Disruption in absorption and metabolism of folate mediates DNA damage activated germline apoptosis in 6-PPD quinone exposed Caenorhabditis elegans.

Exposure to 6-PPD quinone (6-PPDQ) causes both reproductive toxicity and metabolic disruption; however, metabolic basis of 6-PPDQ reproductive toxicity remains unclear. Folate absorption and metabolism are essential for cells by providing one-carbon units required for synthesis of nucleotides and reproduction. Here, we investigated whether disrupted folate absorption and metabolism contribute to 6-PPDQ-induced reproductive damage. In nematodes, 0.1-10 μg/L 6-PPDQ reduced folate and tetrahydrofolate (THF) contents and decreased expressions of folate transporter gene folt-1 and dihydrofolate reductase gene dhfr-1. RNAi of folt-1 and dhfr-1 aggravated 6-PPDQ-caused reduction in reproductive capacity, abnormal gonad development, induction of germline apoptosis, and activation of DNA damage checkpoints. Moreover, 6-PPDQ inhibited folate receptor gene folr-1 expression, and RNAi of folt-1 and dhfr-1 enhanced inhibition in folr-1 expression caused by 6-PPDQ exposure. RNAi of folr-1 exacerbated 6-PPDQ-caused reproductive decline, germline apoptosis, activation of DNA damage checkpoints, and altered germline nuclear hormone receptor (NHR) expressions, whereas folate supplementation alleviated these induced by 6-PPDQ exposure. Therefore, our results demonstrated the disruption in folate absorption and metabolism by 6-PPDQ at environmentally relevant concentrations, and this disruption mediated the 6-PPDQ-caused reproductive damage.