Department of Safety, Health and Environmental Engineering, National Kaohsiung University of Science and Technology, Kaohsiung 81157, Taiwan.
Department of Nursing, Chung-Jen College of Nursing, Health Sciences and Management, Chiayi 62241, Taiwan.
Int J Mol Sci. 2021 Apr 16;22(8):4131. doi: 10.3390/ijms22084131.
Di(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in the manufacture of polyvinylchloride plastics and has been associated with concerns regarding male reproductive toxicity. In this study, we hypothesized that maternal exposure to DEHP induces transgenerational inheritance of adult-onset adverse reproductive outcomes through the male germline in the F1, F2, and F3 generations of male offspring. Pregnant rats were treated with 5 or 500 mg of DEHP/kg/day through gavage from gestation day 0 to birth. The offspring body weight, anogenital distance (AGD), anogenital index (AGI), sperm count, motility, and DNA fragmentation index (DFI) were measured for all generations. Methyl-CpG binding domain sequencing was performed to analyze sperm DNA methylation status in the F3. DEHP exposure at 500 mg/kg affected AGD, AGI, sperm count, mean DFI, and %DFI in the F1; AGD, sperm count, and mean DFI in the F2; and AGD, AGI, mean DFI, and %DFI in the F3. DEHP exposure at 5 mg/kg affected AGD, AGI, sperm count, and %DFI in the F1; sperm count in the F2; and AGD and AGI in F3. Compared with the control group, 15 and 45 differentially hypermethylated genes were identified in the groups administered 5 mg/kg and 500 mg/kg DEHP, respectively. Moreover, 130 and 6 differentially hypomethylated genes were observed in the groups administered 5 mg/kg and 500 mg/kg DEHP. Overall, these results demonstrated that prenatal exposure to DEHP caused transgenerational epigenetic effects, which may explain the observed phenotypic changes in the male reproductive system.
邻苯二甲酸二（2-乙基己基）酯（DEHP）广泛用作聚氯乙烯塑料的增塑剂，与男性生殖毒性有关。在这项研究中，我们假设母体暴露于 DEHP 通过雄性生殖细胞在 F1、F2 和 F3 代雄性后代中诱导成年后不良生殖结局的跨代遗传。妊娠大鼠从妊娠第 0 天到出生时通过灌胃给予 5 或 500mg/kg/天的 DEHP。测量所有世代的后代体重、肛门生殖器距离（AGD）、肛门生殖器指数（AGI）、精子计数、活力和 DNA 碎片化指数（DFI）。进行甲基-CpG 结合域测序以分析 F3 代精子 DNA 甲基化状态。500mg/kg 的 DEHP 暴露影响 F1 的 AGD、AGI、精子计数、平均 DFI 和%DFI；F2 的 AGD、精子计数和平均 DFI；F3 的 AGD、AGI、平均 DFI 和%DFI。5mg/kg 的 DEHP 暴露影响 F1 的 AGD、AGI、精子计数和%DFI；F2 的精子计数；以及 F3 的 AGD 和 AGI。与对照组相比，分别给予 5mg/kg 和 500mg/kg DEHP 的组中鉴定出 15 个和 45 个差异超甲基化基因。此外，在给予 5mg/kg 和 500mg/kg DEHP 的组中观察到 130 个和 6 个差异低甲基化基因。总的来说，这些结果表明产前暴露于 DEHP 导致了跨代表观遗传效应，这可能解释了雄性生殖系统中观察到的表型变化。
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