Methylmercury (MeHg) is a well-known environmental neurotoxicant affecting millions worldwide who consume contaminated fishes and other food commodities. Exposure to MeHg has been shown to associate positively with some chronic diseases including cardiovascular diseases, but the mechanism is poorly characterized. MeHg had been shown to affect prostaglandin (PG) regulations in in vitro studies, but neither in vivo nor human studies investigating the effects of MeHg on PG regulations has been reported. Thus, the current study aimed to investigate the association between MeHg exposure and serum PG concentrations in a cross-sectional study among human adults followed by a validation investigation on the cause-effect relationship using a rat model. First, a total of 121 women were recruited from two cities: Wanshan and Leishan in Guizhou, China. Statistical analysis of the human data showed a positive association between blood total mercury (THg) levels and serum concentrations of PGF2a, 15-deoxy-PGJ2, and PGE2 after adjusting for site effects. In the animal study, adult female Sprague-Dawley rats were dosed with 40 mu g MeHg/kg body weight/day for 12 weeks. Serum 15-deoxy-PGJ2 and 2,3d-6-keto-PGFla concentrations were found to increase significantly after 6 and 10 weeks of MeHg dosing, respectively, while serum PGF2a concentration increased significantly after 12 weeks of MeHg dosing. Combined results of our human and rat studies have shown that chronic MeHg exposure induced dysregulation of PG metabolism. As PGs are a set of mediators with very diverse functions, its abnormal production may serve as the missing mechanistic link between chronic MeHg exposure and various kinds of associated clinical conditions including neurodegeneration and cardiovascular diseases.