Male obesity impacts DNA methylation reprogramming in sperm.

BACKGROUND: Male obesity has profound effects on morbidity and mortality, but relatively little is known about the impact of obesity on gametes and the potential for adverse effects of male obesity to be passed to the next generation. DNA methylation contributes to gene regulation and is erased and re-established during gametogenesis. Throughout post-pubertal spermatogenesis, there are continual needs to both maintain established methylation and complete DNA methylation programming, even during epididymal maturation. This dynamic epigenetic landscape may confer increased vulnerability to environmental influences, including the obesogenic environment, that could disrupt reprogramming fidelity. Here we conducted an exploratory analysis that showed that overweight/obesity (n = 20) is associated with differences in mature spermatozoa DNA methylation profiles relative to controls with normal BMI (n = 47). RESULTS: We identified 3264 CpG sites in human sperm that are significantly associated with BMI (p < 0.05) using Infinium HumanMethylation450 BeadChips. These CpG sites were significantly overrepresented among genes involved in transcriptional regulation and misregulation in cancer, nervous system development, and stem cell pluripotency. Analysis of individual sperm using bisulfite sequencing of cloned alleles revealed that the methylation differences are present in a subset of sperm rather than being randomly distributed across all sperm. CONCLUSIONS: Male obesity is associated with altered sperm DNA methylation profiles that appear to affect reprogramming fidelity in a subset of sperm, suggestive of an influence on the spermatogonia. Further work is required to determine the potential heritability of these DNA methylation alterations. If heritable, these changes have the potential to impede normal development.

Replicated umbilical cord blood DNA methylation loci associated with gestational age at birth.

DNA methylation is highly sensitive to in utero perturbations and has an established role in both embryonic development and regulation of gene expression. The foetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behaviour of individual genes. The aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for cis gene relationships in specimens with multi-omic data. Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450 K BeadChip, was associated with GA for 2,372 CpG probes (5% FDR) in both the Pregnancy, Race, Environment, Genes (PREG) and Newborn Epigenetic Study (NEST) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. Gene pathways identified are consistent with the hypothesis of pathogen detection and response by the immune system to elicit premature labour as a consequence of unscheduled inflammation.

Differential methylation values in differential methylation analysis.

MOTIVATION: Both ß-value and M-value have been used as metrics to measure methylation levels. The M-value is more statistically valid for the differential analysis of methylation levels. However, the ß-value is much more biologically interpretable and needs to be reported when M-value method is used for conducting differential methylation analysis. There is an urgent need to know how to interpret the degree of differential methylation from the M-value. In M-value linear regression model, differential methylation M-value ΔM can be easily obtained from the coefficient estimate, but it is not straightforward to get the differential methylation ß-value, Δß since it cannot be obtained from the coefficient alone. RESULTS: To fill the gap, we have built a bridge to connect the statistically sound M-value linear regression model and the biologically interpretable Δß. In this article, three methods were proposed to calculate differential methylation values, Δß from M-value linear regression model and compared with the Δß directly obtained from ß-value linear regression model. We showed that under the condition that M-value linear regression model is correct, the method M-model-coef is the best among the four methods. M-model-M-mean method works very well too. If the coefficients α0, α2,…αp are not given (as 'MethLAB' package), the M-model-M-mean method should be used. The Δß directly obtained from ß-value linear regression model can give very biased results, especially when M-values are not in (-2, 2) or ß-values are not in (0.2, 0.8). AVAILABILITY AND IMPLEMENTATION: The dataset for example is available at the National Center for Biotechnology Information Gene Expression Omnibus repository, GSE104778. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Interplay between exercise and BMI; results from an equal access, racially diverse biopsy study.

PURPOSE: It is unclear if exercise and BMI interact to influence prostate cancer (PC) risk. We hypothesized BMI is linked with increased aggressive PC risk but this link will be attenuated with increased exercise. METHODS: Men undergoing prostate biopsy completed a questionnaire and metabolic equivalent (MET) hours of exercise was calculated. Of 695 men, 349 had PC; 161 low-grade, and 188 high-grade. We assessed the link between exercise and PC risk, high-grade PC (Gleason 7-10), and low-grade PC (Gleason 2-6) using logistic and multinomial logistic regression. Analysis was stratified by BMI. Link between BMI and PC risk and aggressive PC was similarly tested. RESULTS: On multivariable analysis, there was no link between exercise and PC diagnosis in the entire cohort (p trend = 0.18-0.71) or across BMI groups (p trend = 0.15-0.97). For the entire cohort, higher BMI was linked with increased risk of high-grade PC (OR 1.06, p = 0.008). When stratified by exercise groups, the trend for higher BMI and increased risk of high-grade PC remained (OR 1.03-1.15, p = 0.02-0.66). There were no interactions between exercise and BMI in predicting PC risk (all p ≥ 0.31). CONCLUSIONS: Regardless of exercise, higher BMI was linked with higher risk of aggressive PC, while exercise was unrelated to PC risk. Confirmatory studies are needed.

Androgenetic alopecia at various ages and prostate cancer risk in an equal-access multiethnic case-control series of veterans.

PURPOSE: Epidemiological data are conflicting regarding the association between androgenetic alopecia (AA) and prostate cancer (CaP). We examined the relationship between these two conditions. MATERIALS AND METHODS: We performed a case-control study at a Veterans Affairs Hospital among 708 men: 312 healthy controls, 167 men with CaP, and 229 men without CaP on prostate biopsy. Participants were asked to self-describe hair patterns at ages 30 and 40 and at study enrollment. We tested the association between hair pattern (overall, vertex, or frontal) and CaP status using logistic regression analysis adjusting for multiple clinical features. Disease grade was similarly examined as a secondary outcome. RESULTS: Relative to healthy controls, younger age of AA onset was significantly associated with increased CaP risk (p = 0.008). Similar patterns were noted for frontal (p = 0.005) and not vertex balding (p = 0.22). When compared with biopsy-negative men, a similar pattern was seen with younger age of AA onset having higher risk of CaP, though this was not significant (p = 0.07). A suggestion for younger age of AA onset for frontal (p = 0.07) being associated with CaP versus biopsy-negative men was also observed. Overall balding (yes/no) was associated with greater than twofold increase in high-grade disease (p = 0.02). CONCLUSIONS: Men reporting earlier AA onset were at increased CaP risk and suggestively had more aggressive disease. Contrary to other studies, frontal balding was the predominant pattern associated with elevated CaP risk. Further study is required to confirm these findings in a larger sample and to better understand the role of AA, androgens, and CaP biology.

Genetic variants in IGF-I, IGF-II, IGFBP-3, and adiponectin genes and colon cancer risk in African Americans and Whites.

PURPOSE: Evaluating genetic susceptibility may clarify effects of known environmental factors and also identify individuals at high risk. We evaluated the association of four insulin-related pathway gene polymorphisms in insulin-like growth factor-1 (IGF-I) (CA)( n ) repeat, insulin-like growth factor-2 (IGF-II) (rs680), insulin-like growth factor-binding protein-3 (IGFBP-3) (rs2854744), and adiponectin (APM1 rs1501299) with colon cancer risk, as well as relationships with circulating IGF-I, IGF-II, IGFBP-3, and C-peptide in a population-based study. METHODS: Participants were African Americans (231 cases and 306 controls) and Whites (297 cases, 530 controls). Consenting subjects provided blood specimens and lifestyle/diet information. Genotyping for all genes except IGF-I was performed by the 5'-exonuclease (Taqman) assay. The IGF-I (CA)(n) repeat was assayed by PCR and fragment analysis. Circulating proteins were measured by enzyme immunoassays. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated by logistic regression. RESULTS: The IGF-I (CA)( 19 ) repeat was higher in White controls (50 %) than African American controls (31 %). Whites homozygous for the IGF-I (CA)(19) repeat had a nearly twofold increase in risk of colon cancer (OR = 1.77; 95 % CI = 1.15-2.73), but not African Americans (OR = 0.73, 95 % CI 0.50-1.51). We observed an inverse association between the IGF-II Apa1 A-variant and colon cancer risk (OR = 0.49, 95 % CI 0.28-0.88) in Whites only. Carrying the IGFBP-3 variant alleles was associated with lower IGFBP-3 protein levels, a difference most pronounced in Whites (p-trend <0.05). CONCLUSIONS: These results support an association between insulin pathway-related genes and elevated colon cancer risk in Whites but not in African Americans.

Exercise and prostate cancer risk in a cohort of veterans undergoing prostate needle biopsy.

PURPOSE: Epidemiological and molecular evidence suggest potential associations between exercise and prostate cancer risk reduction. We further characterized this relationship by examining exercise and cancer risk among men undergoing prostate needle biopsy. MATERIALS AND METHODS: A total of 190 men who underwent prostate biopsy at the Durham Veterans Affairs Medical Center completed a questionnaire on current exercise behavior. Participants were asked average frequency of mild, moderate and strenuous intensity exercise in a typical week, as well as average duration as assessed by the Godin Leisure Time Exercise Questionnaire. Total current exercise was calculated in terms of metabolic equivalent task hours per week. Primary outcome measures were prostate biopsy result and Gleason sum. RESULTS: After adjusting for age, race, body mass index, prostate specific antigen, digital rectal examination, family history, previous prostate biopsy and comorbidity score, men who reported 9 or more metabolic equivalent task hours per week of exercise were significantly less likely to have cancer on biopsy (OR 0.35, CI 0.17-0.75, p = 0.007). Furthermore, among men with malignant biopsy results, reporting moderate exercise (3 to 8.9 metabolic equivalent task hours weekly) was associated with a lower risk of high grade disease (Gleason 7 or greater, OR 0.14, CI 0.02-0.94, p = 0.04). CONCLUSIONS: To our knowledge these results provide the first evidence of an association between exercise and prostate cancer risk as well as grade at diagnosis in men scheduled to undergo prostate biopsy. Specifically moderate exercise was associated with a lower risk of prostate cancer and in men with cancer, lower grade disease. Further investigation using an objective measure of exercise in a larger sample size is required to confirm these findings.

Fear of Sexually Transmitted Infections among Women with Male Migrant Partners-Relationship to Oscillatory Migration Pattern and Risk-Avoidance Behaviour

Background. In South Africa; former apartheid lasw encouraged rural males seeking employment to migrate to urban areas; movig weekly; monthly or annually between their rural families and urban workplaces. The combination of the migrant labour system and long family separations caused an explosion of serious health consequences; among others sexually transmitted infections (STIs) in the migrant population. Objective. To describe some correlates of male migration patterns for the rural women left behind; especially the fear of STIs that this engendered in theem and their risk-aoidance Setting and subjects. In KwaZulu-Natal; 208 parentatal paients who were partners of oscillating male migrant workers were interviewed to determine their demographic and charactetistics; and their fear of STIs. Results. Thirty-six per cent of the rural women said that they were afraid of contracting STIs from thair returning migrant partners; Women who saw their partners infrequently were more fearful of STI transmission; and were less able to have sexual communication. However; almost none of the women protected themselves; while only 8used condoms; primarily for contraceptive purposes. Conclusions. These results reflect the gender-based-power relationships of South African male migrants and their rural partners; the social and economic dependency of the women on their migrant partners; and the women's social responsibility to bear children. The results point to the need to go beyond interventions that simply seek to modify behaviour without altering the forces that promote risk taking and discourage risk reduction; and the need to develop appropriate interventions to curb STIs and decrease HIV