nAChRs-ERK1/2-Egr-1 signaling participates in the developmental toxicity of nicotine by epigenetically down-regulating placental 11β-HSD2

作者：Zhou, Jin; Liu, Fulin; Yu, Luting; Xu, Dan; Li, Bin; Zhang, Guohui; Huang, Wen; Li, Lu; Zhang, Yuanzhen; Zhang, Wei^*; Wang, Hui^*

来源：Toxicology and Applied Pharmacology, 2018, 344: 1-12.

DOI：10.1016/j.taap.2018.02.017

• Prenatal nicotine exposure
• Placenta
• Glucocorticoid
• 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2)
• Early growth response-1 (Egr-1)
• Epigenetics

Impaired placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) activity which inactivates maternal glucocorticoids is associated with poor fetal growth and a higher risk of chronic diseases in adulthood. This study aimed to elucidate the epigenetically regulatory mechanism of nicotine on placental 11 beta-HSD2 expression. Pregnant Wistar rats were administered 1.0 mg/kg nicotine subcutaneously twice a day from gestational day 9 to 20. The results showed that prenatal nicotine exposure increased corticosterone levels in the placenta and fetal serum, disrupted placental morphology and endocrine function, and reduced fetal bodyweight. Meanwhile, histone modification abnormalities (decreased acetylation and increased di-methylation of histone 3 Lysine 9) on the HSD11B2 promoter and lower-expression of 11 beta-HSD2 were observed. Furthermore, the expression of nicotinic acetylcholine receptor (nAChR) alpha 4/beta 2, the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and Ets-like protein-1 (Elk-1), and the expression of early growth response-1 (Egr-1) were increased in the nicotine groups. In human BeWo cells, nicotine decreased 11 beta-HSD2 expression, increased nAChR alpha 9 expression, and activated ERK1/2/Elk-1/Egr-1 signaling in the concentration (0.1-10 mu M)-dependent manner. Antagonism of nAChRs, inhibition of ERIC1/2 and Egr-1 knockdown by siRNA were able to block/abrogate the effects of nicotine on histone modification and expression of 11 beta-HSD2. Taken together, nicotine can impair placental structure and function, and induce fetal developmental toxicity. The underlying mechanism involves histone modifications and down-regulation of 11 beta-HSD2 through nAChRs/ERK 1/2/Elk-1/Egr-1 signaling, which increases active glucocorticoids levels in the placenta and fetus, and eventually inhibits the fetal development.

• 出版日期2018-4-1
• 单位武汉大学