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Moreover, key genes (daf-2, age-1, and skn-1) in the insulin/IGF-like signaling (IIS) pathway actively responded to the nTiO2 exposure, which further optimized the selective expression of downstream genes, increased the antioxidant enzyme activities and antioxidant contents, and thereby increased the stress resistance and longevity of survived nematodes across successive generations. Our findings highlight the crucial role of bio-responses in the progressively decreased toxicity of nTiO2, and add new knowledge on the long-term impact of