Impact of chlordecone in active chronic hepatitis progression – HEPATOCHLOR

Infectious disease and environmental health have been intertwined in the studies of public health during long time, however since several decades of years the fields of environmental health and infectious disease have diverged in many countries where these fields are currently treated as distinct entities. So today, the field of research on how pathogens and toxic agents interact to increase risks and severity of diseases and dysfunctions is relatively poor while hundreds of millions people (> 1000 M) worldwide are developing a chronic disease of infectious origin, taking place over 20-30 years of life, and are co-exposed, during this time to environmental chemical agents. This is the case for the co-exposure of humans to viruses inducing hepatitis and pesticides used in agriculture as chlordecone. Indeed, chlordecone is a chlorinated pesticide (also called Kepone) used in the French West Indies on banana plantations. Its use, from 1973 to 1993, resulted in substantial and permanent pollution of soils and contamination of water, plants and foodstuffs. Consequently, human beings continued to be exposed to this chemical as evidenced by the presence of chlordecone in the blood of adult men and women, pregnant women and infants. One of the characteristics of chlordecone is to accumulate mainly in the liver. In addition, chlordecone although it is not an hepatoxic agent presents the remarkable property at non-toxic doses and on short periods of time (several days), to potentiate, up to 6700%, the deleterious action of hepatotoxic agents, as demonstrated in mice or rats. Moreover, it has been reported that chlordecone has immunoregulatory effects. Beside, in the French West Indies, the percentage of people infected by hepatitis B virus is at least three times higher in French West Indies than in Metropolitan France and still remains the first cause of hepatocellular carcinoma in this population.
Our project aimed to assess the impact of chlordecone exposure on the development of chronic active hepatitis and liver fibrosis. Our project includes a comprehensive epidemiological study (Task 2, Partner 2), an experimental study in mice (Task 3, Partner 1) and the development innovative methods to localise, characterize and quantify chlordecone but also to identify its protein partners in liver based on MALDI mass spectrometry imaging technologies (Task 4, Partner 3). Concerning the epidemiological study, the goal is to know whether co-exposition to chlordecone can favours evolution of chronic hepatitis to cirrhosis. It will be divided in two sub-tasks: a) comprehensive identification of prevalent cases of chronic active hepatitis in Guadeloupe due to hepatitis C or B or to alcohol. Among them, we will assess a group of patients without liver fibrosis and a group of patients with cirrhosis: b) comparison of chlordecone exposure between patient with and without hepatic fibrosis. Chlordecone exposure will be assessed by measuring blood chlordecone concentration. Concerning the experimental studies in mice, we will develop two types of mouse models of hepatic fibrosis: 1) due to repeated treatments of carbon tetrachloride, CCl4, and 2) due to excessive daily consumption of alcohol. All mice will be treated by the fibrosis-inducing agent, and co-exposed to the presence or absence of chlordecone. Quantitative analysis of liver fibrosis, partly by second harmonic generation technique, and of inflammatory cytokines will be undertaken. Finally, the liver of murine models (Chlordecone + hepatotoxic agents inducing liver fibrosis) will be used as template to develop an innovative method to localise at cellular level the chlordecone present in liver in MALDI mass spectrometry imaging.
Thus, this global project will allow a better understanding of the phenomena of liver fibrosis in kind of co-exposure with chlordecone plus hepatotoxic agents inducing chronic hepatitis.