中国药理学与毒理学杂志2025，Vol.39Issue(6)：432-443,12.DOI:10.3867/j.issn.1000-3002.2025.08212
高脂饮食和慢性应激加重孕期乙醇暴露所致成年子代大鼠肾上腺功能紊乱
High-fat diet and unpredictable chronic stress aggravate adrenal dysfunction of adult offspring rats induced by prenatal ethanol exposure
摘要
Abstract
OBJECTIVE To investigate the mechanisms of adrenal dysfunction among adult offspring rats caused by prenatal ethanol exposure(PEE)aggravated by high-fat diet(HFD)and unpredictable chronic stress(UCS).METHODS Pregnant rats were randomly divided into the control group(saline,ig,once)and PEE group(4 g·kg-1,ig,once)from gestational day(GD)11 until delivery.At postnatal week 4(PW4),offspring rats from the control group and PEE group were randomly assigned to three sub-groups:the normal diet(ND)group,HFD group,and HFD-UCS group(n=20 per subgroup,at an equal male-to-female ratio).The rats in each group were given a corresponding diet until PW24.The HFD-UCS group received HFD until PW24,with additional UCS treatment initiated at PW21 and continued for 3 weeks.Serum adrenocorticotropic hormone(ACTH)levels were measured by radioimmunoassay,and corticosterone(CORT)levels were quantified via enzyme-linked immunosorbent assay(ELISA).Adrenal mRNA expressions of steroidogenic factor 1(Sf1),steroidogenic acute regulatory protein(Star),cyto-chrome P450 cholesterol side chain cleavage(P450scc),3β-hydroxysteroid dehydrogenase(3β-Hsd),steroid 21-hydroxylase(P450c21),steroid 11β-hydroxylase(P450c11),11β-hydroxysteroid dehydrogenase type 1(11β-Hsd1),11β-Hsd 2,mineralocorticoid receptor(Mr),glucocorticoid receptor(Gr),insulin-like growth factor 1(Igf1),IGF1 receptor(Igf1r),and serine/threonine kinase 1(Akt1)were determined using real-time quantitative PCR.Protein expressions of Akt1 and phosphorylated Akt1(p-Akt1)were analyzed via immunohistochemistry.RESULTS In male offspring,HFD/PEE significantly reduced serum ACTH and CORT levels,downregulated Star,P450scc,3β-Hsd and P450c11 mRNA,decreased 11β-Hsd1 mRNA expressions and 11β-Hsd1/11β-Hsd2 ratio,but increased Igf1,Igf1r mRNA,and p-Akt1 protein.Conversely,HFD-UCS/PEE elevated ACTH,CORT,P450scc,3β-Hsd and P450c11 mRNA,increased 11β-Hsd1 and 11β-Hsd1/11β-Hsd2 ratio while suppressing Igf1 mRNA,and p-Akt1 protein.In females,HFD/PEE decreased ACTH but upregulated Igf1,Akt1 mRNA,and p-Akt1 protein.HFD-UCS/PEE increased ACTH,CORT,Sf1,Star,P450scc and P450c11 mRNA,and 11β-Hsd1/11β-Hsd2 ratio,but reduced lgf1 and Igf1r mRNA.CONCLUSION HFD/UCS can aggravate PEE-induced adrenal dysfunction in adult offspring.The adrenal"GC-IGF1 axis"is an endocrine negative feedback one,and its decompensation may increase the susceptibility of a wide range of GC-related adult chronic diseases,such as diabetes.关键词
孕期乙醇暴露/肾上腺甾体合成/宫内编程/糖皮质激素活化系统Key words
prenatal ethanol exposure/adrenal steroidogenesis/intrauterine programming/gluco-corticoid-insulin-like growth factor 1 axis分类
医药卫生引用本文复制引用
黄鹤归,熊颖,张顶梅,何正,汪晖..高脂饮食和慢性应激加重孕期乙醇暴露所致成年子代大鼠肾上腺功能紊乱[J].中国药理学与毒理学杂志,2025,39(6):432-443,12.基金项目
国家自然科学基金(82301937) （82301937）
湖北省自然科学基金(2023AFB1053) National Natural Science Foundation of China(82301937) （2023AFB1053）
and the Natural Science Foundation of Hubei Province of China(2023AFB1053) （2023AFB1053）
