Mutation pattern of Cancer suppressor p53 gene in factory workers exposed to Polypropylene and impact on their reproductive hormones.

BACKGROUND: Polypropylene is a thermoplastic polymer playing the role of an endocrine disruptor that interferes with the union, emission, transport, or elimination of normal hormones. Epidemiological information indicated the relation of endocrine-disturbing chemicals with prostate cancer, testis tumor, and diminished fertility. p53 is a key tumor silencer gene. The present study aims to evaluate Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) levels and the risk of p53 mutations due to exposure to Polypropylene in non-tumorous adult male factory workers.

METHODS: A total of 150 (controls=35, workers=115) subjects were recruited. Groups were maintained according to the tenure of exposure G1 (1-5 years), G2 (6-10 years), G3 (11-15 years), and G4 (16-20 years). Concentrations of LH and FSH were determined through the Enzyme-Linked Immunosorbent Assay (ELISA). Genotyping analysis was performed by polymerase chain reaction (PCR) based gel electrophoresis followed by DNA sequencing. The structural and functional impact of the mutation on the p53 structure was evaluated using 50 ns MD simulations and protein-DNA docking.

RESULTS: Mean plasma LH levels were significantly decreased in G1 (p>0.05) as well as G2, G3, and G4 (p>0.001) group, similarly FSH levels were significant decrease in G1 (p>0.05), G2 (p>0.01), G3 (p>0.001) and G4 (P>0.001) as compared to control group. Sequencing results found three variants i.e. g.13450T>G, g.13430C>T, and g.13737G>A. One of them was predicted to be disease-causing others are polymorphisms. MD simulation of missense mutation R273H showed no structural impact on the protein structure in MD simulation but it resulted in weaker binding of p53 with the DNA that might lower the gene expression of cell cycle regulatory proteins.

CONCLUSION: These findings predict decreased fertility and risk of malignancies in the future. The spectrum of p53 mutations due to polypropylene exposure in the Pakistani population has not been investigated before. Further studies and meta-analyses are required to elucidate the role of different plasticizers in reproduction and cancer-causing risk factors in a larger population.