基于胎儿睾酮生物学相关降低的剂量相加模型准确预测了大鼠邻苯二甲酸酯混合物对产后生殖道的改变。

Dose Addition Models Based on Biologically Relevant Reductions in Fetal Testosterone Accurately Predict Postnatal Reproductive Tract Alterations by a Phthalate Mixture in Rats.

作者信息

Howdeshell Kembra L, Rider Cynthia V, Wilson Vickie S, Furr Johnathan R, Lambright Christy R, Gray L Earl

机构信息

*Division of the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), PO Box 12233, Research Triangle Park (RTP), North Carolina 27709 and

*Division of the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), PO Box 12233, Research Triangle Park (RTP), North Carolina 27709 and.

出版信息

Toxicol Sci. 2015 Dec;148(2):488-502. doi: 10.1093/toxsci/kfv196. Epub 2015 Sep 8.

Abstract

Challenges in cumulative risk assessment of anti-androgenic phthalate mixtures include a lack of data on all the individual phthalates and difficulty determining the biological relevance of reduction in fetal testosterone (T) on postnatal development. The objectives of the current study were 2-fold: (1) to test whether a mixture model of dose addition based on the fetal T production data of individual phthalates would predict the effects of a 5 phthalate mixture on androgen-sensitive postnatal male reproductive tract development, and (2) to determine the biological relevance of the reductions in fetal T to induce abnormal postnatal reproductive tract development using data from the mixture study. We administered a dose range of the mixture (60, 40, 20, 10, and 5% of the top dose used in the previous fetal T production study consisting of 300 mg/kg per chemical of benzyl butyl (BBP), di(n)butyl (DBP), diethyl hexyl phthalate (DEHP), di-isobutyl phthalate (DiBP), and 100 mg dipentyl (DPP) phthalate/kg; the individual phthalates were present in equipotent doses based on their ability to reduce fetal T production) via gavage to Sprague Dawley rat dams on GD8-postnatal day 3. We compared observed mixture responses to predictions of dose addition based on the previously published potencies of the individual phthalates to reduce fetal T production relative to a reference chemical and published postnatal data for the reference chemical (called DAref). In addition, we predicted DA (called DAall) and response addition (RA) based on logistic regression analysis of all 5 individual phthalates when complete data were available. DA ref and DA all accurately predicted the observed mixture effect for 11 of 14 endpoints. Furthermore, reproductive tract malformations were seen in 17-100% of F1 males when fetal T production was reduced by about 25-72%, respectively.

摘要

抗雄激素邻苯二甲酸酯混合物累积风险评估面临的挑战包括缺乏所有单个邻苯二甲酸酯的数据,以及难以确定胎儿睾酮(T)降低对出生后发育的生物学相关性。本研究的目的有两个:(1)基于单个邻苯二甲酸酯的胎儿T生成数据,测试剂量相加的混合物模型是否能预测5种邻苯二甲酸酯混合物对雄激素敏感的出生后雄性生殖道发育的影响;(2)利用混合物研究的数据,确定胎儿T降低与诱导出生后生殖道发育异常之间的生物学相关性。我们通过灌胃给妊娠第8天至出生后第3天的斯普拉格-道利大鼠母鼠施用一系列剂量的混合物(占先前胎儿T生成研究中最高剂量的60%、40%、20%、10%和5%,该研究中每种化学物质的剂量为300 mg/kg,包括苄基丁基邻苯二甲酸酯(BBP)、二正丁基邻苯二甲酸酯(DBP)、邻苯二甲酸二(2-乙基己基)酯(DEHP)、邻苯二甲酸二异丁酯(DiBP),以及100 mg/kg的邻苯二甲酸二戊酯(DPP);基于它们降低胎儿T生成的能力,单个邻苯二甲酸酯以等效剂量存在)。我们将观察到的混合物反应与基于先前公布的单个邻苯二甲酸酯相对于参考化学物质降低胎儿T生成的效力以及参考化学物质的已公布出生后数据(称为DAref)的剂量相加预测进行了比较。此外,当完整数据可用时,我们基于对所有5种单个邻苯二甲酸酯的逻辑回归分析预测了剂量相加(称为DAall)和反应相加(RA)。DAref和DAall准确预测了14个终点中的11个观察到的混合物效应。此外,当胎儿T生成分别降低约25%-72%时,17%-100%的F1雄性出现了生殖道畸形。

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