Dioxin and t(14;18) translocations
Our Center for Global Health is conducting a NIOSH RO1 funded study to investigate the association between occupational exposure to dioxins and the frequency of the t(14;18) chromosomal translocation that is an early step in the carcinogenesis pathway for follicular lymphoma. Dr. Hryhorczuk leads a study team that includes collaborators from the UIC Colleges of Medicine and Public Health, the University of Milan, Griefswald University in Germany, the U.S. Centers for Disease Control and Prevention, and research institutes in Russia.
Dioxins are widespread environmental contaminants that exert a broad range of adverse health effects. In humans and other vertebrates dioxins have been shown be risk factors for cancer, immune deficiency; reproductive and developmental abnormalities; endocrine disruption, including diabetes and thyroid disorders, pulmonary disease; altered serum testosterone level; eyelid pathology, including meibomian gland hypersecretion and hyperpigmented conjunctivae; gum pigmentation; nausea, vomiting; loss of appetite; chloracne; hypertrichosis; liver damage; elevated serum cholesterol and triglycerides; and enamel hypomineralization of permanent first molars in children. An increased risk of mortality was associated with high levels of occupational exposure to dioxins with acute ischemic cardiovascular events.
Several epidemiologic studies have reported increased relative risks of NHL among individuals exposed to chlorophenols, phenoxy acids, and their dioxin contaminants in farmers, pesticide applicators, paper and pulp-mill workers, chemical workers, and in the Seveso cohort. Our collaborators from the University of Milan had previously observed an increase in the frequency of t(14;18) translocations with higher plasma TCDD levels in a small subgroup of the Seveso population. These findings showed for the first time in a human study that TCDD exposure is associated with clonal expansion of pre-cancer cells. The t(14;18) translocation is widely recognized as the hallmark genetic event in the development of follicular lymphoma. The t(14;18) translocation results from a reciprocal translocation that juxtaposes the BCL-2 (B- Cell Leukemia/Lymphoma 2) gene on chromosome 18q21 near the immunoglobulin heavy chain (IgH) locus at chromosome 14q32. In t(14;18), the anti-apoptotic BCL-2 gene comes under the control of the IgH gene promoter, causing overexpression of the BCL-2 protein. The major breakpoint region, which is involved in approximately 70% of observed translocations, is in the untranslated region 3’ of the last exon of the BCL-2 gene. BCL-2 protein is an inner mitochondrial membrane protein that extends the survival of certain cells by blocking programmed cell death. The overexpression of a structurally intact and functional BCL-2 anti- apoptotic protein leads to accumulation of inappropriately rescued long-lived B cells.
We recruited 323 former workers from a chemical plant in Russia who were engaged in the production of chlorophenols with known dioxin contamination and are comparing them to a control group of 150 individuals who were frequency-matched to the exposed on relevant demographic variables. We hypothesize the frequency of t(14;18) translocations in these individuals will increase with increasing dioxin levels.
We are also investigating gene expression in 83 candidate genes in a subset of these workers and controls to explore the molecular mechanisms of action of dioxin.