Critical time window of fenvalerate-induced fetal intrauterine growth restriction in mice

Fenvalerate (FEN), a representative type II pyrethroid, is a widely used pyrethroid insecticide and a potential environmental contaminant. Several studies demonstrated that gestational FEN exposure induced intrauterine growth restriction (IUGR). However, the critical time window of FEN-induced fetal IUGR remains obscure. The present study aimed to identify the critical window of FEN-induced fetal IUGR. Pregnant mice were administered corn oil or FEN (20 mg/kg) by gavage daily at the early gestational stage (GD0-GD6), middle gestational stage (GD7-GD12) or late gestational stage (GD13-GD17). The results showed that the rates of fetal IUGR were markedly increased only in the mice exposed to FEN on GD13-GD17 but not in the mice exposed to FEN on GD7-GD12 or GD0-GD6. Further analysis showed that the blood sinusoid area in the placental labyrinth layer was reduced in the mice exposed to FEN on GD13-GD17. In addition, CD34(+) microvessel density in the labyrinthine region was decreased in the male and female fetuses whose mothers were exposed to FEN on GD13-GD17. Mechanistic analysis found that the glutathione level was decreased in the FEN-exposed placentas. In contrast, the levels of 3-nitrotyrosine and malondialdehyde, two oxidative stress markers, were increased in FEN-exposed placentas. Heme oxygenase-1, inducible nitric oxide synthase, catalase and peroxiredoxin-3, which are antioxidant enzymes, were upregulated in the FEN-exposed placentas. The present study suggests that the late gestational stage is a critical time window of FEN-induced fetal IUGR. Placental oxidative stress may be, at least partially, involved in the process of FEN-induced placental damage and fetal IUGR.