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A Combined Morphometric and Statistical Approach to Assess Nonmonotonicity in the Developing Mammary Gland of Rats in the CLARITY-BPA Study.
Environmental Health Perspectives ( IF 10.4 ) Pub Date : 2020-05-20 , DOI: 10.1289/ehp6301
Maël Montévil 1 , Nicole Acevedo 1 , Cheryl M Schaeberle 1 , Manushree Bharadwaj 2 , Suzanne E Fenton 2 , Ana M Soto 1
Affiliation  

BACKGROUND The Consortium Linking Academic and Regulatory Insights on Bisphenol-A (CLARITY-BPA) is a rare collaboration of guideline-compliant (core) studies and academic hypothesis-based studies to assess the effects of bisphenol A (BPA). OBJECTIVES We aimed to a) determine whether BPA showed effects on the developing rat mammary gland using new quantitative and established semiquantitative methods in two laboratories, b) develop a software tool for automatic evaluation of quantifiable aspects of the mammary ductal tree, and c) compare those methods. METHODS Sprague-Dawley rats were exposed to BPA, vehicle, or positive control [ethinyl estradiol (EE2)] by oral gavage beginning on gestational day (GD)6 and continuing with direct dosing of the pups after birth. There were two studies: subchronic and chronic. The latter used two exposure regimes, one stopping at postnatal day (PND)21 (stop-dose) the other continuing until tissue harvest (continuous). Glands were harvested at multiple time points; whole mounts and histological specimens were analyzed blinded to treatment. RESULTS The subchronic study's semiquantitative analysis revealed no significant differences between control and BPA dose groups at PND21, whereas at PND90 there were significant differences between control and the lowest BPA dose and between control and the lowest EE2 dose in animals in estrus. Quantitative, automatized analysis of the chronic PND21 specimens displayed nonmonotonic BPA effects, with a breaking point between the 25 and 250μg/kg body weight (BW) per day doses. This breaking point was confirmed by a global statistical analysis of chronic study animals at PND90 and 6 months analyzed by the quantitative method. The BPA response was different from the EE2 effect for many features. CONCLUSIONS Both the semiquantitative and the quantitative methods revealed nonmonotonic effects of BPA. The quantitative unsupervised analysis used 91 measurements and produced the most striking nonmonotonic dose-response curves. At all time points, lower doses resulted in larger effects, consistent with the core study, which revealed a significant increase of mammary adenocarcinoma incidence in the stop-dose animals at the lowest BPA dose tested. https://doi.org/10.1289/EHP6301.

中文翻译:

在 CLARITY-BPA 研究中评估发育中大鼠乳腺的非单调性的组合形态测量和统计方法。

背景 将双酚 A 的学术和监管见解联系起来的联盟 (CLARITY-BPA) 是一项罕见的符合指南(核心)研究和基于学术假设的研究的合作,旨在评估双酚 A (BPA) 的影响。目标 我们的目标是 a) 在两个实验室中使用新的定量和已建立的半定量方法确定 BPA 是否对发育中的大鼠乳腺有影响,b) 开发一种用于自动评估乳腺导管树可量化方面的软件工具,以及 c) 比较那些方法。方法 Sprague-Dawley 大鼠从妊娠日 (GD)6 开始通过口服管饲法将 Sprague-Dawley 大鼠暴露于 BPA、载体或阳性对照 [乙炔雌二醇 (EE2)],并在幼崽出生后继续直接给药。有两项研究:亚慢性和慢性。后者使用了两种曝光方案,一个在产后一天 (PND)21 停止(停止剂量),另一个持续到组织收获(连续)。在多个时间点收获腺体;在对治疗不知情的情况下分析整个坐骑和组织学标本。结果 亚慢性研究的半定量分析显示,在 PND21 时,对照组和 BPA 剂量组之间没有显着差异,而在 PND90 时,在发情期动物中,对照组和最低 BPA 剂量之间以及对照组和最低 EE2 剂量之间存在显着差异。对慢性 PND21 样本的定量、自动化分析显示出非单调的 BPA 效应,在每天 25 和 250μg/kg 体重 (BW) 之间具有断点。通过定量方法分析的 PND90 和 6 个月慢性研究动物的全球统计分析证实了这一突破点。BPA 响应与许多功能的 EE2 效果不同。结论 半定量和定量方法都揭示了 BPA 的非单调效应。定量无监督分析使用了 91 次测量并产生了最引人注目的非单调剂量反应曲线。在所有时间点,较低剂量会产生较大的影响,这与核心研究一致,该核心研究显示,在测试的最低 BPA 剂量下,停药动物的乳腺癌发病率显着增加。https://doi.org/10.1289/EHP6301。结论 半定量和定量方法都揭示了 BPA 的非单调效应。定量无监督分析使用了 91 次测量并产生了最引人注目的非单调剂量反应曲线。在所有时间点,较低剂量会产生较大的影响,这与核心研究一致,该核心研究显示,在测试的最低 BPA 剂量下,停药动物的乳腺癌发病率显着增加。https://doi.org/10.1289/EHP6301。结论 半定量和定量方法都揭示了 BPA 的非单调效应。定量无监督分析使用了 91 次测量并产生了最引人注目的非单调剂量反应曲线。在所有时间点,较低剂量会产生较大的影响,这与核心研究一致,该核心研究显示,在测试的最低 BPA 剂量下,停药动物的乳腺癌发病率显着增加。https://doi.org/10.1289/EHP6301。这表明在测试的最低 BPA 剂量下,停药动物的乳腺癌发病率显着增加。https://doi.org/10.1289/EHP6301。这表明在测试的最低 BPA 剂量下,停药动物的乳腺癌发病率显着增加。https://doi.org/10.1289/EHP6301。
更新日期:2020-05-20
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