Dataset Information

Urine mercury levels correlate with DNA methylation of imprinting gene H19 in the sperm of reproductive-aged men.

ABSTRACT:

Background

Mercury (Hg) is a well-recognized environmental pollutant known by its toxicity of development and neurotoxicity, which results in adverse health outcomes. However, the mechanisms underlying the teratogenic effects of Hg are not well understood. Imprinting genes are emerging regulators for fetal development subjecting to environmental pollutants impacts. In this study, we examined the association between preconceptional Hg exposure and the alteration of DNA methylation of imprinting genes H19, Meg3, and Peg3 in human sperm DNA.

Methods

A total of 616 men, aged from 22 to 59, were recruited from Reproductive Medicine Clinic of Maternal and Child Care Service Center and the Urologic Surgery Clinic of Shanxi Academy of Medical Sciences during April 2015 and March 2016. Demographic information was collected through questionnaires. Urine was collected and urinary Hg concentrations were measured using a fully-automatic double-channel hydride generation atomic fluorescence spectrometer. Methylation of imprinting genes H19, Meg3 and Peg3 of sperm DNA from 242 participants were examined by bisulfite pyrosequencing. Spearman's rank and multivariate regression analysis were used for correlation analysis between sperm DNA methylation status of imprinting genes and urinary Hg levels.

Results

The median concentration of Hg for 616 participants was 9.14?g/l (IQR: 5.56-12.52 ?g/l; ranging 0.16-71.35?g/l). A total of 42.7% of the participants are beyond normal level for non-occupational exposure according to the criterion of Hg poisoning (?10 ?g/L). Spearman's rank analysis indicated a negative correlation between urinary Hg concentrations and average DNA methylation levels of imprinted genes H19 (rs = -0.346, p <0.05), but there was no such a correlation for Peg3 and Meg3. Further, we analyzed the correlation between methylation level at individual CpG site of H19 and urinary Hg level. The results showed a negative correlation between urinary Hg concentrations and three out of seven CpG sites on H19 DMR, namely CpG2 (rs = -0.137, p <0.05), CpG4 (rs = -0.380, p <0.05) and CpG6 (rs = -0.228, p <0.05). After adjusting age, smoking, drinking, intake of aquatic products and education by multivariate regression analysis, the results have confirmed the correlation as mentioned above.

Conclusions

Mercury non-occupational environmental exposure in reproductive-aged men was associated with altered DNA methylation outcomes at imprinting gene H19 in sperm, implicating the susceptibility of the developing sperm for environmental insults.

SUBMITTER: Lu Z

PROVIDER: S-EPMC5919660 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Urine mercury levels correlate with DNA methylation of imprinting gene H19 in the sperm of reproductive-aged men.

Lu Zhaoxu Z Ma Yufeng Y Gao Linying L Li Yingjun Y Li Qiang Q Qiang Mei M

PloS one 20180426 4

<h4>Background</h4>Mercury (Hg) is a well-recognized environmental pollutant known by its toxicity of development and neurotoxicity, which results in adverse health outcomes. However, the mechanisms underlying the teratogenic effects of Hg are not well understood. Imprinting genes are emerging regulators for fetal development subjecting to environmental pollutants impacts. In this study, we examined the association between preconceptional Hg exposure and the alteration of DNA methylation of impr ...[more]

PMID: 29698523

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Project description:BACKGROUND: In the last few years, an increase in imprinting anomalies has been reported in children born from Assisted Reproductive Technology (ART). Various clinical and experimental studies also suggest alterations of embryo development after ART. Therefore, there is a need for studying early epigenetic anomalies which could result from ART manipulations, especially on single embryos. In this study, we evaluated the impact of superovulation, in vitro fertilization (IVF) and embryo culture conditions on proper genomic imprinting and blastocyst development in single mouse embryos. In this study, different experimental groups were established to obtain embryos from superovulated and non-superovulated females, either from in vivo or in vitro fertilized oocytes, themselves grown in vitro or not. The embryos were cultured either in M16 medium or in G1.2/G2.2 sequential medium. The methylation status of H19 Imprinting Control Region (ICR) and H19 promoter was assessed, as well as the gene expression level of H19, in individual blastocysts. In parallel, we have evaluated embryo cleavage kinetics and recorded morphological data. RESULTS: We show that: 1. The culture medium influences early embryo development with faster cleavage kinetics for culture in G1.2/G2.2 medium compared to M16 medium. 2. Epigenetic alterations of the H19 ICR and H19 PP are influenced by the fertilization method since methylation anomalies were observed only in the in vitro fertilized subgroup, however to different degrees according to the culture medium. 3. Superovulation clearly disrupted H19 gene expression in individual blastocysts. Moreover, when embryos were cultured in vitro after either in vivo or in vitro fertilization, the percentage of blastocysts which expressed H19 was higher in G1.2/G2.2 medium compared to M16. CONCLUSION: Compared to previous reports utilizing pools of embryos, our study enables us to emphasize a high individual variability of blastocysts in the H19 ICR and H19 promoter methylation and H19 gene expression, with a striking effect of each manipulation associated to ART practices. Our results suggest that H19 could be used as a sensor of the epigenetic disturbance of the utilized techniques.

Project description:Polycyclic aromatic hydrocarbons (PAHs) are known environmental pollutants. Studies are very limited regarding the impacts of paternal PAHs exposure on birth outcomes as well as the underpinning mechanisms in human. In this study, 302 reproductive-aged males (22-46 years old) were enrolled and demographic informatics data were obtained by questionnaires. The levels of urinary hydroxylated PAHs (OH-PAHs) were assessed by ultra-high performance liquid chromatography-tandem mass spectrometry; and methylation levels of the imprinting genes H19, Meg3, and Peg3 of sperm DNA were evaluated via bisulfite pyrosequencing. The analysis of the correlation between OH-PAHs levels and methylation levels of imprinting genes showed that OH-PAHs are correlated with some CpG sites in H19, Peg3, and Meg3. To further investigate an association of urinary OH-PAHs with birth outcomes, follow-up study of wives of these subjects has been performed for 1-3 years. As the result, a total of 157 babies were born. The birth outcomes parameters including birth weight (BW), length (BL), and ponderal index (PI) were recorded. The further analysis of generalized estimating equation indicated a negative correlation between urinary total OH-PAHs levels and newborn BW (β = -0.081, p = 0.020); but this association has not been found for BL and PI. Furthermore, a logistic regression analysis was employed for examining associations of the methylation of imprinting genes with birth outcomes parameters, which indicated a negative correlation between BW and H19, namely, each unit percent (%) elevation in methylation of H19 (but not Peg3 and Meg3) was significantly associated with a 0.135 g reduction of BW (β = -0.135; 95% CI 0.781-0.978). Putting together, these results show that paternal non-occupational environmental exposure to PAHs is associated with newborn BW. And imprinting gene H19 methylation may be involved in the underlying mechanisms. This study in human population adds a support for previous animal study and implies that environmental impact on the offspring through paternal pathway.

Project description:UnlabelledBackgroundThe insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity.DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression.ResultsThe principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. ?-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC.ConclusionsAs greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required.

Project description:Imprinted genes play important roles in placental differentiation, growth and function, with profound effects on fetal development. In humans, H19 and IGF2 are imprinted, but imprinting of IGF2R remains controversial. The H19 non-coding RNA is a negative regulator of placental growth and altered placental imprinting of H19-IGF2 has been associated with pregnancy complications such as preeclampsia, which have been attributed to abnormal first trimester placentation. This suggests that changes in imprinting during the first trimester may precede aberrant placental morphogenesis. To better understand imprinting in the human placenta during early gestation, we quantified allele-specific expression for H19, IGF2 and IGF2R in first trimester (6-12 weeks gestation) and term placentae (37-42 weeks gestation) using pyrosequencing. Expression of IGF2R was biallelic, with a mean expression ratio of 49:51 (SD = 0.07), making transient imprinting unlikely. Expression from the repressed H19 alleles ranged from 1-25% and was higher (P<0.001) in first trimester (13.5 ± 8.2%) compared to term (3.4 ± 2.1%) placentae. Surprisingly, despite the known co-regulation of H19 and IGF2, little variation in expression of the repressed IGF2 alleles was observed (2.7 ± 2.0%). To identify regulatory regions that may be responsible for variation in H19 allelic expression, we quantified DNA methylation in the H19-IGF2 imprinting control region and H19 transcription start site (TSS). Unexpectedly, we found positive correlations (P<0.01) between DNA methylation levels and expression of the repressed H19 allele at 5 CpG's 2000 bp upstream of the H19 TSS. Additionally, DNA methylation was significantly higher (P<0.05) in first trimester compared with term placentae at 5 CpG's 39-523 bp upstream of the TSS, but was not correlated with H19 repressed allele expression. Our data suggest that variation in H19 imprinting may contribute to early programming of placental phenotype and illustrate the need for quantitative and robust methodologies to further elucidate the role of imprinted genes in normal and pathological placental development.

Dataset Information

Urine mercury levels correlate with DNA methylation of imprinting gene H19 in the sperm of reproductive-aged men.

Background

Methods

Results

Conclusions

Publications

Urine mercury levels correlate with DNA methylation of imprinting gene H19 in the sperm of reproductive-aged men.

Similar Datasets

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