Project description:The current study investigates the direct effects of in utero vinclozolin exposure on the developing rat testis transcriptome. Vinclozolin is a commonly used fungicide in agriculture and is an endocrine disruptor with anti-androgenic activity. Previous studies have demonstrated that exposure to vinclozolin during embryonic gonadal sex determination induces epigenetic modifications of the germ line and transgenerational adult onset disease states that include spermatogenic cell defects, prostate disease, kidney disease, and tumor development. An investigation of the molecular actions of vinclozolin was initiated through an analysis of direct actions on the F1 generation embryonic testis development. Microarray analyses were performed to compare control and vinclozolin treated testis transcriptomes at embryonic day 13, 14 and 16. A total of 576 differentially expressed genes were identified and the major cellular functions and pathways associated with these altered transcripts were examined. The sets of regulated genes at the different development periods were found to be transiently altered and distinct. Interestingly, genes previously shown to be regulated during normal male sex determination were not altered by vinclozolin treatment. Categorization by major known functions of all 576 genes altered by in utero vinclozolin exposure demonstrates transcription, signaling, cytoskeletal and extra cellular matrix associated transcripts are highly represented. Specific cellular process and pathway analyses suggest the involvement of Wnt and calcium signaling, vascular development and epigenetic mechanisms as potential mediators of the direct F1 generation actions of vinclozolin. For Samples 1-12: We used microarrays to determine genes expressed differentially between control and in utero Vinclozolin treated E13, E14, and E16 rat testis. For Samples 13-16: We used microarrays to determine genes expressed differentially between control and in vitro Vinclozolin treated E13 cultured rat testis. For Samples 17-20: We used microarrays to determine genes expressed differentially between control and in vitro Flutamide treated rat E13 cultured testis.

Project description:The current study investigates the direct effects of in utero vinclozolin exposure on the developing rat testis transcriptome. Vinclozolin is a commonly used fungicide in agriculture and is an endocrine disruptor with anti-androgenic activity. Previous studies have demonstrated that exposure to vinclozolin during embryonic gonadal sex determination induces epigenetic modifications of the germ line and transgenerational adult onset disease states that include spermatogenic cell defects, prostate disease, kidney disease, and tumor development. An investigation of the molecular actions of vinclozolin was initiated through an analysis of direct actions on the F1 generation embryonic testis development. Microarray analyses were performed to compare control and vinclozolin treated testis transcriptomes at embryonic day 13, 14 and 16. A total of 576 differentially expressed genes were identified and the major cellular functions and pathways associated with these altered transcripts were examined. The sets of regulated genes at the different development periods were found to be transiently altered and distinct. Interestingly, genes previously shown to be regulated during normal male sex determination were not altered by vinclozolin treatment. Categorization by major known functions of all 576 genes altered by in utero vinclozolin exposure demonstrates transcription, signaling, cytoskeletal and extra cellular matrix associated transcripts are highly represented. Specific cellular process and pathway analyses suggest the involvement of Wnt and calcium signaling, vascular development and epigenetic mechanisms as potential mediators of the direct F1 generation actions of vinclozolin. For Samples 1-12: We used microarrays to determine genes expressed differentially between control and in utero Vinclozolin treated E13, E14, and E16 rat testis. For Samples 13-16: We used microarrays to determine genes expressed differentially between control and in vitro Vinclozolin treated E13 cultured rat testis. For Samples 17-20: We used microarrays to determine genes expressed differentially between control and in vitro Flutamide treated rat E13 cultured testis. For Samples 1-12: RNA samples from two control groups are compared to two Vinclozolin treated groups for each E13, E14, E16 testis. For Samples 13-16: RNA samples from two control groups of E13 cultured testis are compared to two Vinclosolin treated groups of E13 cultured testis. For Samples 17-20: RNA samples from two control groups of E13 cultured testis are compared to two Flutamide treated groups of E13 cultured testis.

Project description:Cyclooxygenase (COX) inhibition is of concern in fish because COX inhibitors (e.g., ibuprofen) are ubiquitous in aquatic systems/fish tissues, and can disrupt synthesis of prostaglandins that modulate a variety of essential biological functions including reproduction. Transcriptomic data and publicly available high throughput toxicity data were utilized to develop putative adverse outcome pathways (AOPs) for molecular initiating event (MIE) of COX inhibition. Effects of a waterborne exposure to indomethacin (IN; 100 Âµg/L), ibuprofen (IB; 200 Âµg/L) and celecoxib (CX; 20 Âµg/L) on liver metabolome and ovarian gene expression (using oligonucleotide microarrays) in sexually mature fathead minnows were examined. Metabolomic profiles of IN, IB and CX were not significantly different from control or one another. Exposure to IB and CX resulted in differential expression of comparable numbers of genes (IB = 433, CX= 545). In contrast, 2558 genes were differentially expressed in IN-treated fish. Functional analyses (canonical pathway and gene set enrichment) indicated extensive effects of IN on prostaglandin synthesis pathway, oocyte meiosis and several other processes consistent with physiological roles of prostaglandins. Transcriptomic data was congruent with apical endpoint data - IN reduced plasma prostaglandin F2 alpha concentrations, and ovarian COX activity, whereas IB and CX did not. Putative AOPs pathways for COX inhibition (MIE) leading to reproductive failure (adverse outcome) via reduction of: 1) ovulation, 2) reproductive behaviors mediated by exogenous and endogenous prostaglandins, and 3) oocyte maturation were developed. Adult fathead minnow were exposed to either 100 Âµg/L indomethacin, 200 Âµg/L ibuprofen, 20 Âµg/L celecoxib or UV-treated Lake Superior (control) water for 96 hours. After exposure, microarray analyses were conducted using the female gonads (n=7-8 per treatment) and metabolomic analyses were conducted using the livers of all the exposed fish.

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In utero exposure to therapeutic doses of acetaminophen and ibuprofen accelerates germ cell differentiation in the mouse embryonic testis

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