title: Detection of expressional changes induced by intrauterine growth restriction in the developing rat mammary gland via exploratory pathways analysis.
abstract: BACKGROUND
  Intrauterine 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.
  
  
  RESULTS
  We 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
  Our 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.
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Lea
authors: L
authors: Beinder
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Nina
authors: N
authors: Faehrmann
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Rainer
authors: R
authors: Wachtveitl
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Ilona
authors: I
authors: Winterfeld
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Andrea
authors: A
authors: Hartner
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Carlos
authors: C
authors: Menendez-Castro
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Manfred
authors: M
authors: Rauh
authors: Department of Gynecology and Obstetrics, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Matthias
authors: M
authors: Ruebner
authors: Department of Gynecology and Obstetrics, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Hanna
authors: H
authors: Huebner
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Stephanie C
authors: SC
authors: Noegel
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Helmuth G
authors: HG
authors: Doerr
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Wolfgang
authors: W
authors: Rascher
authors: Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Fabian B
authors: FB
authors: Fahlbusch
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000378:metabolism*; D020869:Gene Expression Profiling; D007124:Immunoenzyme Techniques; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D038081:Organogenesis / Q000235:genetics*; D011247:Pregnancy; D039401:Prenatal Nutritional Physiological Phenomena; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger