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工作岗位。其成功的关键是有效地生产健康的牛胚胎。尽管生殖生物技术取得了惊人的进展，但牛的总体生育力低至35%，大部分胚胎在发育的最初几周内丢失。了解影响牛胚胎发育的因素为研究其他哺乳动物的机制途径提供了一个模型，同时提高了牛的生育能力。我的主要研究项目结合了对胚胎发育的基本理解，重点关注环境压力因素，特别是内分泌干扰化合物（EDCs）对早期胚胎丢失的影响，以及限制胚胎在发育第一周内丢失的长期目标，从而增加生产健康牛胚胎的机会，并改善农场动物的生殖生物技术。本项目主要研究特定EDCs对牛早期胚胎发育的影响，短期目标是研究双酚A （BPA）和双酚S （BPS）对牛早期胚胎发育的影响及其作用机制。EDCs是一种环境压力源，具有类似雌激素的潜在影响生育能力，BPA是世界上产量最高的化学品之一。我们已经证明，牛卵母细胞暴露于BPA会导致纺锤体异常、减数分裂进程减少、囊胚发育减少、细胞凋亡增加以及基因和蛋白质的变化。对双酚a影响的担忧导致使用其类似物BPS，但它也对卵母细胞成熟有负面影响。BPA和BPS在牛体内引起纺锤体异常和染色体畸变的浓度明显低于在人体内观察到的浓度，这表明牛的生殖系统更容易受到双酚类物质的影响。这些数据支持了我们的理论，即双酚类物质，尤其是双酚a，会影响牛的繁殖能力。因此，我们假设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在诱导早期胚胎骤停中的作用。目的3：研究BPA和BPS在体外发育过程中引起的表观遗传变化。目的4：确定体外发育过程中BPA和BPS暴露导致的代谢组学变化。更好地了解接触EDCs与牛的繁殖能力下降之间的联系，在科学和经济上具有越来越重要的意义。我们的研究项目1)可以为评估BPS是否是BPA的有效替代品做出实质性贡献；2)可以推动农场动物环境/喂养系统的变化，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.