Project description:Toxicity of PBDE for male reproductive system was shown in several human and animal studies, however long lasting effects of perinatal exposures on male reproduction are yet poorly understood. In this study pregnant Wistar rats were exposed to 0.2 mg/kg 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47) from gestation day 8 till postnatal day 21 and testis transcriptome was analyzed on postnatal day 120 in offspring. Exposed animals had significant change in testes transcriptome including suppression of genes essential for spermatogenesis and activation of immune response genes. In particular exposed animals had on average 4 fold decreased expression of protamine and transition protein genes in testes suggesting that histone-protamine exchange may be dysregulated in the course of spermatogenesis resulting in exposure legacy transfer to the next generation via aberrant sperm epigenome.
Project description:Analysis of developmental toxicity of environmental toxin 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) at the level of gene expression. Dams of Wistar rats were exposed to environmentaly relevant doses of BDE-47 at gestation and lactation. Gene expression in total brains and frontal lobes was analysed in offspring on postnatal day 10.
Project description:To develop molecular indicators of neurodevelopmental disorders related to the exposure to external chemicals, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to influence neuronal differentiation from embryonic stem cells. Thalidomide (TMD), bisphenol A (BPA), 4-hydroxy-2,2',3,4',5,5',6-heptachlorobiphenyl (4OH-PCB187) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) were exposed to human embryonic stem (ES) cell-derived sphere on day 3 after starting sphere formation for 72 hours. Gene expression analysis on the stage of sphere development showed chemical specific characteristics.
Project description:Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives in a wide range of polymers starting in 1965 and were recently withdrawn from commerce in North America and Europe. Generations that were exposed perinatally to the highest environmental doses of PBDE have now reached 5-20 years of age and in the U.S. account for 1/5 of the total population. Emerging data indicates long-term impairment of metabolic health by PBDE exposure in humans and laboratory animals. We hypothesize that exposure to PBDE during sensitive developmental windows may result in long-lasting changes in liver metabolism. In this study pregnant CD-1 mice were exposed to 0.2 mg/kg 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47) from gestation day 8 till postnatal day 21 and liver RNA-seq was performed on the last day of dam exposure and on postnatal week 20 in male offspring. Several groups of metabolic genes, including ribosomal and mitochondrial genes were significantly upregulated at both time-points. Genes regulated via mechanistic target of rapamycin (mTOR pathway), the gatekeeper of metabolic homeostasis, were whether up- or down- regulated at both time-points. Thus, perinatal exposure to environmentally relevant doses of BDE-47 in laboratory mice results in long-lasting changes in liver metabolism. Our evidence suggests involvement of the mTOR pathway in the observed metabolic programming of liver.
Project description:Advanced paternal age at fertilization has been suggested to be a risk factor for neurodevelopmental, psychiatric and other disorders in offspring. One emerging hypothesis suggests that altered offspring phenotype is linked with age-related accumulation of epigenetic changes in the sperm of fathers. Given that paternal age is increasing in the developed world, understanding aging-related epigenetic changes in sperm is needed as well as environmental factors that modify such changes. In this study, we characterize age-dependent changes in sperm DNA methylation profiles between young pubertal (postnatal day (PNDs) 65) and mature (PND120) Wistar rats. We also analyze these changes in rats exposed perinatally to 0.2 mg/kg of ubiquitous environmental xenobiotic 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47). Reduced representation bisulfite sequencing (RRBS) libraries were prepared from caudal epididymal sperm DNA and differentially methylated regions (DMRs; ≥ 10x coverage depth, ≥ 3 CpGs per cluster, ≥ 5% methylation change, q < 0.05) were identified via MethPipe package. We identified 21 and 9 exposure-related DMRs in sperm collected on PND65 and PND120, respectively. Two DMRs overlapped between the two time-points. This is the first study to demonstrate that environmentally-relevant perinatal exposure to PBDE results in long-lasting changes in sperm DNA methylation. In control animals, 5,319 age-dependent DMRs were identified, with 99.3% DMRs hypermethylated in mature animals compared to young pubertal rats. These age-related DMRs were enriched for functional categories essential for embryonic development, such as pattern specification, forebrain and sensory organ development, and the Wnt pathway. In BDE-47 exposed rats, sperm DNA methylation was higher in young pubertal and lower in mature animals when compared to controls, which resulted in a significant attenuation in the number of age-dependent DMRs (N = 189) identified in the exposed group. In conclusion, our results indicate that the natural aging process has profound effects on sperm methylation levels and this effect may be modified by environmental exposures. Moreover, our results further support the role of sperm DNA methylation as a likely mechanism by which advanced paternal age is associated with adverse offspring health and development.
Project description:Changes in rat sperm DNA methylation induced by age and by perinatal exposure to brominated flame retardant flame retardants 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47)
