Neonatal immune challenges have a long-lasting influence on immune response. Using male Sprague-Dawley rats, we examined whether neonatal lipopolysaccharide (LPS) challenge alters the sensitivity of male reproductive function to adult LPS challenge and at which level (central or testes) the alteration occurs. We also examined the mRNA expression of proinflammatory cytokines in the hypothalamus and testes because they have a pivotal role in immune stress-induced suppression of gonadotropin secretion and testosterone synthesis. On day 10 after birth, all the pups were injected with LPS (100 microg/kg, i.p.) or saline. Thereafter, LPS (100 microg/kg, i.p.) or saline was injected in adulthood at 8 weeks of age. The serum LH concentration was decreased by LPS injection during adulthood in the neonatal saline-injected rats. This suppressive effect was not seen in the neonatal LPS-injected rats. The serum testosterone concentration was decreased by adult LPS injection in both the neonatal LPS-injected and neonatal saline-injected rats. The expression levels of KiSS-1, which encodes kisspeptin, known to have a crucial role in the regulation of gonadotropin secretion, and GnRH mRNA in the hypothalamus and LHbeta mRNA in the pituitary were not influenced by neonatal or adult LPS injection. On the other hand, the expression levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA in the hypothalamus and testes were increased by adult LPS injection in both the neonatal LPS-injected and neonatal saline-injected rats. Furthermore, the expression levels of these factors in the hypothalamus after adult LPS injection were significantly lower in the neonatal LPS-injected rats than in the neonatal saline-injected rats. These findings indicate that neonatal LPS challenge reduces the sensitivity of male reproductive function to the suppressive effects of LPS, mainly at the central level. Attenuation of proinflammatory cytokine synthesis in the hypothalamus might be involved in this alteration.