Jayadev Raju
Health Canada, Canada
Title: Toxicological and toxicogenomic responses in male and female F344 rats following 28-days repeated dose sub-acute dietary exposure to 2-monochloro-1,3-propanediol (2-MCPD)
Biography
Biography: Jayadev Raju
Abstract
Introduction: Monochloropropanediols (MCPDs) are a class of chemicals that are generated as a result of high temperature processing of vegetable oils and foods that contain such refined oils. The toxicology of 3-MCPD is well-understood and is classified as a ‘possible human carcinogen’ (IARC Group 2B); however, there is insufficient data to characterize the toxicity of 2-MCPD, a related compound.
Objective: This study was conducted to fill a regulatory data gap in identifying the mode of action of dietary 2-MCPD in tissues of F344 rats exposed for 28 days according to the Organization of Economic Cooperation and Development (OECD) test guideline-407 using both apical and toxicogenomic endpoints.
Methodology: Weanling male and female F344 rats (n=10 rats/group/sex) were fed ad libitum AIN-93G diets containing 2-MCPD to provide estimated daily doses of 25, 50, 100 or 200 mg/kg body weight (BW). Rats were killed 28 days (unless found moribund) after exposure and their tissues processed for endpoint analyses.
Findings: Within the first week of exposure, female rats in the 100 and 200 mg/kg BW dose groups of 2-MCPD became moribund and were euthanized. Male rats were spared from exposure to these high doses and these groups were excluded from the study. Non-cancerous lesions with minimal to moderate scores were observed specifically in the kidney and spleen (50 mg/kg BW in males), heart (50 mg/kg BW in females) and thyroid (25 and 50 mg/kg BW in males and 50 mg/kg BW in females). Weights of kidneys in both sexes were significantly higher in the 2-MCPD groups along with higher levels of creatine kinase and lower levels of blood urea nitrogen. Heart weights were significantly higher in the 50 mg/kg BW groups in both sexes. Additionally, we observed significantly lower ALT and AST in males at both 25 and 50 mg/kg BW 2-MCPD, together with lower levels of high-density lipoproteins and cholesterol at 50 mg/kg BW 2-MCPD in both sexes. Genomic data indicated that in treated kidneys, 2-MCPD significantly increased Hmox1 and Ptgs2 genes, both involved intrinsically in inflammation. Several pathways were targeted in the heart as a consequence of 2-MCPD exposure such as angiogenesis, metabolic regulation and cell migration. The liver tissue only showed limited changes in the battery of genes tested.
Conclusion: For 2-MCPD (a) at the lowest tested dose of 25 mg/kg BW, treatment-related changes were notable in the kidneys and thyroid, (b) sex-specific changes in certain biochemical and hematological parameters were apparent, (c) pathological changes were observed in the kidney, heart, and thyroid, and (d) a no-observed-effect level (NOEL) was not reached in this study. Genomic analysis of the three tissues identified differential expression of key genes in the kidney and heart of animals treated with 2-MCPD.
Significance: This detailed sub-acute dietary exposure study provides toxicology and toxicogenomic data to support the hazard characterization of food-borne 2-MCPD for regulatory purposes; however, the lack of a NOEL provides impetus to further study 2-MCPD exposure.
