Lee Sunghoon, Martinez-Arguelles Daniel B, Campioli Enrico, Papadopoulos Vassilios
Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada
Departments of Biochemistry, McGill University, Montreal, Quebec, Canada.
Endocrinology. 2017 Feb 1;158(2):304-318. doi: 10.1210/en.2016-1604.
In utero exposure to endocrine disrupting chemicals (EDCs) may affect adult health. Di-(2-ethylhexyl) phthalate (DEHP) is an EDC widely used in the production of polyvinyl chloride products and an ubiquitous environmental contaminant. We used a rat model system to show that fetal exposure to DEHP decreased levels of major steroid hormones in adulthood and that environmentally-relevant levels of DEHP affected both gene expression and epigenomic loci that were affected by exposure to high levels. In the adrenal gland, we reported that the peroxisome proliferator-activated receptor (PPAR) and cholesterol biosynthesis pathways were sensitive targets of DEHP. We hypothesized that low levels of DEHP exposure insult the endocrine system (a "first hit") and increase its susceptibility to later exposure ("second hit") and subsequent disease. Here, we demonstrate that a second hit in the adult offspring exposed in utero to low levels of DEHP affected serum aldosterone levels. To unveil the first hit influence of early DEHP exposure, we treated in utero DEHP-exposed adult offspring with stressors that targeted the PPAR or cholesterol biosynthesis pathways. Treatment with the PPAR-gamma antagonist T0070907 reduced serum aldosterone compared to animals not exposed to DEHP in utero. Analysis of gene expression in animals that were subjected to both early and late exposure revealed deregulation of genes for the potassium channel Kcnk5 and the retinoid-X receptors (RXR) Rxra and Rxrb, indicating that these entities are linked to endocrine disruption. We propose that early exposure to environmental doses of DEHP predisposes the animal for disease later in life.
子宫内暴露于内分泌干扰化学物质（EDCs）可能会影响成年后的健康。邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种广泛用于生产聚氯乙烯产品的EDC，也是一种普遍存在的环境污染物。我们使用大鼠模型系统表明，胎儿期暴露于DEHP会降低成年期主要甾体激素的水平，并且与环境相关水平的DEHP会影响基因表达和表观基因组位点，而这些位点也会受到高水平暴露的影响。在肾上腺中，我们报道过过氧化物酶体增殖物激活受体（PPAR）和胆固醇生物合成途径是DEHP的敏感靶点。我们假设低水平的DEHP暴露会损害内分泌系统（“首次打击”），并增加其对后续暴露（“二次打击”）及随后疾病的易感性。在此，我们证明，子宫内暴露于低水平DEHP的成年后代受到二次打击会影响血清醛固酮水平。为了揭示早期DEHP暴露的首次打击影响，我们用针对PPAR或胆固醇生物合成途径的应激源处理子宫内暴露于DEHP的成年后代。与未在子宫内暴露于DEHP的动物相比，用PPAR-γ拮抗剂T0070907处理可降低血清醛固酮水平。对早期和晚期均暴露的动物进行基因表达分析发现，钾通道Kcnk5以及视黄酸X受体（RXR）Rxra和Rxrb的基因失调，这表明这些实体与内分泌干扰有关。我们提出，早期暴露于环境剂量的DEHP会使动物在生命后期易患疾病。
