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Acrylamide (AA) has recently been recognized as an immediate hazardous chemical compound owing to its various toxicities and unavoidable contamination of certain daily foods prepared at a high temperature. AA in foods is thus a worldwide concern; however, its toxicity at the dietary relevant concentration has yet to be experimentally elucidated. To determine whether dietary AA intake causes adverse health effects, adult zebrafish were fed a diet containing AA at a relevant dose for one month. Although AA-fed zebrafish showed no superficial abnormalities, their spleen was severely swollen. Therefore, their spleen was analyzed histologically and pathologically and the changes in cytokine expression in their spleen were also examined. Based on our findings, the intake of AA-containing food caused splenic damages, including cyst formation, hemorrhage, and inflammation, which were accompanied by immune responses as indicated by the appearance of a melanomacrophage center, activation of macrophages, and upregulation of major inflammatory cytokines in the spleen. Collectively, for the first time, we provided experimental evidence of the splenic toxicity caused by dietary AA intake.

Müller glia, the principal glial cell type in the retina, have the potential to reenter the cell cycle after retinal injury. In mammals, proliferation of Müller glia is followed by gliosis, but not regeneration of neurons. Retinal injury is also accompanied by phagocytic removal of degenerated cells. We here investigated the possibility that proliferation and gliosis of Müller glia and phagocytosis of degenerated cells may be regulated by the same molecular pathways. After N-methyl-N–nitrosourea-induced retinal injury, degenerated photoreceptors were eliminated prior to the infiltration of microglia/macrophages into the outer nuclear layer, almost in parallel with cell cycle reentry of Müller glia. Inhibition of microglia/macrophage activation with minocycline did not affect the photoreceptor clearance. Accumulation of lysosomes and rhodopsin-positive photoreceptor debris within the cytoplasm of Müller glia indicated that Müller glia phagocytosed most photoreceptor debris. Pharmacological inhibition of phosphatidylserine and Rac1, key regulators of the phagocytic pathway, prevented cell cycle reentry, migration, upregulation of glial fibrillary acidic protein, and phagocytic activity of Müller glia. These data provide evidence that phosphatidylserine and Rac1 may contribute to the crosstalk between different signaling pathways activated in Müller glia after injury.

PURPOSE Muller glia, the principal glial cell type in the retina, have the potential to proliferate and regenerate neurons after retinal damage. However, unlike the situation in fish and birds, this capacity of Muller glia is extremely limited in mammals. To gain new insights into the mechanisms that hamper retinal regeneration in mammals, we examined the cell cycle progression and DNA damage response in Muller glia after retinal damage. METHODS Expression of cell cycle-related proteins and DNA damage response were analyzed in adult rat and mouse retinas after N-methyl-N-nitrosourea (MNU)- or N-methyl-D-aspartate (NMDA)-induced retinal damage. Zebrafish and postnatal rat retinas were also investigated for comparison. Analysis was conducted by using immunofluorescence, Western blotting, and quantitative real-time polymerase chain reaction. RESULTS In the rat retina, most Muller glia reentered the cell cycle after MNU-induced photoreceptor damage while no proliferative response was observed in the mouse model. Cell cycle reentry of rat Muller glia was accompanied by DNA damage response including the phosphorylation of the histone variant H2AX and upregulation of p53 and p21. The DNA damage response was also observed in rat Muller glia after NMDA-induced loss of inner retinal neurons, but not in zebrafish Muller glia or rat retinal progenitor cells. CONCLUSIONS Our findings suggest that the DNA damage response induced by unscheduled cell cycle reentry may be one of the mechanisms that limit the proliferative and regenerative capacity of Muller glia in the mammalian retina.