Earl Gray L, Lambright Christy S, Evans Nicola, Ford Jermaine, Conley Justin M
Reproductive and Developmental Toxicology Branch, PHITD, CPHEA, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27703, United States.
Center for Computational Toxicology and Exposure, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27703, United States.
Curr Res Toxicol. 2024 Jun 11;7:100180. doi: 10.1016/j.crtox.2024.100180. eCollection 2024.
Administration of phthalates disrupts gene expression and hormone levels in the fetal rat testis, which are key events in an Adverse Outcome Pathway (AOP) for the Phthalate Syndrome. These measures can be used to predict the postnatal adverse effects of phthalate esters (PEs) on male rat sexual differentiation. Here, pregnant rats were exposed to dibutyl (DBP)- and diisononyl (DINP) phthalate on gestational days 14 to 18 individually and as a mixture (DBP,250 mg/kg/d; DINP, 750 mg/kg/d; and DBP 250 mg/kg/d plus DINP 750 mg/kg/d). We found that each PE reduced testosterone production (T Prod) and related gene transcripts by about 50 % and that they acted in a dose additive manner, reducing T Prod and gene expression by 75 % as a mixture. Based upon effects on T Prod, DINP was 0.33 times as potent as DBP and thus the DBP + DINP mixture was predicted to be equivalent to 500 mg DBP/kg/d. Logistic regression models of T Prod predicted that the adverse effects of the DBP + DINP mixture group versus the DBP and DINP individual treatments would reduce anogenital distance (AGD) by 27 % versus 10 %, increase hypospadias in 18 % versus < 1 %, induce epididymal agenesis in 46 % versus 10 %, and increase areolae/nipples in 4.8 % versus < 0.1 % of the, respectively. These predictions were highly consistent with effects from previously published dose response studies on the male reproductive effects of DBP. In summary, these results support the use of this New Approach Method to predict the detrimental effects of PEs and PE mixtures, replacing or reducing the need to run long-term, resource and animal use intensive extended one-generation reproduction studies for this class of chemicals.
邻苯二甲酸盐的施用会扰乱胎鼠睾丸中的基因表达和激素水平，而这是邻苯二甲酸盐综合征不良结局途径（AOP）中的关键事件。这些指标可用于预测邻苯二甲酸酯（PEs）对雄性大鼠性分化的产后不良影响。在此，将怀孕大鼠在妊娠第14至18天分别单独或混合暴露于二丁基（DBP）和二异壬基（DINP）邻苯二甲酸盐（DBP，250毫克/千克/天；DINP，750毫克/千克/天；以及DBP 250毫克/千克/天加DINP 750毫克/千克/天）。我们发现，每种PE均使睾酮生成（T Prod）和相关基因转录本减少约50%，且它们以剂量相加的方式起作用，混合时使T Prod和基因表达减少75%。基于对T Prod的影响，DINP的效力是DBP的0.33倍，因此预测DBP + DINP混合物相当于500毫克DBP/千克/天。T Prod的逻辑回归模型预测，DBP + DINP混合物组与DBP和DINP单独处理相比，肛门生殖器距离（AGD）减少的幅度分别为27%和10%，尿道下裂增加的比例分别为18%和<1%，附睾发育不全诱导率分别为46%和10%，乳晕/乳头增加的比例分别为4.8%和<0.1%。这些预测与先前发表的关于DBP对雄性生殖影响的剂量反应研究结果高度一致。总之，这些结果支持使用这种新方法来预测PEs及其混合物的有害影响，从而取代或减少对这类化学品进行长期、资源和动物使用密集型的一代繁殖研究的需求。
