Abstract
BackgroundIntrauterine growth restriction (IUGR) is thought to lead to fetal programming that in turn contributes to developmental changes of many organs postnatally. There is evidence that IUGR is a risk factor for the development of metabolic and cardiovascular disease later in life. A higher incidence of breast cancer was also observed after IUGR. This could be due to changes in mammary gland developmental pathways. We sought to characterise IUGR-induced alterations of the complex pathways of mammary development at the level of the transcriptome in a rat model of IUGR, using pathways analysis bioinformatics.Methodology/Principal FindingsWe analysed the mammary glands of Wistar rats with IUGR induced by maternal low protein (LP) diet at the beginning (d21) and the end (d28) of pubertal ductal morphogenesis. Mammary glands of the LP group were smaller in size at d28, however did not show morphologic changes. We identified multiple differentially expressed genes in the mammary gland using Agilent SurePrint arrays at d21 and d28. In silico analysis was carried out using Ingenuity Pathways Analysis. In mammary gland tissue of LP rats at d21 of life a prominent upregulation of WT1 and CDKN1A (p21) expression was observed. Differentially regulated genes were associated with the extracellular regulated kinase (ERK)-1/-2 pathway. Western Blot analysis showed reduced levels of phosphorylated ERK-1/-2 in the mammary glands of the LP group at d21. To identify possible changes in circulating steroid levels, serum LC-Tandem mass-spectrometry was performed. LP rats showed higher serum progesterone levels and an increased corticosterone/dehydrocorticosterone-ratio at d28.Conclusions/SignificanceOur data obtained from gene array analysis support the hypothesis that IUGR influences pubertal development of the rat mammary gland. We identified prominent differential regulation of genes and pathways for factors regulating cell cycle and growth. Moreover, we detected new pathways which appear to be programmed by IUGR.
Highlights
Epidemiological studies showed that intrauterine growth restriction (IUGR) is a risk factor for the development of adult disease: An increased incidence of cardiovascular disease [1], insulin resistance, type-2 diabetes [2] and obesity [3] was detected in individuals after Intrauterine growth restriction (IUGR)
The main finding of our gene array analysis in developing mammary glands of IUGR rats is an altered expression of genes involved in cell cycle and growth
In silico pathway analysis ranked Wilms tumor 1 (WT1) among the top-induced genes in the IUGR group, which was confirmed by RT-PCR and immunohistochemistry
Summary
Epidemiological studies showed that intrauterine growth restriction (IUGR) is a risk factor for the development of adult disease: An increased incidence of cardiovascular disease [1], insulin resistance, type-2 diabetes [2] and obesity [3] was detected in individuals after IUGR.In humans, epidemiological data indicate a relation between birth weight and breast cancer risk [4,5,6]. Fernandez-Twinn et al [12] showed that female offspring which were kept on a low protein diet until puberty, have a significantly increased incidence of early-onset mammary adenocarcinomas following nitrosomethylurea (NMU) treatment. This finding supports the notion that fetal and possibly early postnatal environment plays an important role for the developmental initiation of mechanisms underlying the programming of adult disease [13,14]. Further investigations by Fernandez-Twinn et al [17] revealed that the in utero (LP diet) and postnatal environments (high calorie intake after puberty) act independently and additively to contribute to the increased breast cancer risk following intrauterine LP diet. We sought to characterise IUGR-induced alterations of the complex pathways of mammary development at the level of the transcriptome in a rat model of IUGR, using pathways analysis bioinformatics
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