背景:下丘脑-垂体-肾上腺(HPA)和性腺(HPG)轴是连接脊椎动物神经和内分泌系统的两条主要途径。诸如产前应激和母体暴露于外源性类固醇的因素已显示在胎儿发育期间影响这些途径。另一个研究较少的因素是多胎妊娠中激素在胎儿之间的转移。这种形式的转移已被证明会影响形态,解剖学,生理学,和后代在携带垃圾的哺乳动物中的行为,这种影响称为宫内位置(IUP)效应。在这项研究中,我们试图描述IUP如何影响HPA和HPG脑受体,肽,和子宫内的酶(以下简称成分)以及这些影响在男性和女性之间可能有什么不同。
方法:我们使用了非常规的自由放养营养学家(Myocastorcoypus)模型,具有很大的自然变异。我们收集了营养胎儿的脑组织,并量化了三个大脑区域中关键HPA和HPG成分的表达:前额叶皮质,下丘脑,和纹状体。
结果:我们在盐皮质激素受体(MR)中发现了性别与IUP之间的相互作用,促性腺激素释放激素受体(GNRHR),雄激素受体(AR),和雌激素受体α(ESR1)。IUP在促性腺激素释放激素(GnRH)及其受体GNRHR中均有显著意义,但以不同的方式。在下丘脑,与同性邻居相邻的胎儿的GnRH表达高于与异性相邻的胎儿。相反,在大脑皮层,GNRHR表现出相反的模式,与异性相邻的胎儿的表达水平高于与同性相邻的胎儿。不管IUP,在大多数表现出显著性别差异的成分中,女性胎儿的mRNA表达水平高于男性胎儿。我们还发现HPA和HPG成分在妊娠早期高度相关,性别和发育阶段之间存在相互作用。在怀孕的早期阶段,女性成分表达水平比男性更相关,但在怀孕的最后三个月,男性成分比女性成分更相关。
结论:这项研究表明,在胎儿发育过程中,有不同的调节HPA和HPG轴的机制。内分泌轴成分的mRNA表达水平较高可能是帮助女性应对长期妊娠期雄激素暴露的机制。此外,这些发现表明,在胎儿发育阶段,男性和女性内分泌轴的协调要求不同。
BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes are two major pathways that connect the neural and endocrine systems in vertebrates. Factors such as prenatal stress and maternal exposure to exogenous steroids have been shown to affect these pathways during fetal development. Another less studied factor is the transfer of hormones across fetuses in multifetal pregnancies. This form of transfer has been shown to influence the morphology, anatomy, physiology, and behavior of the offspring in litter-bearing mammals, an influence termed the intrauterine position (IUP) effect. In this study, we sought to delineate how the IUP effects HPA and HPG brain receptors, peptides, and enzymes (hereafter components) in utero and how these influences may differ between males and females.
METHODS: We utilized the unconventional model of culled free-ranging nutria (Myocastor coypus), with its large natural variation. We collected brain tissues from nutria fetuses and quantified the expression of key HPA and HPG components in three brain regions: prefrontal cortex, hypothalamus, and striatum.
RESULTS: We found an interaction between sex and IUP in the mineralocorticoid receptor (MR), gonadotropin-releasing hormone receptor (GNRHR), androgen receptor (AR), and estrogen receptor alpha (ESR1). IUP was significant in both gonadotropin-releasing hormone (GnRH) and its receptor GNRHR, but in different ways. In the hypothalamus, fetuses adjacent to same-sex neighbors had higher expression of GnRH than fetuses neighboring the opposite sex. Conversely, in the cortex, GNRHR exhibited the inverse pattern, and fetuses that were neighboring the opposite sex had higher expression levels than those neighboring the same sex. Regardless of IUP, in most components that showed significant sex differences, female fetuses had higher mRNA expression levels than male fetuses. We also found that HPA and HPG components were highly related in the early stages of gestation, and that there was an interaction between sex and developmental stage. In the early stages of pregnancy, female component expression levels were more correlated than males\', but in the last trimester of pregnancy, male components were more related to each other than female\'s.
CONCLUSIONS: This study suggests that there are sexually different mechanisms to regulate the HPA and HPG axes during fetal development. Higher mRNA expression levels of endocrine axes components may be a mechanism to help females cope with prolonged androgen exposure over a long gestational period. Additionally, these findings suggest different coordination requirements of male and female endocrine axes during stages of fetal development.