Among the EPA metabolites, most difference in 12/15-hydroxyeicosapentaenoic acids (HEPE) levels was observed this explanation (Fig. 2). As for DHA, there was no metabolite showing a significant difference between fat-1 and wild type mice (Fig. 2). In contrast, AA metabolites in fat-1 mice were generally lower than those in the wild type mice (Fig. 2). Next, peritoneal exudates were collected from the endometriosis-present peritoneal cavity of fat-1 or wild type mice and were assessed for PUFA metabolite profiles. Again, there was no difference in the amounts of DHA metabolites between fat-1 and wild type mice (data not shown). The main products derived from EPA and AA in peritoneal cavity were shown in Fig. 3. Peritoneal fluids were abundant in 12/15-HEPE in EPA metabolites and 12/15-hydroxyeicosatetraenoic acids (HETE) in AA metabolites.

The amounts of 12/15-HEPE in fat-1 mice were significantly greater than that in wild type mice, as shown in endometriotic lesions (Fig. 3, center panel). Among AA metabolites, a significant difference in the amounts of 12/15-HETE between fat-1 and wild type mice was shown (Fig. 3, upper panel). These were the same findings as those shown in endometriotic lesions. Taken together, the increased amount of 12/15-HEPE was characterized markedly in both the endometriotic lesions and peritoneal cells of fat-1 mice. Figure 2 Lipid mediator analyses of endometriotic lesions: wild type vs. fat-1 mice. Figure 3 Lipid mediator analyses of peritoneal fluids: wild type vs. fat-1 mice.

Endometriosis in the 12/15-LOX-KO mice EPA-derived 12/15-HEPE was higher and AA-derived 12/15-HETE was lower in the endometriotic lesions of fat-1 mice than of those in wild type mice. Since both 12/15-HEPE and 12/15-HETE are converted by 12/15-LOX, 12/15-LOX-related mediators may play a role in protection against the development of peritoneal endometriotic lesions. Then 12/15-LOX-KO and wild type mice were administered EPA orally to address the effect of 12/15-LOX-related mediators on endometriotic lesions by comparing the number of the lesions with that of wild type mice. Endometriotic lesions were generated in wild type and 12/15-LOX-KO mice with or without EPA administration (n=4 in each group) (Fig. 4). EPA administration decreased significantly the number of endometriotic lesions in wild type mice. However, the suppressive effect by EPA administration on the development of endometriotic AV-951 lesions was cancelled in 12/15-LOX-KO mice. In 12/15-LOX-KO mice with or without EPA administration, the number of endometriotic lesions was the same level as that of wild type mice with no administration. Figure 4 Comparison of the number of endometriotic lesions between wild type and 12/15-LOX-KO mice with or without EPA administration.