Rubin Beverly S, Schaeberle Cheryl M, Soto Ana M
Department of Immunology, Tufts University School of Medicine, Boston, MA, United States.
Front Endocrinol (Lausanne). 2019 Feb 6;10:30. doi: 10.3389/fendo.2019.00030. eCollection 2019.
Since the inception of the term endocrine disruptor, the idea that the environment is an important determinant of phenotype has motivated researchers to explore the effect of low dose exposure to BPA during organogenesis. The syndrome observed was complex, affecting various endpoints such as reproduction and reproductive tissues, behavior, mammary gland development and carcinogenesis, glucose homeostasis, and obesity. This constellation of impacted endpoints suggests the possibility of complex interactions among the multiple effects of early BPA exposure. One key finding of our rodent studies was alterations of energy and amino-acid metabolism that were detected soon after birth and continued to be present at all time points examined through 6 months of age. The classical manifestations of obesity and associated elements of metabolic disease took a longer time to become apparent. Here we examine the validity of the often-mentioned lack of reproducibility of obesogenic effects of BPA, starting from the known environmental causes of variation, which are diverse and range from the theoretical like the individuation process and the non-monotonicity of the dose-response curve, to the very pragmatic like housing, feed, and time and route of exposure. We then explore environmental conditions that may hinder reproducibility and discuss the effect of confounding factors such as BPA-induced hyperactivity. In spite of all the potential sources of variation, we find that some obesogenic or metabolic effects of BPA are reproducibly observed when study conditions are analogous. We recommend that study authors describe details of their study conditions including the environment, husbandry, and feed. Finally, we show that when experimental conditions are strictly maintained, reproducibility, and stability of the obese phenotype is consistently observed.
自从“内分泌干扰物”这一术语出现以来，环境是表型的重要决定因素这一观点促使研究人员探索在器官发生过程中低剂量接触双酚A（BPA）的影响。观察到的综合征很复杂，影响多个终点，如生殖和生殖组织、行为、乳腺发育和致癌作用、葡萄糖稳态以及肥胖。这一系列受影响的终点表明，早期BPA暴露的多种效应之间可能存在复杂的相互作用。我们在啮齿动物研究中的一个关键发现是，在出生后不久就检测到能量和氨基酸代谢的改变，并且在6个月龄之前的所有检测时间点都持续存在。肥胖的经典表现和代谢疾病的相关因素需要更长时间才会显现出来。在这里，我们从已知的多种环境变异原因出发，研究常被提及的BPA致肥胖效应缺乏可重复性这一观点的正确性，这些原因从理论上的个体化过程和剂量反应曲线的非单调性，到非常实际的饲养环境、饲料以及暴露时间和途径等。然后，我们探讨可能阻碍可重复性的环境条件，并讨论诸如BPA诱导的多动等混杂因素的影响。尽管存在所有这些潜在的变异来源，但我们发现，当研究条件相似时，BPA的一些致肥胖或代谢效应是可以重复观察到的。我们建议研究作者描述其研究条件的详细信息，包括环境、饲养管理和饲料。最后，我们表明，当严格维持实验条件时，肥胖表型的可重复性和稳定性是一致可观察到的。
