〔Abstract〕 Objective To explore the effects of exposure to lipopolysaccharides in late pregnancy on age-related cognitive changes in offspring of mice, and to investigate whether there is a gender specific genetic effect. Methods Institute of cancer research(ICR)CD-1 mice during gestational days 15-17 were injected with lipopolysaccharide daily(LPS group, 50 μg/kg), or equal volume of normal saline(CON group). At the age of 2 months after their delivery, LPS treated offspring mice(F1-LPS, male and female) were randomly selected and hybridized with age-matched wild-type CD-1 mice. F1-LPS males and females with different littermates, and F1-CON males and females were hybridized to obtain F2 generations of different lineages. Similarly, F2-LPS mice were mated with wild-type mice to conceive the F3 generation. At the age of 3 and 18 months old, F1, F2, and F3 mice(n=8 in each group) were randomly selected to complete the Morris maze experiment in order to test their cognitive abilities. Results Compared with 3-month-old CON mice, 18-month-old CON mice showed poorer learning and memory abilities, especially in females. For F1 generation, the learning and memory abilities of the 3-month-old and 18-month-old F1-LPS mice were inferior to those of the same aged CON mice. For F2 generation, the 3-month-old F2-LPS-parental mice had poorer learning and memory compared to the same aged CON mice, while the F2-LPS-paternal mice only had poorer memory compared to the same aged CON group. The learning and memory abilities of 18-month-old F2-LPS paternal and F2-LPS-parental mice were inferior to those of the same aged CON mice. The learning and memory abilities of F2-LPS maternal male mice were inferior to those of CON male mice, and the memory abilities of F2-LPS maternal mice were stronger than those of F2-LPS-parental mice. With regards to the F3 generation, the memory of the 3-month-old F3-LPS-parental mice was poorer than that of the same aged CON mice. The learning and memory abilities of F3-LPS paternal and F3-LPS-parental mice at 18 months old were inferior to those of CON mice of the same age. The 18-month-old F3-LPS maternal and paternal male mice had better memory than F3-LPS-parental male mice. Conclusion Exposure to lipopolysaccharides in late pregnancy can accelerate age-related cognitive decline in offspring mice, and it has a cross generational genetic effect and gender differences, mainly in paternal inheritance.