6-PPD Quinone Inhibits Phosphatidic Acid Synthesis Associated with an Increase in Intestinal Barrier Permeability in C. elegans

6-PPD quinine (6-PPDQ) affects intestinal barrier function; however, its underlying mechanisms remain largely unknown. In the current study, we examined the role of reduction in phosphatidic acid synthesis in mediating the toxicity of 6-PPDQ in affecting intestinal barrier function. In <i>Caenorhabditis elegans</i>, 6-PPDQ exposure reduced the phosphatidic acid content, which was accompanied by the decreased expression of <i>acl-5</i> and <i>acl-6</i> encoding glycerol-3-phosphate acyltransferase. The RNAi of <i>acl-5</i> and <i>acl-6</i> lowered the phosphatidic acid content, enhanced intestinal permeability, and resulted in the increased accumulation of 6-PPDQ. Meanwhile, <i>acl-5</i> and <i>acl-6</i> RNAi caused susceptibility to 6-PPDQ toxicity by upregulating the expressions of insulin ligands and receptor genes and downregulating the expressions of <i>daf-16</i> and its target genes. Moreover, the RNAi of <i>acl-5</i> and <i>acl-6</i> elevated the expression of <i>let-363</i>, and the RNAi of <i>let-363</i> could reduce the expressions of insulin ligand genes and confer resistance to 6-PPDQ toxicity. The double RNAi of <i>acl-5</i> and <i>acl-6</i> caused more severe enhanced intestinal permeability and 6-PPDQ toxicity. Therefore, 6-PPDQ exposure potentially disrupts phosphatidic acid synthesis to affect intestinal barrier function by downregulating <i>acl-5</i> and <i>acl-6</i> expressions.