A molecular and phenotypic integrative approach to identify a no effect dose level for anti-androgen induced testicular toxicity
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE28202 | GEO | 2011/03/29
SECONDARY ACCESSION(S): PRJNA139641
REPOSITORIES: GEO
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Project description:With the advent of high information content technologies, especially microarrays, it is pertinent to determine the impact of molecular data on the NOAELs. Consequently, we conducted an integrative study to identify a no transcriptomic effect dose using microarray analyses coupled with qPCR and determined how this correlated with the NOAEL. We assessed the testicular effects of the antiandrogen, flutamide (FM), in a rat 28-day toxicity study using doses of 0.2-30 mg/kg/day. Concerning molecular data, we observed differential gene expression starting from 1 mg/kg/day and a deregulation of more than 1500 genes at 30 mg/kg/day. Dose-related changes were identified for the major pathways associated with the testicular lesion (eg fatty acid metabolism), that were confirmed by qPCR. These data, along with standard measurements supported the no effect dose of 0.2 mg/kg/day. Flutamide was administered in suspension to rats (7 weeks old at start of treatment, 10 per group) by oral gavage at a daily dose of 0 (control), 0.2, 1, 6 and 30 mg/kg body weight, for 28 consecutive days. Dose-related changes in gene expression were determined in the testes using whole genome oligonucleotide microarrays.
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Project description:2-Isopropylthioxanthone (2-ITX), a photoinitiator used in ink for printing of food packaging materials, has been detected in products like milk and fruit beverages. Previous in vitro research demonstrated 2-ITX to 1) exert agonistic effects on the aryl hydrocarbon receptor (AhR), 2) exert antagonistic effects on both the androgen (AR) and estrogen receptor (ER), and 3) to increase aromatase activity. To validate these findings in vivo, male rats were treated by gavage with 50, 150 or 500 mg 2-ITX/kg b.w. per day from postnatal day 23 to 53. For comparison, other groups were treated with 50 ng TCDD/kg b.w./day (AhR agonist), 30 mg bicalutamide/kg b.w./day (Casodex, AR antagonist) or 50 mg flutamide/kg b.w./day (AhR agonist and AR antagonist). 2-ITX, from the lowest dose onwards, decreased the weight of the ventral prostate, and from the middle dose onwards the weight of the seminal vesicles and coagulating gland. The highest dose of 2-ITX reduced the number of spermatozoa in the cauda of the epididymis. Similar effects, but more severe, were induced by flutamide and bicalutamide. Epididymal weight, caput sperm count and preputial separation were negatively affected by Casodex and flutamide but not by 2-ITX. The two highest doses of 2-ITX as well as TCDD increased liver weight. Whole genome mRNA expression profiling of the liver revealed similarity between the effects of 2-ITX and flutamide. In addition, many genes induced by TCDD were also induced by 2-ITX and flutamide. These results demonstrate 2-ITX to express AhR agonistic and AR antagonistic activities, both in vitro and in vivo.
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Project description:In this dose series pregnant CD-1 (outbred) dams were exposed to methylmercury (MeHg) as monomethylmercuric chloride injected intraperitoneally on 9 d.p.c. Test doses were 10.0 mg/kg and below. This regimen induces symptoms of Fetal Minimata Disease (FMD) in term fetuses. Risks with respect to FMD for the various test doses were 10.0 mg/kg (40% risk), 5.0 mg/kg (20% risk), 2.5 mg/kg (NOAEL), and 1.25 mg/kg (subNOAEL). All measurements were on RNA from the embryonic forebrain (prosencephalon and surrounding tissue) at 3.0h post-treatment. Keywords = dose series Keywords = mercury Keywords = embryo Keywords = Fetal Minamata Disease Keywords: dose response
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Project description:Dibutyl phthalate was administered to pregnant Sprague Dawley rats from gestational days 16-20 at either a 100 mg/kg/day or 500 mg/kg/day dose level. This timeframe covers the reproductive masculinization window which corresponds to increased androgen signalling. Dibutyl phthalate has been shown to disrupt testosterone production leading to male reproductive abnormalities. As such, we selected this exposure window for our study and examined gene expression changes in the male rat foreskin, which expresses the androgen receptor. We collected tissue samples at both gestational day 20 to identify gene expression changes immediately after exposure, and postnatal day 5 to identify gene expression changes persisting after birth using microarray analysis (Illumina RatRef 12 Bead Chips). To determine whether gene expression changes were brought on by decreased androgen signalling or additional effects of dibutyl phthalate exposure, we exposed rats to the potent androgen receptor antagonist flutamide (5 mg/kg/day) during the same period of development. Gene expression changes were compared to determine which were brought on by disruption of androgen signalling and which were the result of other aspects of chemical exposure. The flutamide exposure study consisted of seven control dams administered corn oil and seven dams treated with 5 mg/kg/day flutamide. Two foreskin samples per litter were pooled for gene expression microarray analysis using the Affymetrix Gene 1.0 ST Array.
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Project description:Dibutyl phthalate was administered to pregnant Sprague Dawley rats from gestational days 16-20 at either a 100 mg/kg/day or 500 mg/kg/day dose level. This timeframe covers the reproductive masculinization window which corresponds to increased androgen signalling. Dibutyl phthalate has been shown to disrupt testosterone production leading to male reproductive abnormalities. As such, we selected this exposure window for our study and examined gene expression changes in the male rat foreskin, which expresses the androgen receptor. We collected tissue samples at both gestational day 20 to identify gene expression changes immediately after exposure, and postnatal day 5 to identify gene expression changes persisting after birth using microarray analysis (Illumina RatRef 12 Bead Chips). To determine whether gene expression changes were brought on by decreased androgen signalling or additional effects of dibutyl phthalate exposure, we exposed rats to the potent androgen receptor antagonist flutamide (5 mg/kg/day) during the same period of development. Gene expression changes were compared to determine which were brought on by disruption of androgen signalling and which were the result of other aspects of chemical exposure.
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Project description:Dibutyl phthalate was administered to pregnant Sprague Dawley rats from gestational days 16-20 at either a 100 mg/kg/day or 500 mg/kg/day dose level. This timeframe covers the reproductive masculinization window which corresponds to increased androgen signalling. Dibutyl phthalate has been shown to disrupt testosterone production leading to male reproductive abnormalities. As such, we selected this exposure window for our study and examined gene expression changes in the male rat foreskin, which expresses the androgen receptor. We collected tissue samples at both gestational day 20 to identify gene expression changes immediately after exposure, and postnatal day 5 to identify gene expression changes persisting after birth using microarray analysis (Illumina RatRef 12 Bead Chips). To determine whether gene expression changes were brought on by decreased androgen signalling or additional effects of dibutyl phthalate exposure, we exposed rats to the potent androgen receptor antagonist flutamide (5 mg/kg/day) during the same period of development. Gene expression changes were compared to determine which were brought on by disruption of androgen signalling and which were the result of other aspects of chemical exposure.
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Project description:Bisphenol A (BPA) is used in the plastic industry as the monomer of polycarbonates and epoxy resins. Heat and changes in pH conditions lead to its leakage from the plastics in which it is incorporated. This largely contributes to the widespread exposure of the general population to this environmental contaminant. The exposure levels in humans are likely below the Tolerable Daily Intake (TDI: 50 µg/kg/day) and well below the No Observable Adverse Effect Level (NOAEL: 5000 µg/kg/day) defined from reprotoxicity studies. However, several studies suggest that BPA could induce deleterious effects specifically at low, environmentally relevant, doses. BPA has been described as an endocrine disruptor with estrogenic activity. Recently, it has been shown that BPA exposure has an impact on metabolic functions including stimulation of adipogenesis and of insulin production by the pancreas. Here, we investigated the effects of oral exposure to low (TDI) and high (NOAEL) doses of BPA on mouse liver transcriptome. Liver gene expression was measured from CD-1 mice (6 mice/group) exposed for 28 days to bisphenol A at doses 0 (controls), 50 (TDI or low dose) or 5000 µg/kg/day (NOAEL or high dose) via food contamination.
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