Curi Tatiana Zauer, Neubert da Silva Gabriela, Passoni Marcella Tapias, Lima Tolouei Sara Emilia, Meldola Heloísa, Romano Renata Marino, Grechi Nicole, Dalsenter Paulo Roberto, Martino-Andrade Anderson Joel
Reproductive Toxicology Laboratory, Department of Pharmacology, Federal University of Paraná (UFPR), Curitiba, PR 81531-980, Brazil.
Animal Endocrine and Reproductive Physiology Laboratory, Department of Physiology, Federal University of Paraná (UFPR), Curitiba, PR 81531-980, Brazil.
Toxicol Sci. 2019 Oct 1;171(2):347-358. doi: 10.1093/toxsci/kfz159.
A previous study has demonstrated exposure of Brazilian pregnant women to diisopentyl phthalate (DiPeP), which reduces fetal rat testosterone production in a dose-responsive manner. In this study, we examined gene expression of steroidogenic proteins in rat fetal testes and investigated the effects of in utero and lactational DiPeP exposure on male rat reproductive development and function. For the prenatal experiment, we orally exposed pregnant Wistar rats to DiPeP or di-n-butyl phthalate (reference phthalate) at 0, 125, 250, and 500 mg/kg/day from gestation day 14-18 and the fetal testis was evaluated for transcript expression of Star, Cyp11a1, Cyp17a1, Cyp19a1, Insl3, Ar, Esr1, Esr2, and Gper1 by real-time quantitative PCR (RT-qPCR). Diisopentyl phthalate lowered mRNA levels of key steroidogenic proteins, lending support to the previously reported reductions in fetal testosterone production. Diisopentyl phthalate also lowered fetal testis transcript levels of Insl3 and changed gene expression of some steroid hormones receptors. For the postnatal experiment, pregnant rats were exposed orally to vehicle (canola oil) and 4 DiPeP doses (1, 10, 100, and 300 mg/kg/day) between gestation day 10 and postnatal day 21. Diisopentyl phthalate induced a range of reproductive and antiandrogenic effects that are typical of the rat phthalate syndrome, including reduced anogenital distance at the highest dose, reduced weight of seminal vesicles at 10 mg/kg/day and above, and testicular morphological and functional changes. Signs of fetal toxicity were observed at the highest dose. Together, our results indicate that DiPeP, a compound relevant to the human exposure scenario, is one of the most active antiandrogenic phthalates.
先前的一项研究表明，巴西孕妇接触过邻苯二甲酸二异戊酯（DiPeP），该物质会以剂量反应方式降低胎鼠的睾酮生成。在本研究中，我们检测了大鼠胎儿睾丸中类固醇生成蛋白的基因表达，并研究了子宫内和哺乳期接触DiPeP对雄性大鼠生殖发育和功能的影响。对于产前实验，我们在妊娠第14至18天，将怀孕的Wistar大鼠分别以0、125、250和500mg/kg/天的剂量口服给予DiPeP或邻苯二甲酸二正丁酯（参考邻苯二甲酸酯），并通过实时定量PCR（RT-qPCR）评估胎儿睾丸中Star、Cyp11a1、Cyp17a1、Cyp19a1、Insl3、Ar、Esr1、Esr2和Gper1的转录表达。邻苯二甲酸二异戊酯降低了关键类固醇生成蛋白的mRNA水平，这支持了先前报道的胎儿睾酮生成减少的现象。邻苯二甲酸二异戊酯还降低了胎儿睾丸中Insl3的转录水平，并改变了一些类固醇激素受体的基因表达。对于产后实验，怀孕大鼠在妊娠第10天至出生后第21天期间，分别口服给予赋形剂（菜籽油）和4种DiPeP剂量（1、10、100和300mg/kg/天）。邻苯二甲酸二异戊酯诱导了一系列典型的大鼠邻苯二甲酸酯综合征的生殖和抗雄激素作用，包括最高剂量下肛门与生殖器距离缩短、10mg/kg/天及以上剂量时精囊重量减轻，以及睾丸形态和功能改变。在最高剂量下观察到了胎儿毒性迹象。总之，我们的结果表明，DiPeP这种与人类接触情况相关的化合物，是活性最强的抗雄激素邻苯二甲酸酯之一。
