The Effect Of Exposure To BDE209 During Pregnancy On The Expression Of Placental Deiodinase Of Mice And Its Significance In The Developmental Neurotoxicity Of Offspring Mice

Polybrominated diphenyl ethers(PBDEs) are a class of global organic pollutants which widely exist in the environment. In recent years, the level of PBDEs in placenta of pregnant women has been increasing, which poses potential risk to the placenta and fetal development. Animal studies have shown that PBDEs exposure during pregnancy can cause neurotoxic effects in offspring, manifested mainly in damage of motor behavior and cognitive ability. However, the underlying mechanisms have yet to be understood, while the interference of thyroid hormone by PBDEs is considered to be the one of the factors. Thyroid hormones are regulated by three types deiodinases(DI-1, 2, 3), which differentially distribute in different tissues and control the biological activity of thyroid hormone locally and in cells by different ways to removal iodine, and eventually have effects on levels of circulating thyroid hormones. During early pregnancy, the thyroxine hormones of developing fetuses completely come from maternal source, and rely on placenta deiodinase to adjust thyroid hormones, to ensure the normal development of vital organs(including brain) of fetuses. The placental DI-3 is highly expressed and actively controls the high activity of thyroxine hormone T3 and T4 that are transported from maternal circulation, therefore protecting fetuses from overexposure to maternal T3 and T4. Due to the fact that pregnancy is crucial period of time for brain development, damage to placental DI-3 may have consequences of not only an interference of fetal thyroid hormone and also an injury to brain development, leading to toxic effects in central nervous system in offspring. This inference agrees with the assumption that the interference of thyroid hormone may underlie the developmental neurotoxic effects caused by PBDEs. Nevertheless, the effect of PBDEs on placental deiodinases has not been reported.Objectives: To verify that placental DI-3 is the target of BDE 209 exposed during pregnancy and the indicator of toxic effect index of BDE 209; BDE 209 exposure during pregnancy induces interference of fetal thyroid hormone mainly through placental DI-3, and therefore results in developmental neurotoxicity.Methods: BDE 209 is one of the main congeners of PBDEs. In this study, we expose femal mice to BDE 209 before mating and throughout pregnancy with different doses(low dose: 1.5mg/kg.d; high dose: 225mg/kg.d). On the 20 th day of pregnancy, the gene expression of three deiodinases in placenta was detected by Real-time quantitative PCR. In male offspring mice, the circulating thyroid hormones levels were measured by chemiluminescent enzyme immunoassay(CLEIA) on days of 30 and 60 after birth, and their learning and memory ability were tested using Morris water maze. In addition, the gene and protein expressions of DI-3 in liver and hippocampus of male offspring mice were detected by Real-time quantitative PCR and Western Blot.Result: 1) BDE 209 exposure during pregnancy has overall effects on the growth and development of male offspring mice after birth, manifested by decrease in body weight;2) Even at an environmentally relevant low dose, BDE 209 exposure during pregnancy can cause damage in spatial learning and memory ability in male offspring mice after birth, which demonstrates a dose-effect relationship and deteriorates with age; 3) BDE 209 exposure during pregnancy can down-regulate the gene expression of all three placental deiodinase, especially in DI-3 with a dose-effect relationship. Compare to DI-3 gene and protein expression in liver and hippocampus of male offspring mice, there is high agreement between the gene expression of placental DI-3 and BDE 209-induced developmental neurotoxic effects, indicating that placental DI-3 may be the target of BDE 209 exposure during pregnancy and may serve as a potential biological indicator of BDE 209-induced developmental neurotoxic effect; 4) BDE 209 expose during pregnancy induce interference of thyroid hormone in male offspring mice after birth, but with a tendency of recovery with age, suggesting that the interference of thyroid hormone in male offspring mice by BDE 209 mainly come from the late effect of BDE 209-mediated damage in placental DI-3 expression, which underlies BDE 209 developmental neurotoxicity.Conclusion: BDE 209 exposure during pregnancy induces an interference of thyroxine hormone, and subsequently the developmental neurotoxic effects, mainly through placental deiodinases, especially DI-3; Placental DI-3 may be the target of PBDEs during pregnancy and the index of PBDEs toxic effect, therefore may be used as a sensitive marker of PBDEs developmental toxicity.The findings from our study not only provide a new direction for the mechanistic study of PBDEs developmental neurotoxicity but also provide a non-invasive sensitive marker to guide the PBDEs epidemiological study, and make it possible for early screening and clinical intervention for newborns.