Department of Pharmacology & Therapeutics, McGill University, Montreal, QC H3G1Y6, Canada.
Department of Obstetrics & Gynecology, McGill University, Montreal, QC, H4A3J1, Canada.
Toxicol Sci. 2018 Jul 1;164(1):129-141. doi: 10.1093/toxsci/kfy072.
Di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, is a ubiquitous environmental contaminant and may act as an endocrine disruptor. Early life exposures to DEHP may result in anti-androgenic effects, impairing the development of the male reproductive tract. However, data on the long-lasting consequences of such DEHP exposures on adult male reproductive function are still rare and discrepant. Previously, we identified 2 novel plasticizers, 1,4-butanediol dibenzoate (BDB) and dioctyl succinate (DOS), as potential substitutes for DEHP that did not reproduce classically described endocrine disrupting phenotypes in prepubertal male offspring after maternal exposure. Here, we investigated the consequences of in utero and lactational exposure to BDB and DOS on adult male rat reproductive function in a comparative study with DEHP and a commercially available alternative plasticizer, 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH). Timed pregnant Sprague Dawley rats were gavaged with vehicle or a test chemical (30 or 300 mg/kg/day) from gestation day 8 to postnatal day 21. While DEHP exposure (300 mg/kg/day) significantly increased epididymal weight in the adult, exposure to DINCH, BDB, or DOS did not affect reproductive organ weights, steroid levels, or sperm quality. Using a toxicogenomic microarray approach, we found that adult testicular gene expression was affected by exposure to the higher dose of DEHP; transcripts such as Nr5a2, Ltf, or Runx2 were significantly downregulated, suggesting that DEHP was targeting estrogen signaling. Lesser effects were observed after treatment with either DINCH or BDB. DOS exposure did not produce such effects, confirming its potential as a responsible substitute for DEHP.
邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种广泛使用的增塑剂，也是一种普遍存在的环境污染物，可能具有内分泌干扰作用。生命早期接触 DEHP 可能导致抗雄激素作用，损害男性生殖管道的发育。然而，关于此类 DEHP 暴露对成年男性生殖功能的长期后果的数据仍然很少且存在差异。此前，我们发现了 2 种新型增塑剂，1,4-丁二醇二苯甲酸酯（BDB）和二辛基琥珀酸酯（DOS），它们可能是 DEHP 的替代品，在母体暴露后，不会在青春期前雄性后代中再现经典描述的内分泌干扰表型。在这里，我们在一项与 DEHP 和一种市售替代增塑剂 1,2-环己烷二羧酸二异壬酯（DINCH）的比较研究中，研究了宫内和哺乳期接触 BDB 和 DOS 对成年雄性大鼠生殖功能的影响。在妊娠第 8 天至产后第 21 天，给定时怀孕的 Sprague Dawley 大鼠灌胃给予载体或受试化学物质（30 或 300mg/kg/天）。虽然 DEHP 暴露（300mg/kg/天）显著增加了成年雄性大鼠附睾的重量，但暴露于 DINCH、BDB 或 DOS 并不影响生殖器官的重量、类固醇水平或精子质量。使用毒理基因组学微阵列方法，我们发现，雄性睾丸的基因表达在较高剂量的 DEHP 暴露后受到影响；Nr5a2、Ltf 或 Runx2 等转录物的表达显著下调，表明 DEHP 针对的是雌激素信号。用 DINCH 或 BDB 处理时，观察到的影响较小。DOS 暴露没有产生这种影响，证实了其作为 DEHP 负责任替代品的潜力。
