Abstract

Background:

Many pesticides can antagonize the androgen receptor (AR) or inhibit androgen synthesis in vitro but their potential to cause reproductive toxicity related to disruption of androgen action during fetal life is difficult to predict. Currently no approaches for using in vitro data to anticipate such in vivo effects exist. Prioritization schemes that limit unnecessary in vivo testing are urgently needed.

Objectives:

The aim was to develop a quantitative in vitro to in vivo extrapolation (QIVIVE) approach for predicting in vivo anti-androgenicity arising from gestational exposures and manifesting as a shortened anogenital distance (AGD) in male rats.

Methods:

We built a physiologically based pharmacokinetic (PBK) model to simulate concentrations of chemicals in the fetus resulting from maternal dosing. The predicted fetal levels were compared with analytically determined concentrations, and these were judged against in vitro active concentrations for AR antagonism and androgen synthesis suppression.

Results:

We first evaluated our model by using in vitro and in vivo anti-androgenic data for procymidone, vinclozolin, and linuron. Our PBK model described the measured fetal concentrations of parent compounds and metabolites quite accurately (within a factor of five). We applied the model to nine current-use pesticides, all with in vitro evidence for anti-androgenicity but missing in vivo data. Seven pesticides (fludioxonil, cyprodinil, dimethomorph, imazalil, quinoxyfen, fenhexamid, $o$-phenylphenol) were predicted to produce a shortened AGD in male pups, whereas two ($\mathrm{\lambda }\text{-cyhalothrin}$, pyrimethanil) were anticipated to be inactive. We tested these expectations for fludioxonil, cyprodinil, and dimethomorph and observed shortened AGD in male pups after gestational exposure. The measured fetal concentrations agreed well with PBK-modeled predictions.

Discussion:

Our QIVIVE model newly identified fludioxonil, cyprodinil, and dimethomorph as in vivo anti-androgens. With the examples investigated, our approach shows great promise for predicting in vivo anti-androgenicity (i.e., AGD shortening) for chemicals with in vitro activity and for minimizing unnecessary in vivo testing. https://doi.org/10.1289/EHP6774

中文翻译：

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体外定量外推法 (QIVIVE) 用于预测雄性生殖障碍啮齿动物模型中抗雄激素农药产生的肛门生殖器距离缩短

 抽象的

 背景：

许多农药可以在体外拮抗雄激素受体（AR）或抑制雄激素合成，但它们引起与胎儿期雄激素作用破坏相关的生殖毒性的可能性很难预测。目前尚不存在使用体外数据来预测此类体内效应的方法。迫切需要限制不必要的体内测试的优先计划。

 目标：

目的是开发一种定量的体外到体内外推（QIVIVE）方法，用于预测由妊娠暴露引起的体内抗雄激素作用，并表现为雄性大鼠肛门生殖器距离缩短（AGD）。

 方法：

我们建立了一个基于生理学的药代动力学 (PBK) 模型来模拟因母体给药而导致胎儿体内化学物质的浓度。将预测的胎儿水平与分析确定的浓度进行比较，并根据 AR 拮抗和雄激素合成抑制的体外活性浓度进行判断。

 结果：

我们首先评估了 $o$ 我们使用速克利、乙烯菌核利和利谷隆的体外和体内抗雄激素数据建立了模型。我们的 PBK 模型非常准确地描述了母体化合物和代谢物的胎儿浓度测量值（五分之一以内）。我们将该模型应用于九种当前使用的农药，所有农药都有抗雄激素的体外证据，但缺少体内数据。七种农药（咯菌腈、嘧菌环胺、烯酰吗啉、抑霉唑、喹氧芬、环菌胺、$\mathrm{<span\; data-immersive-translate-walked="9532953d-ffda-49d8-a6f8-b80056d190c5">哦</span>}$-苯基苯酚）预计会在雄性幼崽中产生缩短的 AGD，而两个（$\mathrm{<span\; data-immersive-translate-walked="9532953d-ffda-49d8-a6f8-b80056d190c5">\lambda </span>}\text{<span data-immersive-translate-walked="9532953d-ffda-49d8-a6f8-b80056d190c5">-氯氟氰菊酯</span>}$、嘧霉胺）预计没有活性。我们测试了咯菌腈、环丙环胺和烯酰吗啉的这些预期，并观察到妊娠暴露后雄性幼犬的 AGD 缩短。测量的胎儿浓度与 PBK 模型预测非常吻合。

 讨论：

我们的 QIVIVE 模型新鉴定了咯菌腈、环丙环胺和烯酰吗啉作为体内抗雄激素。通过研究的例子，我们的方法显示出预测具有体外活性的化学物质的体内抗雄激素性（即 AGD 缩短）和最大限度地减少不必要的体内测试的巨大前景。 https://doi.org/10.1289/EHP6774