Research Paper Volume 12, Issue 20 pp 19954—19978

Identification of potential molecular pathways involved in prostate carcinogenesis in offspring exposed to maternal malnutrition

Sérgio Alexandre Alcantara Santos1, *, , Ana Carolina Lima Camargo1, *, , Flávia Bessi Constantino1, , Ketlin Thassiani Colombelli1, , Luiz Marcos Frediani Portela1, , Matheus Naia Fioretto1, , José Cavalcante Souza Vieira2, , Pedro Magalhães Padilha2, , Mateus Betta de Oliveira1, , Sergio Luis Felisbino1, , Robson Francisco Carvalho1, , Luis Antonio Justulin1, ,

  • 1 Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu 18618-689, São Paulo, Brazil
  • 2 Department of Chemical and Biological Sciences, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu 18618-689, São Paulo, Brazil
* Equal contribution

Received: June 8, 2020       Accepted: September 5, 2020       Published: October 13, 2020
How to Cite

Copyright: © 2020 Santos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The developmental origins of health and disease concept links adult diseases with early-life exposure to inappropriate environmental conditions. Intrauterine and postnatal malnutrition may lead to an increased incidence of type 2 diabetes, obesity, and cardiovascular diseases. Maternal malnutrition (MM) has also been associated with prostate carcinogenesis. However, the molecular mechanisms associated with this condition remain poorly understood. Using a proteomic analysis, we demonstrated that MM changed the levels of proteins associated with growth factors, estrogen signaling, detoxification, and energy metabolism in the prostate of both young and old rats. These animals also showed increased levels of molecular markers of endoplasmic reticulum function and histones. We further performed an in silico analysis that identified commonly deregulated proteins in the ventral prostate of old rats submitted to MM with a mouse model and patients with prostate cancer. In conclusion, our results demonstrated that estrogenic signaling pathways, endoplasmic reticulum functions, energy metabolism, and molecular sensors of protein folding and Ca2+ homeostasis, besides histone, and RAS-GTPase family appear to be involved in this process. Knowledge of these factors may raise discussions regarding the role of maternal dietary intervention as a public policy for the lifelong prevention of chronic diseases.


CALR: Calreticulin; CR: Caloric restriction; CTR: Control group; DAB: 3,3′-Diaminobenzidine; DEP: Differentially expressed proteins; DOHaD: developmental origins of health and disease; EGF: Epidermal growth factor; EMT: Epithelial to mesenchymal transition; FGF: Fibroblast growth factor; FOAD: Fetal Origin of Adult Diseases; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase; GD: Gestational day; GEPIA: Gene Expression Profiling Interactive Analysis; GLLP: Gestational and lactational low protein group; GLOBOCAN: Global Cancer Statistics; GSTM2: Glutathione S-transferase Mu 2; GTEx: Genotype-Tissue Expression; GUSB: β-glucuronidase; H2AFJ: Histone H2A.J; HBA1: Hemoglobin Subunit Alpha 1; HE: Hematoxylin–eosin; HPA: Human Protein Atlas; HSPA5: Heat shock protein family A member 5; LPD: Low Protein Diet; MAPK: Mitogen-activated protein kinase; MM: Maternal malnutrition; P4HB: Protein disulfide isomerase-4; PBS: Phosphate-buffered saline; PCa: Prostate cancer; PDIA6: Protein Disulfide Isomerase Family A Member 6; PI3K: Phosphatidylinositol 3'-kinase; PIN: Intraepithelial neoplasia; PND: Post-natal day; PPI: Protein-Protein interaction; PRDX5: Peroxiredoxin-5; RAB: Ras-related protein; RAP1: Ras-proximate-1; RAS: Rat sarcoma; RIN: RNA integrity number; TCGA: The Cancer Genomic Atlas; TXN1: Thioredoxin 1; UniProt: Universal Protein Resource; VP: Ventral prostate.