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Exposure to an environmentally relevant phthalate mixture during prostate development induces microRNA upregulation and transcriptome modulation in rats.

ABSTRACT: Environmental exposure to phthalates during intrauterine development might increase susceptibility to neoplasms in reproductive organs such as the prostate. Although studies have suggested an increase in prostatic lesions in adult animals submitted to perinatal exposure to phthalates, the molecular pathways underlying these alterations remain unclear. Genome-wide levels of mRNAs and miRNAs were monitored with RNA-seq to determine if perinatal exposure to a phthalate mixture in pregnant rats is capable of modifying gene expression expression during prostate development of the filial generation. The mixture contains diethyl-phthalate, di-(2-ethylhexyl)-phthalate, dibutyl-phthalate, di-isononyl-phthalate, di-isobutyl-phthalate, and benzylbutyl-phthalate. Pregnant females were divided into 4 groups and orally dosed daily from GD10 to PND21 with corn oil (Control:C) or the phthalate mixture at three doses (20??g/kg/d:T1; 200??g/kg/d:T2; 200?mg/kg/d:T3). The phthalate mixture decreased anogenital distance, prostate weight and decreased testosterone level at the lowest exposure dose at PND22. The mixture also increased inflammatory foci and focal hyperplasia incidence at PND120. miR-184 was upregulated in all treated groups in relation to control and miR-141-3p was only upregulated at the lowest dose. In addition, 120 genes were deregulated at the lowest dose with several of these genes related to developmental, differentiation and oncogenesis. The data indicate that phthalate exposure at lower doses can cause greater gene expression modulation as well as other downstream phenotypes than exposure at higher doses. A significant fraction of the downregulated genes were predicted to be targets of miR-141-3p and miR-184, both of which were induced at the lower exposure doses.

SUBMITTER: Scarano WR

PROVIDER: S-EPMC6736208 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Exposure to an Environmentally Relevant Phthalate Mixture During Prostate Development Induces MicroRNA Upregulation and Transcriptome Modulation in Rats.

Scarano Wellerson R WR Bedrat Amina A Alonso-Costa Luiz G LG Aquino Ariana M AM Fantinatti Bruno E A BEA Justulin Luis A LA Barbisan Luis F LF Freire Paula P PP Flaws Jodi A JA Lemos Bernardo B

Toxicological sciences : an official journal of the Society of Toxicology 20190901 1

Environmental exposure to phthalates during intrauterine development might increase susceptibility to neoplasms in reproductive organs such as the prostate. Although studies have suggested an increase in prostatic lesions in adult animals submitted to perinatal exposure to phthalates, the molecular pathways underlying these alterations remain unclear. Genome-wide levels of mRNAs and miRNAs were monitored with RNA-seq to determine if perinatal exposure to a phthalate mixture in pregnant rats is c ...[more]

PMID: 31199487

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Project description:BackgroundWe have previously shown that chronic exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate (DEHP) altered male sexual behavior and induced down-regulation of the androgen receptor (AR) in the neural circuitry controlling this behavior.ObjectivesThe cellular mechanisms induced by chronic exposure of adult male mice to low doses of DEHP alone or in an environmental phthalate mixture were studied.MethodsTwo-month-old C57BL/6J males were exposed orally for 8 wk to DEHP alone (0, 5, or 50μg/kg/d) or to DEHP (50μg/kg/d) in a phthalate mixture. Behavior, dendritic density per 50-μm length, pre-/postsynaptic markers, synapse ultrastructure, and bioenergetic activity were analyzed.ResultsMice exposed to DEHP either alone or in a phthalate mixture differed in mating, emission of ultrasonic vocalizations, and the ability to attract receptive females in urinary preference tests from control mice. Analyses in the medial preoptic area, the key hypothalamic region involved in male sexual behavior, showed lower dendritic spine density and protein levels of glutamate receptors and differences in other postsynaptic components and presynaptic markers between the treated groups. Ultrastructural observation of dendritic synapses by electron microscopy showed comparable morphology between the treated groups. Metabolic analyses highlighted differences in hypothalamic metabolites of males exposed to DEHP alone or in a phthalate mixture compared to control mice. These differences included lower tryptophan and higher NAD+ levels, respectively, a precursor and end product of the kynurenine pathway of tryptophan metabolism. The protein amounts of the xenobiotic aryl hydrocarbon receptor, one of the targets of this metabolic pathway and known negative regulator of the AR, were higher in the medial preoptic area of exposed male mice.DiscussionDifferences in behavior of male mice exposed to environmental doses of phthalates were associated with differences in neural structure and metabolism, with possibly a key role of the kynurenine pathway of tryptophan metabolism in the effects mediated by these substances. https://doi.org/10.1289/EHP11514.

Dataset Information

Exposure to an environmentally relevant phthalate mixture during prostate development induces microRNA upregulation and transcriptome modulation in rats.

Publications

Exposure to an Environmentally Relevant Phthalate Mixture During Prostate Development Induces MicroRNA Upregulation and Transcriptome Modulation in Rats.

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