Transgenerational epigenetic and transcriptomic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure in rat [array]

In rats, direct exposure to TCDD causes myriad toxicities. Exposed rats experience hepatotoxicity, wasting syndrome and immune suppression, amongst others. “Inherited exposure”, as occurs in the F3 generation of directly exposed F0 animals, has also been shown to cause toxicity: both male and female F3 rats demonstrate an increased incidence of adult onset disease, females also display reproductive abnormalities and increased incidence of ovarian diseases while males show increased incidence of kidney disease and an altered sperm epigenome. Here, we explore the hepatic transcriptomic profile of male and female F3 Sprague-Dawley rats bred through the paternal germ line from F0 dams exposed to a single dose of TCDD (0, 30, 100, 300 or 1000 ng/kg body weight) by oral gavage. We hypothesize that RNA transcripts with altered abundance in livers of unexposed F3 progeny of treated F0 Sprague-Dawley rats may result from epigenetic modifications to the genome. Female F3 rats demonstrated more TCDD-mediated hepatic transcriptomic changes than males, with differences primarily in the lowest dose group.针对大鼠的直接暴露实验表明，四氯二苯并二噁英（TCDD）可引发多种毒性反应。暴露大鼠会出现肝毒性、恶病质综合征以及免疫抑制等多种病症。直接暴露的F0代动物所繁育的F3代子代所呈现的“遗传性暴露”现象，同样被证实可诱发毒性：雌雄F3代大鼠均表现出成年发病疾病的发生率升高；其中雌性大鼠还出现生殖系统异常与卵巢疾病发生率上升，雄性大鼠则表现为肾脏疾病发生率升高以及精子表观基因组发生改变。本研究针对通过父系生殖系繁育的、亲代F0代母鼠经口灌胃给予单剂量四氯二苯并二噁英（TCDD，剂量分别为0、30、100、300或1000 ng/kg体重）的雌雄F3代斯普拉格-道利（Sprague-Dawley, SD）大鼠的肝脏转录组谱展开分析。本研究提出假说：经TCDD处理的F0代斯普拉格-道利大鼠的未暴露F3子代肝脏中，表达量异常的RNA转录本可能源于基因组的表观遗传修饰。相较于雄性F3代大鼠，雌性F3代大鼠呈现出更多由TCDD介导的肝脏转录组变化，且此类差异主要集中于最低剂量给药组。