Oncotoxicological programming by the material exposure to the mixture of different fatalatos: multigenerational effect on prostate of rats and gene and epigenetic aspects related to prostate adenocarcinoma

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. With regard to cancer, the temporal factor distances in 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, the interest in environmental factors that interfere with intrauterine development and promote transient or permanent morphofunctional, genetic and epigenetic changes, including those that can be transmitted to offspring, constitute an area called toxicological fetal programming. 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 that we call oncotoxicology. 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 different concentrations of a phthalates mixture is able of modifying rat prostate morphology, as well as altering the expression of mRNAs and miRNAs in the F1 and F2 generations, and to verify if these changes are related to changes observed in prostate tumors of rodents and humans through analysis of molecular data deposited in platforms such as the Cancer Genome Atlas (Cancer Genome). To reach this goal, male rats (Fischer 344) from the F1 generation of exposed mothers from gestational day 12 (DG12) to postnatal day 21 (DPN21) will be euthanized in PND22 and PND120. Male rats from F1 generation will be mated to non-exposed females and their offspring (F2) will be euthanized at DPN22 for the same analyzes. The exposed mothers will be randomly divided into 4 experimental groups: control (vehicle); 20 ¼g / kg / day, 200 ¼g / kg / day, 200 mg / kg / day) and receive the respective doses of the gavage mixture in the following ratio: 19% DEHP (Bis (2-ethylhexyl) phthalate), 36% DEP (Diethyl phthalate), 15% DBP (Di-n-butyl phthalate), 10% DiBP (Diisobutyl Phthalate), 8% BBzP (Butyl benzyl phthalate), and 10% DiNP (Diisononyl phthalate). The mixture was based on the composition of phthalates detected in urine samples from pregnant women in Illinois (USA).The ventral prostate (F1 and F2) will be collected for morphological and molecular analysis (transcriptome and miRNoma) by sequencing Generation (HigSeq-2000 Illumina). After the proposed analyzes, the data will be integrated and compared between the experimental groups and related with the data for prostatic adenocarcinoma in databases available in the literature and in fragments of adenocarcinoma from rats. (AU)