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Hepatopancreas necrosis disease (HPND) is a disease and serious impacts on the industry of Chinese mitten crabs (Eriocheir sinensis) culture, however the actual cause of this disease is still not known. In the present study, to explore the pathogenic changes and risk factors caused by HPND, ultrathin sections of different tissues from the diseased crabs were observed with transmission electron microscope. The hepatopancreatic cells, spermatogonium, gill tissues and muscle cells of the diseased crabs showed severe structural and morphological changes. To further investigate whether HPND was caused by pathogenic microorganism, the healthy crabs were fed/injected with diseased tissues, the symptoms of HPND were not found, suggesting that HPND was not caused by virus or microsporidian infections. In addition, the toxic effect of avermectin and high pH water were also examined in this study. 40% (p<0.01) crabs with HPND symptoms were found after breeding crabs in water with 9.5 pH to 10 pH for 14 days, but the crabs with no HPND symptoms were found when they were raised in water with different concentrations of avermectin. The results indicated that HPND was not caused by virus or microsporidian and might be induced by water of high pH value or other environmental factors.