (1) differences in fetal weight of controls between the right and left horns in the middle position, and (2) differential effects of single whole-body pulmonary exposure to titanium dioxide nanoparticles on fetal weight by position and window of maternal exposure. In conclusion, these results indicate that consideration for intrauterine position, maternal weight, and number of feti per horn provides a more sensitive assessment of FGR from rodent reproductive and developmental studies.
Highlights
Fetal growth restriction (FGR) is a pathology where the full in utero growth potential for a fetus is not met during the period of gestation (Wollmann, 1998)
Upon further evaluation using our revised approach we observed that under control conditions, feti implanted in the left uterine horn tended to be smaller in body weight at term compared with feti implanted in the right uterine horn
These analyses demonstrated significant FGR in exposed animals compared with controls, separated by uterine horn and intrauterine position, outcomes that were lost with traditional approaches
Summary
Fetal growth restriction (FGR) is a pathology where the full in utero growth potential for a fetus is not met during the period of gestation (Wollmann, 1998). Surviving newborns face an increased likelihood of developing cardiovascular disease, asthma, type 2 diabetes, and metabolic disorders later in life (Hales et al, 1991; Martyn et al, 1995; Curhan et al, 1996; Leon et al, 1998; Barker, 2006; Xu et al, 2014). Because of these associations with short- and long-term health conditions, FGR is a condition of concern for obstetric, pediatric, and primary care practitioners as well as reproductive and developmental scientists. Accumulating evidence has suggested that pregnant women environmentally exposed to components of air pollution (e.g., fine/ultrafine fractions of particulate matter) or occupationally exposed to nanoparticles are at increased risk for FGR (Rogers and Dunlop, 2006; Manangama et al, 2019; Bekkar et al, 2020)
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