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Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm.

ABSTRACT: Emerging evidence suggests that early exposure to endocrine disrupting chemicals has long-term consequences that can influence disease risk in offspring. During gametogenesis, imprinted genes are reasonable epigenetic targets with the ability to retain and transfer environmental messages. We hypothesized that exposures to organophosphate (OP) flame-retardants can alter DNA methylation in human sperm cells affecting offspring's health. Sperm and urine samples were collected from 67 men in North Carolina, USA. Urinary metabolites of a chlorinated OP, tris(1,3-dichloro-2-propyl) phosphate, and two non-chlorinated OPs, triphenyl phosphate and mono-isopropylphenyl diphenyl phosphate, were measured using liquid-chromatography tandem mass-spectrometry. Sperm DNA methylation at multiple CpG sites of the regulatory differentially methylated regions (DMRs) of imprinted genes GRB10, H19, IGF2, MEG3, NDN, NNAT, PEG1/MEST, PEG3, PLAGL1, SNRPN, and SGCE/PEG10 was quantified using bisulfite pyrosequencing. Regression models were used to determine potential associations between OP concentrations and DNA methylation. We found that men with higher concentrations of urinary OP metabolites, known to originate from flame-retardants, have a slightly higher fraction of sperm cells that are aberrantly methylated. After adjusting for age, obesity-status and multiple testing, exposure to mono-isopropylphenyl diphenyl phosphate was significantly related to hypermethylation at the MEG3, NDN, SNRPN DMRs. Exposure to triphenyl phosphate was associated with hypermethylation at the GRB10 DMR; and tris(1,3-dichloro-2-propyl) phosphate exposure was associated with altered methylation at the MEG3 and H19 DMRs. Although measured methylation differences were small, implications for public health can be substantial. Interestingly, our data indicated that a multiplicity of OPs in the human body is associated with increased DNA methylation aberrancies in sperm, compared to exposure to few OPs. Further research is required in larger study populations to determine if our findings can be generalized.

SUBMITTER: Soubry A

PROVIDER: S-EPMC5804543 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm.

Soubry Adelheid A Hoyo Cathrine C Butt Craig M CM Fieuws Steffen S Price Thomas M TM Murphy Susan K SK Stapleton Heather M HM

Environmental epigenetics 20170101 1

Emerging evidence suggests that early exposure to endocrine disrupting chemicals has long-term consequences that can influence disease risk in offspring. During gametogenesis, imprinted genes are reasonable epigenetic targets with the ability to retain and transfer environmental messages. We hypothesized that exposures to organophosphate (OP) flame-retardants can alter DNA methylation in human sperm cells affecting offspring's health. Sperm and urine samples were collected from 67 men in North C ...[more]

PMID: 29492305

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Project description:BackgroundAltered sperm DNA methylation patterns of imprinted genes as well as certain spermatogenesis-related genes has been proposed as a possible mechanism of male subfertility. Some reports suggest that there is an elevated risk of congenital diseases, associated with imprinted genes, in children conceived via intra-cytoplasmic sperm injection, due to the involvement of spermatozoa with aberrant imprinted genes obtained from infertile men.MethodsIn this study, the DNA methylation status of the promoter regions of six imprinted genes, namely potassium voltage-gated channel subfamily Q member 1 (KCNQ1), maternally expressed gene 3 (MEG3), insulin-like growth factor 2 (IGF-2), KCNQ1 overlapping transcript 1 (KCNQ1OT1), mesoderm specific transcript (MEST), and paternally expressed gene 3 (PEG3), were detected by a next generation sequencing-based multiple methylation-specific polymerase chain reaction analysis of sperm samples obtained from 166 men who sought fertility evaluation in our Reproductive Medicine Center. Thereafter, the semen samples were classified into subgroups according to sperm motility and DNA integrity status.ResultsAs compared to the normozoospermic group, the samples of the asthenospermic group exhibited significant hypermethylation in two CpG sites of IGF-2 and significant hypomethylation in one CpG site of KCNQ1 as well as three CpG sites of MEST (P < 0.05). However, we did not observe any significant differences in the overall methylation levels of these six imprinted genes (P > 0.05). Additionally, we found that 111 of 323 CpG sites were hypomethylated in the group with DNA fragmentation index (DFI) ≥ 30% as compared to the group with DFI < 30% (P < 0.05). In this case, there were significant differences in the overall methylation levels of MEG3, IGF-2, MEST, and PEG3 (P < 0.05), but not in that of KCNQ1OT1 and KCNQ1 (P > 0.05). Hence, aberrant methylation patterns of imprinted genes were more prevalent in males with poor sperm quality, especially in those with severe sperm DNA damage.ConclusionIn conclusion, abnormal DNA methylation of some CpG sites of imprinted genes are associated with poor sperm quality, including asthenospermia and severe sperm DNA impairment.

Project description:BackgroundMale infertility is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. Abnormal epigenetic programming has been proposed as a possible mechanism compromising male fertility. Recent studies suggest that aberrant imprinting in spermatozoa in a subset of infertile men is a risk factor for congenital diseases in children conceived via assisted reproduction techniques. In this study, we examined the DNA methylation status of CpG sites within the differentially methylated regions (DMRs) of three imprinted genes, H19, GNAS, and DIRAS3, using combined bisulfite PCR restriction analysis and bisulfite sequencing in sperm obtained from 135 men with idiopathic male infertility, including normozoospermia (n = 39), moderate oligozoospermia (n = 45), and severe oligozoospermia (n = 51), and fertile controls (n = 59). The percentage of global methylation was compared between fertile controls and infertile patients displaying abnormal DNA methylation status of imprinted loci. Moreover, we also analyzed whether the DNA methyltransferases (DNMTs) polymorphisms impact upon the methylation patterns of imprinted genes in idiopathic infertile males.ResultsAberrant methylation patterns of imprinted genes were more prevalent in idiopathic infertile males, especially in patients with oligozoospermia. Infertile males with aberrant methylation patterns of imprinted genes displayed a tendency of lower global methylation levels, although not reaching statistical significance (P = 0.13). In the genotype-epigenotype correlation analysis, no significant association was observed between aberrant methylation patterns of the three imprinted genes and genotypes of the four DNA methyltransferase (DNMT) genes.ConclusionWe conclude that abnormalities of DMR within imprinted genes may be associated with idiopathic male infertility. Disruption in methylation pattern of the three imprinted genes does not occur in high-risk genotypes of DNMTs.

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:Offspring of persons exposed to childhood abuse are at higher risk of neurodevelopmental and physical health disparities across the life course. Animal experiments have indicated that paternal environmental stressors can affect sperm DNA methylation and gene expression in an offspring. Childhood abuse has been associated with epigenetic marks in human blood, saliva, and brain tissue, with statistically significant methylation differences ranging widely. However, no studies have examined the association of childhood abuse with DNA methylation in gametes. We examined the association of childhood abuse with DNA methylation in human sperm. Combined physical, emotional, and sexual abuse in childhood was characterized as none, medium, or high. DNA methylation was assayed in 46 sperm samples from 34 men in a longitudinal non-clinical cohort using HumanMethylation450 BeadChips. We performed principal component analysis and examined the correlation of principal components with abuse exposure. Childhood abuse was associated with a component that captured 6.2% of total variance in DNA methylation (p?<?0.05). Next, we investigated the regions differentially methylated by abuse exposure. We identified 12 DNA regions differentially methylated by childhood abuse, containing 64 probes and including sites on genes associated with neuronal function (MAPT, CLU), fat cell regulation (PRDM16), and immune function (SDK1). We examined adulthood health behaviors, mental health, and trauma exposure as potential mediators of an association between abuse and DNAm, and found that mental health and trauma exposure partly mediated the association. Finally, we constructed a parsimonious epigenetic marker for childhood abuse using a machine learning approach, which identified three probes that predicted high vs. no childhood abuse in 71% of participants. Our results suggested that childhood abuse is associated with sperm DNA methylation, which may have implications for offspring development. Larger samples are needed to identify with greater confidence specific genomic regions differentially methylated by childhood abuse.

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Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm.

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Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm.

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