Inverse association between plasma chlordecone concentrations and progression of alcoholic liver fibrosis: the role of liver metabolism

IF 5.3 2区 环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES
Moana Gelu-Simeon, Marie-Josée Lafrance, Leah Michineau, Eric Saillard, Jean Pierre Thomé, Claude Emond, Michel Samson, Luc Multigner
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Abstract

Chlordecone is a persistent organochlorinated insecticide, extensively used in the French West Indies and has been contaminating the population for more than thirty years. Its potentiation effect on hepatotoxic agents has been demonstrated in animal models. We investigated the relationship between environmental exposure to chlordecone and the progression of liver fibrosis. This study included 182 consecutive patients with chronic alcoholic hepatitis whose liver fibrosis was assessed using non-invasive methods. Measured plasma chlordecone concentrations at inclusion were used as surrogate of long-term exposure under steady-state conditions. As the pharmacokinetic processing of chlordecone is largely determined by the liver, we used a human physiologically based pharmacokinetic model to predict plausible changes in the steady-state blood chlordecone concentrations induced by liver fibrosis. With a median follow-up of 27.1 years after the onset of alcohol consumption, we found a significant decrease in the risk of advanced liver fibrosis with increasing plasma chlordecone concentration (adjusted hazard ratio = 0.56; 95% confidence interval: 0.34–0.95 for the highest vs. lowest tertile, p = 0.04). Changes induced by liver fibrosis influenced the pharmacokinetic processing of chlordecone, resulting in substantial modifications in its steady-state blood concentrations. According to this human model of coexposure to alcohol, reverse causality is the most plausible explanation of this inverse association between plasma chlordecone concentrations and progression of liver fibrosis. This study underlines the importance of considering the pharmacokinetic of environmental contaminants in epidemiological studies when biomarkers of exposure are used to investigate their own impact on the liver. ClinicalTrials.gov Identifier: NCT03373396.
血浆中十氯酮浓度与酒精性肝纤维化进展之间的反向关系:肝脏代谢的作用
十氯酮是一种持久性有机氯杀虫剂,在法属西印度群岛被广泛使用,三十多年来一直污染着当地居民。在动物模型中,十氯酮对肝毒性药物的增效作用已得到证实。我们研究了环境中接触十氯酮与肝纤维化进展之间的关系。这项研究共纳入了182名慢性酒精性肝炎患者,采用非侵入性方法对他们的肝纤维化程度进行了评估。纳入研究时测得的血浆十氯酮浓度被用作稳态条件下长期接触十氯酮的代用指标。由于十氯酮的药代动力学过程主要由肝脏决定,因此我们采用了基于人体生理的药代动力学模型来预测肝纤维化引起的稳态血中十氯酮浓度的合理变化。在对开始饮酒后27.1年的中位随访中,我们发现随着血浆十氯酮浓度的增加,晚期肝纤维化的风险显著降低(调整后的危险比=0.56;95%置信区间:最高与最低三等分位数为0.34-0.95,P=0.04)。肝纤维化引起的变化影响了十氯酮的药代动力学处理,导致其稳态血药浓度发生了重大变化。根据这一人类共同暴露于酒精的模型,反向因果关系是血浆中十氯酮浓度与肝纤维化进展之间存在反向联系的最合理解释。这项研究强调,在流行病学研究中,当使用生物标志物来研究环境污染物对肝脏的影响时,必须考虑到环境污染物的药代动力学。ClinicalTrials.gov Identifier:NCT03373396。
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来源期刊
Environmental Health
Environmental Health 环境科学-公共卫生、环境卫生与职业卫生
CiteScore
10.10
自引率
1.70%
发文量
115
审稿时长
3.0 months
期刊介绍: Environmental Health publishes manuscripts on all aspects of environmental and occupational medicine and related studies in toxicology and epidemiology. Environmental Health is aimed at scientists and practitioners in all areas of environmental science where human health and well-being are involved, either directly or indirectly. Environmental Health is a public health journal serving the public health community and scientists working on matters of public health interest and importance pertaining to the environment.
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