School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, The University of Arizona, Tucson, Arizona 85721, USA.
Environmental Health Sciences Transformative Research Undergraduate Experience Program, The University of Arizona, Tucson, Arizona 85721, USA.
Toxicol Sci. 2021 Aug 30;183(1):117-127. doi: 10.1093/toxsci/kfab085.
Humans are exposed to phthalates daily via items such as personal care products and medications. Reproductive toxicity has been documented in mice exposed to di-n-butyl phthalate (DBP); however, quantitative evidence of its metabolite, mono-n-butyl phthalate (MBP), reaching the mouse ovary and its effects on hepatic and ovarian biotransformation enzymes in treated mice is still lacking. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) was employed to quantify MBP levels in liver, serum, and ovary from mice treated with a single or repeated exposure to the parent compound, DBP. Adult CD-1 females were pipet fed once or for 10 days with vehicle (tocopherol-stripped corn oil) or DBP at 1, 10, and 1000 mg/kg/day. Tissues and serum were collected at 2, 6, 12, and 24 h after the single or final dose and subjected to LC-MS/MS. Ovaries and livers were processed for qPCR analysis of selected phthalate-associated biotransformation enzymes. Regardless of duration of exposure (single vs repeated), MBP was detected in the tissues of DBP-treated mice. In single dose mice, MBP levels peaked at ≤6 h and fell close to background levels by 24 h post-exposure. Following the last repeated dose, MBP levels peaked at ≤2 h and fell to background levels by 12 h. Hepatic and ovarian expression of Lpl, Aldh1a1, Adh1, Ugt1a6a, and Cyp1b1 were altered in DBP-treated mice in a time- and dose-specific manner. These findings confirm that MBP reaches the mouse liver and ovary after oral exposure to DBP and influences the expression of hepatic and ovarian phthalate-associated biotransformation enzymes.
人类每天通过个人护理产品和药物等物品接触邻苯二甲酸酯。已在接触邻苯二甲酸二丁酯(DBP)的小鼠中记录到生殖毒性;然而,其代谢物单丁基邻苯二甲酸酯(MBP)到达小鼠卵巢及其对处理后小鼠肝和卵巢生物转化酶的影响的定量证据仍然缺乏。采用液相色谱/串联质谱(LC-MS/MS)法测定单次或重复暴露于母体化合物 DBP 的小鼠肝脏、血清和卵巢中的 MBP 水平。成年 CD-1 雌性小鼠经吸管喂食,单次或连续 10 天给予载体(生育酚去油玉米油)或 DBP,剂量为 1、10 和 1000mg/kg/天。单次或最后一次给药后 2、6、12 和 24 小时采集组织和血清,并进行 LC-MS/MS 分析。对选定的与邻苯二甲酸酯相关的生物转化酶进行卵巢和肝脏 qPCR 分析。无论暴露时间(单次 vs 重复)如何,在 DBP 处理的小鼠的组织中都检测到 MBP。在单次剂量的小鼠中,MBP 水平在≤6 小时内达到峰值,在暴露后 24 小时内降至接近背景水平。在最后一次重复剂量后,MBP 水平在≤2 小时内达到峰值,并在 12 小时内降至背景水平。DBP 处理的小鼠的肝和卵巢中的 Lpl、Aldh1a1、Adh1、Ugt1a6a 和 Cyp1b1 的表达以时间和剂量特异性的方式发生改变。这些发现证实,MBP 经口服暴露于 DBP 后可到达小鼠肝脏和卵巢,并影响肝和卵巢与邻苯二甲酸酯相关的生物转化酶的表达。