Bisphenol A and S affect early embryonic development in cattle

养牛业每年为加拿大经济贡献数十亿美元和数千个就业机会。它成功的一个关键是高效地生产健康的牛胚胎。尽管生殖生物技术的进步是惊人的，但牛的总体生育率低至35%，大部分胚胎在发育的头几周丢失。了解影响牛胚胎发育的因素为研究可以在其他哺乳动物身上翻译的机制途径提供了一个模型，同时提高了牛的生育力。我的初步研究计划结合了对胚胎发育的基本理解，重点关注环境应激源，特别是内分泌干扰化合物(EDCs)对早期胚胎损失的影响，以及长期目标是限制发育第一周的胚胎损失，从而增加产生健康牛胚胎的机会，并改进农场动物的生殖生物技术。本项目主要研究特定的内分泌细胞对牛早期胚胎发育的影响，短期目标是研究双酚A和双酚S对牛早期胚胎发育的影响及其作用机制。内分泌干扰素是一种环境应激源，具有雌激素样的潜在影响生育能力，双酚A是全球产量最大的化学品之一。我们发现，牛卵母细胞暴露于双酚A后，纺锤体异常，减数分裂进程减缓，囊胚发育减慢，细胞凋亡率增加，基因和蛋白质发生变化。对双酚A影响的担忧导致了其类似的BPS的使用，但这也对卵母细胞成熟有负面影响。BPA和BPS在显著低于人类观察到的浓度时，都会导致牛的纺锤体异常和染色体错位，这表明牛的生殖系统更容易受到双酚的影响。这些数据支持我们的理论，即双酚类物质，特别是双酚A，会影响牛的繁殖能力。因此，我们推测BPA和BPS是导致牛繁殖效率下降的原因之一。目的1：探讨BPA和BPS在卵母细胞成熟和早期胚胎发育中的作用机制。目的2：探讨BPA和BPS在诱导早期胚胎停滞中的作用。目的：研究双酚A(BPA)和双酚A(BPS)在体外发育过程中的表观遗传学变化。目的：确定体外发育过程中BPA和BPS暴露对代谢组学的影响。更好地了解EDCs暴露与牛繁殖能力下降之间的联系，具有越来越重要的科学和经济意义。我们的研究计划1)可以在很大程度上有助于评估BPS是否是BPA的有效替代品，以及2)可以推动实施农场动物环境/饲养系统的改变，以限制双酚和EDCs的暴露，以减少它们对牛繁殖能力的潜在影响。

The cattle industry contributes billions of dollars and thousands of jobs annually to the Canadian economy. A key to its success is the efficient production of healthy bovine embryos. Although the advance in reproductive biotechnologies is striking, the overall fertility of cattle is as low as 35% with the majority of embryo loss during the first weeks of development. Understanding factors that affect bovine embryo development offers a model to study mechanistic pathways that can be translated in other mammals, while improving cattle fertility.  My primary research program combines the basic understanding of embryo development to the focus on the effects of environmental stressors, especially Endocrine Disrupting Compounds (EDCs), on early embryonic loss, with the long-term goal of limiting embryo loss during the first week of development, therefore increasing the chances of producing healthy bovine embryos and improving reproductive biotechnologies in farm animals. This project focuses on the effect of specific EDCs, with the short-term goals of investigating the effects and mechanism of action of Bisphenol A (BPA) and Bisphenol S (BPS), on bovine early embryo development. EDCs are environmental stressors with estrogen-like potential that impact fertility, with BPA being one of the highest volume chemicals produced worldwide. We have shown that bovine oocytes exposure to BPA resulted in spindle abnormalities, reduced meiosis progression, decreased blastocyst development, increased apoptosis and changes in genes and proteins. Concerns over BPA effects led to the use of its analog BPS, that however also has negative effects on oocyte maturation. Both BPA and BPS induce spindle abnormalities and chromosome misalignment in bovine at concentrations significantly lower than the ones observed in humans, suggesting the bovine reproductive system is even more susceptible to bisphenols. These data support our rationale that bisphenols, especially BPA, affect cattle reproductive capability. Therefore, we hypothesize that BPA and BPS contribute to the decrease in cattle reproductive efficiency. Objective 1: Investigate BPA and BPS mechanisms of action during oocyte maturation and early embryo development Objective 2: Investigate the role of BPA and BPS in inducing early embryonic arrest. Objective 3: Study the epigenetic changes caused by BPA and BPS during in vitro development. Objective 4: Identify the changes in the metabolomics profile due to BPA and BPS exposure during in vitro development. A better understanding of the link between EDCs exposure and reproductive decline in cattle is of growing scientific and economic importance. Our research program 1) can substantially contribute to assess whether BPS is a valid substitute for BPA and 2) can drive to implement changes in farm animal environment/feeding system to limit the exposure to bisphenols, and EDCs in general, to reduce their potential effects on cattle reproductive capability.