Short- and long-term effects of perinatal phthalate exposures on metabolic pathways in the mouse liver.

IF 4.8 Q1 GENETICS & HEREDITY Environmental Epigenetics Pub Date : 2020-12-23 eCollection Date: 2020-01-01 DOI:10.1093/eep/dvaa017
Kari Neier, Luke Montrose, Kathleen Chen, Maureen A Malloy, Tamara R Jones, Laurie K Svoboda, Craig Harris, Peter X K Song, Subramaniam Pennathur, Maureen A Sartor, Dana C Dolinoy
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引用次数: 10

Abstract

Phthalates have been demonstrated to interfere with metabolism, presumably by interacting with peroxisome proliferator-activated receptors (PPARs). However, mechanisms linking developmental phthalate exposures to long-term metabolic effects have not yet been elucidated. We investigated the hypothesis that developmental phthalate exposure has long-lasting impacts on PPAR target gene expression and DNA methylation to influence hepatic metabolic profiles across the life course. We utilized an established longitudinal mouse model of perinatal exposures to diethylhexyl phthalate and diisononyl phthalate, and a mixture of diethylhexyl phthalate+diisononyl phthalate. Exposure was through the diet and spanned from 2 weeks before mating until weaning at postnatal day 21 (PND21). Liver tissue was analyzed from the offspring of exposed and control mice at PND21 and in another cohort of exposed and control mice at 10 months of age. RNA-seq and pathway enrichment analyses indicated that acetyl-CoA metabolic processes were altered in diisononyl phthalate-exposed female livers at both PND21 and 10 months (FDR = 0.0018). Within the pathway, all 13 significant genes were potential PPAR target genes. Promoter DNA methylation was altered at three candidate genes, but persistent effects were only observed for Fasn. Targeted metabolomics indicated that phthalate-exposed females had decreased acetyl-CoA at PND21 and increased acetyl-CoA and acylcarnitines at 10 months. Together, our data suggested that perinatal phthalate exposures were associated with short- and long-term activation of PPAR target genes, which manifested as increased fatty acid production in early postnatal life and increased fatty acid oxidation in adulthood. This presents a novel molecular pathway linking developmental phthalate exposures and metabolic health outcomes.

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围产期邻苯二甲酸盐暴露对小鼠肝脏代谢途径的短期和长期影响。
邻苯二甲酸酯已被证明干扰代谢,可能是通过与过氧化物酶体增殖激活受体(ppar)相互作用。然而,将发育中邻苯二甲酸盐暴露与长期代谢影响联系起来的机制尚未阐明。我们研究了一种假设,即发育期邻苯二甲酸盐暴露对PPAR靶基因表达和DNA甲基化具有长期影响,从而影响整个生命过程中的肝脏代谢谱。我们利用建立的纵向小鼠模型,围产期暴露于邻苯二甲酸二乙基己酯和邻苯二甲酸二异壬酯,以及邻苯二甲酸二乙基己酯+邻苯二甲酸二异壬酯的混合物。暴露时间为交配前2周至出生后第21天断奶(PND21)。研究人员分析了PND21时暴露小鼠和对照小鼠的后代以及另一组10月龄暴露小鼠和对照小鼠的肝脏组织。RNA-seq和途径富集分析表明,暴露于邻苯二甲酸二异戊二酯的女性肝脏在PND21和10个月时乙酰辅酶a代谢过程发生了改变(FDR = 0.0018)。在该通路中,13个重要基因均为潜在的PPAR靶基因。三个候选基因的启动子DNA甲基化发生了改变,但只在Fasn上观察到持续的影响。目标代谢组学表明,暴露于邻苯二甲酸盐的雌性在PND21时乙酰辅酶a降低,在10个月时乙酰辅酶a和酰基肉碱增加。总之,我们的数据表明围产期邻苯二甲酸盐暴露与PPAR靶基因的短期和长期激活有关,表现为出生后早期脂肪酸生成增加,成年后脂肪酸氧化增加。这提出了一个新的分子途径连接发育邻苯二甲酸盐暴露和代谢健康结果。
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来源期刊
Environmental Epigenetics
Environmental Epigenetics GENETICS & HEREDITY-
CiteScore
6.50
自引率
5.30%
发文量
0
审稿时长
17 weeks
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