Enhancement of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity by lipopolysaccharide in developing zebrafish lacking canonical pattern recognition pathways

Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, is known to be a major inducer of inflammatory responses through Toll-like receptor 4 (TLR4) in mammals. The potentiation of aryl hydrocarbon receptor (AHR)-mediated responses by LPS has been reported in mammalian systems. However, in contrast to mammals, the zebrafish TLR4 homolog does not recognize LPS. This study investigated the effects of LPS on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced pre-cardiac edema in zebrafish larvae. Waterborne LPS alone had no effect on edema; however, it induced edema in the presence of 0.1 ppb TCDD, a concentration ineffective in inducing edema alone. LPS did not affect the expression of type 2 AHR (AHR2) and cytochrome P450 1 A, regardless of the presence of TCDD. Edema induced by LPS and TCDD was reduced by a thromboxane receptor (TP) antagonist, a prostacyclin receptor agonist, an antioxidant, and an activator of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant responses. Furthermore, LPS enhanced TP-induced edema in a manner sensitive to antioxidants and Nrf2 inducers. These results suggest that LPS enhances TP receptor signaling through oxidative stress, leading to increased edema in developing zebrafish exposed to TCDD.