Diabetes teratogenicity in mice is accompanied with distorted expression of TGF‐β2 in the uterus

Abstract

Early embryonic deaths as well as malformed newborns are among complications of the diabetic pregnancy. Cytokines and growth factors operating in the embryonic vicinity are found to be among factors that determine the sensitivity of embryos to external and internal detrimental stimuli, including diabetes. Transforming Growth Factor-β2 (TGF-β2) has been shown to be essential for embryonic development and survival. In the present work, we evaluated the pattern of TGF-β2 expression in the uterus of streptozotocin-induced diabetic mice, demonstrating a decreased reproductive performance and elevated percentage of litters with severely malformed fetuses. Since stimulation of the maternal immune system was found to increase the resistance of mouse embryos to the teratogenic effect of diabetes, the effect of immunopotentiation on the expression of the cytokine was also investigated. TGF-β2 expression was studied at the mRNA level by using the in situ hybridization technique and at the protein level by using the immunohistochemical analysis. A clear decrease in TGF-β2 mRNA expression in the uterus of diabetic mice was observed at examined time points: days 1, 5, and 9 of pregnancy. Also, an evident reduction in TGF-β2, the protein expression in the uterus of diabetic mice, was demonstrated at these time points. Maternal immunopotentiation that improved the reproductive performance of diabetic mice and reduced the number of the litters with malformed fetuses was also accompanied by a clear increase in the level of TGF-β2 mRNA expression in the pregnant uteri. The above results clearly demonstrate that the embryotoxic effect of diabetes is accompanied by an alteration of TGF-β2 ex- pression. Immunopotentiation that was shown to improve the reproductive performance of the diabetic mice was accompanied by a partial normalization of TGF-β2 expression in embryonic vicinity. Teratogenesis Carcinog. Mutagen. 22:59-71, 2002.

Diabetes teratogenicity is accompanied by alterations in macrophages and T cell subpopulations in the uterus and lymphoid organs

“…These results are in agreement with our previous data collected at the end of pregnancy, demonstrating a tendency for an increase in spleen cellularity as well as in the expression of Mac-1 and various T cell subsets markers in the spleen of diabetic mice following maternal immunopotentiation [16]. In addition, in accordance with this study, maternal immunopotentiation was shown by us previously to normalize the expression of TNF-a and TGF-h2 in the uteroplacental unit of diabetic [17,18] or cyclophosphamidetreated mice [23,24] as well as in the uterus of mice with pregnancy loss [25]. In addition, our results concur very well with the study by Punareewattana et al [26], suggesting that the reduction in diabetesinduced birth defects caused by maternal immunostimulation might be mediated by normalization of the altered gene expression by splenocytes associated with the disease.…”

“…The immunopotentiationassociated normalization of Mac-1 expression in the uterus in the later stages of pregnancy was also demonstrated in our previous study following immunopotentiation with CFA, which was accompanied by a decreased resorption rate in the resorption-prone CBA/JXDBA/2J mouse combination [10]. In addition, the present data concur with our previous studies, demonstrating an immunopotentiation-associated improvement in reproductive performance, which was accompanied by normalization of TNFa and TGF-h2 expression in various models of teratogenic activity [17,18,23,24] or pregnancy loss [25]. Altogether, our present data indicate a possible involvement of local maternal immune responses in diabetes teratogenic activity.…”

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

“…Torchinsky et al (1997) stimulated uterine immune cells in pregnant mice in an attempt to reduce fetal resorptions associated with diabetes, and made the unexpected observation of significantly reduced malformed fetuses. These authors later reported beneficial effects of maternal immune stimulation on uterine cytokines tumor necrosis factor-alpha (TNFa; Fein et al, 2001) and transforming growth factor-beta (TGFb; Fein et al, 2002) that show distorted expression in diabetic animals. In this regard, TGFb crosses the mouse placenta (Gato et al, 2002) and has widely demonstrated importance during fetal development, including in craniofacial formation .…”

Developmental exposure of mice to TCDD elicits a similar uterine phenotype in adult animals as observed in women with endometriosis

“…Nevertheless, successful pregnancy, which is reliant on progesterone in either species, is also known to be dependent upon appropriate expression of decidual TGF-β2 in mice [46][47][48]. Therefore, in the current study, we further explored whether the reduced PR expression observed in adult mice uteri subsequent to in vivo TCDD exposure impacted TGF-β2 expression in response to either estradiol alone or estradiol plus progesterone.…”