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Lack of effects on female fertility and prenatal and postnatal offspring development in rats with BNT162b2, a mRNA-based COVID-19 vaccine.

ABSTRACT: BNT162b2 is a vaccine developed to prevent coronavirus disease 2019 (COVID-19). BNT162b2 is a lipid nanoparticle formulated nucleoside-modified messenger RNA (mRNA) encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein locked in its prefusion conformation. A developmental and reproductive toxicity study was conducted in rats according to international regulatory guidelines. The full human BNT162b2 dose of 30 μg mRNA/dose (>300 times the human dose on a mg/kg basis) was administered intramuscularly to 44 female rats 21 and 14 days prior to mating and on gestation days 9 and 20. Half of the rats were subject to cesarean section and full fetal examination at the end of gestation, and the other half were allowed to deliver and were monitored to the end of lactation. A robust neutralizing antibody response was confirmed prior to mating and at the end of gestation and lactation. The presence of neutralizing antibodies was also confirmed in fetuses and offspring. Nonadverse effects, related to the local injection site reaction, were noted in dams as expected from other animal studies and consistent with observations in humans. There were no effects of BNT162b2 on female mating performance, fertility, or any ovarian or uterine parameters nor on embryo-fetal or postnatal survival, growth, physical development or neurofunctional development in the offspring through the end of lactation. Together with the safety profile in nonpregnant people, this ICH-compliant nonclinical safety data supports study of BNT162b2 in women of childbearing potential and pregnant and lactating women.

SUBMITTER: Bowman CJ

PROVIDER: S-EPMC8163337 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRoad traffic air pollution is linked with an increased risk of autistic spectrum disorder (ASD). The aim of this study is to assess the effect of exposure to prenatal or postnatal traffic-related air pollution combining concomitant noise pollution on ASD-related epigenetic and behavioral alternations on offspring.MethodsA 2 × 2 factorial analysis experiment was designed. Wistar rats were exposed at different sites (L group: green space; H group: crossroads) and timings (E group: full gestation; P group: 21 days after birth) at the same time, and air pollutants of nitrogen dioxide (NO2) and fine particles (PM2.5) were meanwhile sampled. On postnatal day 25, brains from offspring of each group were extracted to determine the levels of DNA methylation in Shank3 (three parts: Shank3_01, Shank3_02, Shank3_03) and MeCP2 (two parts: MeCP2_01, MeCP2_02) promoter regions, H3K4me3 and H3K27me3 after three-chamber social test. Meanwhile, the Shank3 and MeCP2 levels were quantified.ResultsThe concentrations of PM2.5 (L: 58.33 µg/m3; H: 88.33 µg/m3, P < 0.05) and NO2 (L: 52.76 µg/m3; H: 146.03 µg/m3, P < 0.01) as well as the intensity of noise pollution (L: 44.4 dB (A); H: 70.1 dB (A), P < 0.001) differed significantly from 18:00 to 19:00 between experimental sites. Traffic pollution exposure (P = 0.006) and neonatal exposure (P = 0.001) led to lower weight of male pups on PND25. Male rats under early-life exposure had increased levels of Shank3 (Shank3_02: timing P < 0.001; site P < 0.05, Shank3_03: timing P < 0.001) and MeCP2 (MeCP2_01: timing P < 0.001, MeCP2_02: timing P < 0.001) methylation and H3K4me3 (EL: 11.94 µg/mg; EH: 11.98; PL: 17.14; PH: 14.78, timing P < 0.05), and reduced levels of H3K27me3 (EL: 71.07 µg/mg; EH: 44.76; PL: 29.15; PH: 28.67, timing P < 0.001; site P < 0.05) in brain compared to those under prenatal exposure. There was, for female pups, a same pattern of Shank3 (Shank3_02: timing P < 0.001; site P < 0.05, Shank3_03: timing P < 0.001) and MeCP2 (MeCP2_01: timing P < 0.05, MeCP2_02: timing P < 0.001) methylation and H3K4me3 (EL: 11.27 µg/mg; EH: 11.55; PL: 16.11; PH: 15.44, timing P < 0.001), but the levels of H3K27me3 exhibited an inverse trend concerning exposure timing. Hypermethylation at the MeCP2 and Shank3 promoter was correlated with the less content of MeCP2 (female: EL: 32.23 ng/mg; EH: 29.58; PL: 25.01; PH: 23.03, timing P < 0.001; site P < 0.05; male: EL: 31.05 ng/mg; EH: 32.75; PL: 23.40; PH: 25.91, timing P < 0.001) and Shank3 (female: EL: 5.10 ng/mg; EH: 5.31; PL: 4.63; PH: 4.82, timing P < 0.001; male: EL: 5.40 ng/mg; EH: 5.48; PL: 4.82; PH: 4.87, timing P < 0.001). Rats with traffic pollution exposure showed aberrant sociability preference and social novelty, while those without it behaved normally.ConclusionsOur findings suggest early life under environmental risks is a crucial window for epigenetic perturbations and then abnormalities in protein expression, and traffic pollution impairs behaviors either during pregnancy or after birth.

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Lack of effects on female fertility and prenatal and postnatal offspring development in rats with BNT162b2, a mRNA-based COVID-19 vaccine.

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