301. Effect of exogenous transforming growth factor beta 1 on reproductive performance in male TGFβ1 null mice

The transforming growth factor beta 1 (TGFβ1) family are potent cytokines that regulate tissue development, inflammation and immunity. Our studies in null mutant mice implicate a key role for TGFβ1 in male reproductive function. The TGFβ1 null mutation results in profound infertility due to inability to copulate successfully associated with reduced testosterone synthesis, although penile erection and sperm production do occur. To investigate whether fertility status can be improved in TGFβ1 null mutant mice by exogenous cytokine replacement, we used Alzet mini-pumps implanted subcutaneously to deliver a constant supply of recombinant latent TGFβ1 to TGFβ–/– mice (n = 7, 2.1µg/day over 2 weeks). Control TGFβ–/– mice (n = 6) and +/+ mice (n = 10) received pumps containing BSA carrier only. Circulating levels of TGFß1 were increased in TGFβ–/– mice and reached levels comparable to those seen in fertile heterozygote littermates. Increased circulating testosterone was evident in a proportion of TGFβ–/– mice after exogenous TGFβ replacement compared with untreated control mice. However, serum testosterone content was widely variable within all groups, so statistical significance was not achieved. Videotaping of nocturnal mating behaviour while caging treated males with normal receptive female mice showed that unlike TGFβ+/+ mice, which successfully mounted and intromitted, untreated TGFβ–/– mice failed to engage in normal mating behaviour. TGFβ–/– mice treated with exogenous cytokine were occasionally seen to intromit but less frequently than TGFβ+/+ controls. Ejaculation did not occur in any of the TGFβ–/– mice regardless of TGFβ replacement, compared with TGFβ+/+ mice where 8/10 mice ejaculated during the 2 h observation period. The trend towards improvement in both testosterone levels and copulation activity of the TGFβ1 null mice treated with exogenous cytokine suggests that systemic TGFβ1 availability may influence reproductive performance in male mice. However, since fertility was not restored by cytokine replacement, locally produced TGFβ in the reproductive tract and/or hypothalamic pituitary axis are also implicated in regulating fertility.