Exogenous transforming growth factor beta1 replacement and fertility in male Tgfb1 null mutant mice

2009 ◽  
Vol 21 (4) ◽  
pp. 561 ◽  
Author(s):  
Leanne J. McGrath ◽  
Wendy V. Ingman ◽  
Rebecca L. Robker ◽  
Sarah A. Robertson

Analysis of Tgfb1 null mutant mice has demonstrated that the cytokine transforming growth factor β1 (TGFB1) has essential non-redundant roles in fertility. The present study attempted to alleviate the infertility phenotype of Tgfb1 null mutant male mice by administration of exogenous TGFB1, either orally by colostrum feeding or subcutaneously by delivery of recombinant human latent TGFB1 (rhLTGFB1) via osmotic mini-pumps. Bovine colostrum and fresh unpasteurised bovine milk were found to be rich sources of TGFB1 and TGFB2; however, feeding Tgfb1 null mutant mice colostrum for 2 days failed to raise serum levels of TGFB1. Administration of rhLTGFB1 (~150 μg in total) over 14 days to Tgfb1 null mutant mice resulted in detectable TGFB1 in serum; however, mean levels remained 10-fold less than in Tgfb1 heterozygous mice. After 7 days and 14 days of rhLTGFB1 administration, serum testosterone, spontaneous non-contact erections and mating behaviour were assessed. Despite the increased serum TGFB1, administration of rhLTGFB1 to Tgfb1 null mutant mice failed to improve these fertility parameters. It is concluded that sustained restoration of circulating latent TGFB1 to levels approaching the normal physiological range does not rescue the infertility phenotype caused by TGFB1 deficiency. Reproductive function in male Tgfb1 null mutant mice may not respond to systemic TGFB1 supplementation due to a requirement for local sources of TGFB1 at the site of action in the reproductive tract, or perturbed development during the neonatal period or puberty such that adult reproductive function is permanently impaired.

2005 ◽  
Vol 17 (9) ◽  
pp. 128
Author(s):  
L. J. McGrath ◽  
R. Robker ◽  
S. A. Robertson

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.


1996 ◽  
Vol 20 (5) ◽  
pp. 477-490 ◽  
Author(s):  
A. Olufemi Williams ◽  
Alan D. Knapton ◽  
Andrew Geiser ◽  
John J. Letterio ◽  
Anita B. Roberts

2009 ◽  
Vol 31 (2) ◽  
pp. 95-107 ◽  
Author(s):  
W. V. Ingman ◽  
L. M. Mcgrath ◽  
W. G. Breed ◽  
I. F. Musgrave ◽  
R. L. Robker ◽  
...  

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 835-845 ◽  
Author(s):  
Wendy V. Ingman ◽  
Rebecca L. Robker ◽  
Karen Woittiez ◽  
Sarah A. Robertson

TGFβ1 is implicated in regulation of ovarian function and the events of early pregnancy. We have investigated the effect of null mutation in the Tgfβ1 gene on reproductive function in female mice. The reproductive capacity of TGFβ1 null mutant females was severely impaired, leading to almost complete infertility. Onset of sexual maturity was delayed, after which ovarian function was disrupted, with extended ovarian cycles, irregular ovulation, and a 40% reduction in oocytes ovulated. Serum FSH and estrogen content were normal, but TGFβ1 null mutant mice failed to display the characteristic proestrus surge in circulating LH. Ovarian hyperstimulation with exogenous gonadotropins elicited normal ovulation rates in TGFβ1 null mutant mice. After mating with wild-type stud males, serum progesterone content was reduced by 75% associated with altered ovarian expression of mRNAs encoding steroidogenic enzymes 3β-hydroxysteroid dehydrogenase-1 and P450 17 α-hydroxylase/C17–20-lyase. Embryos recovered from TGFβ1 null mutant females were developmentally arrested in the morula stage and rarely progressed to blastocysts. Attempts to rescue embryos by exogenous progesterone administration and in vitro culture were unsuccessful, and in vitro fertilization and culture experiments demonstrated that impaired development is unlikely to result from lack of maternal tract TGFβ1. We conclude that embryo arrest is due to developmental incompetence in oocytes developed in a TGFβ1-deficient follicular environment. This study demonstrates that TGFβ1 is a critical determinant of normal ovarian function, operating through regulation of LH activity and generation of oocytes competent for embryonic development and successful initiation of pregnancy.


2002 ◽  
Vol 22 (14) ◽  
pp. 6041-6051 ◽  
Author(s):  
Ping Ye ◽  
Liqin Li ◽  
R. Gregg Richards ◽  
Richard P. DiAugustine ◽  
A. Joseph D'Ercole

1995 ◽  
Vol 33 (2) ◽  
pp. 233-244 ◽  
Author(s):  
Natalia N. Ninkina ◽  
Vladimir L. Buchman ◽  
Armen N. Akopian ◽  
Sally N. Lawson ◽  
Miyuki Yamamoto ◽  
...  

2001 ◽  
Vol 12 (6) ◽  
pp. 477-486 ◽  
Author(s):  
M.P. McDonald ◽  
K.M. Miller ◽  
C. Li ◽  
C. Deng ◽  
J.N. Crawley

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