AhR and reproductive aging

描述(由申请人提供)：芳香烃受体(AhR)是一种孤立的核受体，是一整类环境毒物影响的中心介体。AhR在正常和被破坏的胚胎发育中也有一个未知的角色。在与环境相关的暴露中，2，3，7，8-四氯二苯并对二恶英(TCDD，Dioxin)会加速生殖衰老，这是一种特异而有效的AhR配体，其后果之一是卵母细胞和随后的胚胎质量下降。随着女性越来越多地将怀孕推迟到30多岁或更久，生殖衰老的任何加速都会对成功怀孕的可能性和出生缺陷的风险产生可怕的后果。此外，妇女过早的生殖衰老与寿命和生活质量的降低有关。虽然AhR配体对卵母细胞数量的影响已被广泛研究，但对AhR、卵母细胞质量和随后的早期胚胎组织知之甚少。在我们的初步工作中，我们发现了早期的染色体和细胞骨架缺陷，这些缺陷可能是卵母细胞和胚胎暴露于AhR配体(如二恶英)的病因学；这可以解释随着年龄的增长长期暴露导致生育力下降的原因。该项目的目标是确定受AhR配体调控的卵母细胞发育和早期胚胎发育的检查点。我们的中心假设是，环境中暴露于AhR配体会加剧卵母细胞和胚胎质量随年龄的下降。这项工作一旦完成，有望提供新的见解，防止污染环境中生育力的丧失，并减缓随年龄增长的生育力丧失。研究小组将通过以下具体目标来实现这些实验目标：具体目标1：确定明确的AhR激活对卵母细胞体外成熟和早期胚胎发育关键期的影响。这一目标包括迄今为止对AhR激活或拮抗对卵母细胞和胚胎质量损失的影响的最详细的调查。终点包括胚胎形态、细胞骨架和染色质及其在卵母细胞和胚胎中的表观遗传调节。具体目标2：确定在正常和加速生殖衰老过程中，慢性环境相关AhR的激活和拮抗对卵母细胞和胚胎质量的影响。对幼年和中年大鼠的卵母细胞和胚胎从卵子发生到早期胚胎的形态和细胞骨架构象、染色质重塑、表观遗传修饰和印记进行了评估。这将深入了解卵母细胞、胚胎质量和生育力随年龄的下降，以及AhR途径在卵巢和卵母细胞老化中的重要性。这项工作是新颖的，通过使用现实暴露于AhR激动剂，并专注于微妙的测量，卵母细胞和胚胎质量和表观遗传学。这些研究探索了一种新的诊断指标，即暴露于有毒的AhR配体导致的卵母细胞和胚胎质量受损。该项目将为识别和预防老年母亲因AhR途径引起的不孕不育和出生缺陷提供关键知识。数以百计的人造化合物，包括二恶英、多氯联苯和香烟烟雾中的致癌物，通过芳烃受体(AhR)途径作用于细胞。我们最近报道了AhR激活对卵巢老化的不利影响，以及暴露于AhR配体的雌性卵子和胚胎中的一些缺陷。该项目将为识别和预防老年母亲因AhR途径引起的不孕不育和出生缺陷提供关键知识。

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is an orphan nuclear receptor and a central mediator of the effects of an entire class of environmental toxicants. The AhR has an undefined role in normal and disrupted embryogenesis as well. Reproductive senescence is accelerated by 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD, dioxin), the specific and potent AhR ligand, at environmentally relevant exposures and one consequence is a decline in oocyte and subsequent embryo quality. As women increasingly delay attempts at pregnancy into their 30s and beyond, any acceleration of reproductive aging has dire consequences for the possibility of successful pregnancy and the risk of birth defects. Furthermore, early reproductive senescence in women is associated with decreased lifespan and quality of life. Although the effects of AhR ligands on oocyte numbers have been studied extensively, little is known about the AhR, oocyte quality and subsequent organization of the early embryo. In our preliminary work, we have identified early chromosomal and cytoskeletal defects that may be pathognomonic for exposure of oocytes and embryos to AhR ligands such as dioxins; this can explain the decreased fertility resulting from chronic exposure with age. The objective of this project is to identify checkpoints of oocyte development and early embryogenesis that are regulated by AhR ligands. Our central hypothesis is that environmental exposure to AhR ligands reinforces the decline in oocyte and embryo quality with age. This work, once completed, promises new insights to prevent the loss of fertility in polluted environments and slow the loss of fertility with age. The research team will achieve these experimental goals through the following specific aims: Specific Aim 1: Determine the effect of defined AhR activation on critical periods of oocyte maturation and early embryogenesis in vitro. This aim encompasses the most detailed investigation into the impact of AhR activation or antagonism on the loss of oocyte and embryo quality to date. Endpoints include embryonic morphology, cytoskeleton and chromatin and its epigenetic modulation in oocytes and embryo. Specific Aim 2: Determine the impact of chronic, environmentally relevant AhR activation and antagonism on oocyte and embryo quality during normal and accelerated reproductive senescence. Oocytes and embryos from young and middle aged rats will be assessed for morphological and cytoskeletal conformation and chromatin remodeling and epigenetic modification and imprinting from oogenesis to early embryogenesis. This will provide insight into decreased oocyte and embryo quality and fertility with age and the importance of the AhR pathway in the aging ovary and oocyte. This work is novel through use of realistic exposures to AhR agonists and a focus on subtle measures oocyte and embryo quality and epigenetics. These studies explore a novel diagnostic indicator of compromised oocyte and embryo quality due to exposure to toxic AhR ligands. This project will provide crucial knowledge for the identification and prevention of infertility and birth defects due to the AhR pathway in older mothers. Hundreds of manmade compounds including dioxins, polychlorinated biphenyls and carcinogens in cigarette smoke act on cells through the aryl hydrocarbon receptor (AhR) pathway. We have recently reported detrimental effects of AhR activation on aging of the ovary and a number of defects in eggs and embryos from females exposed to AhR ligands. This project will provide crucial knowledge for the identification and prevention of infertility and birth defects due to the AhR pathway in older mothers.