Oncotoxicological programming by the maternal exposure to the mixture of different phthalates: integration of the miRNAs and mRNAs expression profile for the reconstruction of gene regulation networks associated with oncogenesis

• Grant number: 17/22275-2
• Support Opportunities: Scholarships abroad - Research
• Effective date (Start): July 16, 2018
• Effective date (End): December 15, 2018
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Wellerson Rodrigo Scarano
• Grantee: Wellerson Rodrigo Scarano
• Host Investigator: Bernardo Lemos Ferreira da Silva
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Research place: Harvard University, Cambridge, United States

Abstract

The incidence of chronic diseases such as diabetes and obesity, as well as genetic diseases such as cancer, has increased in recent decades due to several socioeconomic and environmental factors that seem to interfere in the development, incidence and prognosis of these diseases. Regarding cancer, the temporal factor distances up to 50-60 years the stages of initiation and tumor progression, and thus the manifestation of cancer can occur many years after contact with a possible etiological factor. Thus, environmental factors that interfere with intrauterine development and promote transient or permanent morphofunctional, genetic and epigenetic changes, including those that can be transmitted to the offspring, constitute an area of extreme scientific interest. The literature has shown that some toxic substances have the capacity to increase susceptibility to cancer, creating a scientific perspective of great interest to our group. Phthalates represent a group of substances used in industry and are found in different concentrations in the urine and plasma of humans. Thus, the objective of this study will be to investigate whether gestational and lactational exposure to a mixture of different phthalates is capable of altering the expression of mRNAs and miRNAs in the F1 and F2 generations, and also to verify if these alterations are related to targets involved in prostate oncogenesis, as well as, try to correlate these changes with changes observed in prostate tumors of rodents and humans through analysis of molecular data deposited on platforms, such as the TCGA (The Cancer Genome Atlas -Cancer Genome). To reach this goal, Lewis pregnant females rats will be randomly divided into 4 experimental groups: control (vehicle); 20 µg/kg/day, 200 µg/kg/day, 200 µg/kg/day) and receive the respective doses of the gavage mixture in the following ratio: 19% DEHP (Bis (2-ethylhexyl) phthalate), 36% DEP (Diethylphthalate), 15% DBP (Di-n-butylphthalate), 10% DiBP (DiisobutylPhthalate), 8% BBzP (Butylbenzylphthalate), and 10% DiNP (Diisononylphthalate); they will be exposed from gestational day 10 (DG10) to postnatal day 21 (DPN21). The F1 generation males will be euthanized in DPN22 and DPN120. Some F1 males will be mated with non-exposed females and their offspring (F2) will be euthanized in the DPN22. The ventral prostate of the F1 generation animals (DPN22) will be collected for molecular analysis (transcriptome and miRNoma) by sequencing the latest generation (HigSeq-2000 Illumina); while for the DPN120 (F1) and DPN22 (F2) the targets predicted by the sequencing (F1-DPN22) will be evaluated by qRT-PCR. After the proposed analyzes, the data will be worked on, integrated and compared between the experimental groups, with positive samples for prostatic adenocarcinoma in rats (samples bank from our group) and with databases available in the literature, including human prostatic adenocarcinoma data. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SCARANO, WELLERSON R.; BEDRAT, AMINA; ALONSO-COSTA, LUIZ G.; AQUINO, ARIANA M.; FANTINATTI, BRUNO E. A.; JUSTULIN, LUIS A.; BARBISAN, LUIS F.; FREIRE, PAULA P.; FLAWS, JODI A.; LEMOS, BERNARDO. Exposure to an Environmentally Relevant Phthalate Mixture During Prostate Development Induces MicroRNA Upregulation and Transcriptome Modulation in Rats. TOXICOLOGICAL SCIENCES, v. 171, n. 1, p. 84-97, SEP 2019. (17/22275-2, 17/08306-2, 18/50002-3)