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Study questionIs sperm epigenetic aging (SEA) associated with probability of pregnancy among couples in the general population?Summary answerWe observed a 17% lower cumulative probability at 12 months for couples with male partners in the older compared to the younger SEA categories.What is known alreadyThe strong relation between chronological age and DNA methylation profiles has enabled the estimation of biological age as epigenetic 'clock' metrics in most somatic tissue. Such clocks in male germ cells are less developed and lack clinical relevance in terms of their utility to predict reproductive outcomes.Study design, size, durationThis was a population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 and followed for up to 12 months.Participants/materials, setting, methodsSperm DNA methylation from 379 semen samples was assessed via a beadchip array. A state-of-the-art ensemble machine learning algorithm was employed to predict age from the sperm DNA methylation data. SEA was estimated from clocks derived from individual CpGs (SEACpG) and differentially methylated regions (SEADMR). Probability of pregnancy within 1 year was compared by SEA, and discrete-time proportional hazards models were used to evaluate the relations with time-to-pregnancy (TTP) with adjustment for covariates.Main results and the role of chanceOur SEACpG clock had the highest predictive performance with correlation between chronological and predicted age (r = 0.91). In adjusted discrete Cox models, SEACpG was negatively associated with TTP (fecundability odds ratios (FORs)=0.83; 95% CI: 0.76, 0.90; P = 1.2×10-5), indicating a longer TTP with advanced SEACpG. For subsequent birth outcomes, advanced SEACpG was associated with shorter gestational age (n = 192; -2.13 days; 95% CI: -3.67, -0.59; P = 0.007). Current smokers also displayed advanced SEACpG (P

Infertility, which is the inability to achieve clinical pregnancy within 12 months of unprotected sexual intercourse, affects 15% of all couples globally. Emerging evidence shows, just as females, males are equally likely to contribute to couple infertility, suggesting the relevance of male factor in couple reproductive success. The potential factors thought to drive male infertility include male preconception environment and aging. Thus, this dissertation focused on two (DNA methylation and small non-coding RNAs (sncRNAs)) of the three major potential epigenetic mediators that occur during spermatogenesis and sperm maturation prior to conception using human and mice model. First, to explore the current state of knowledge on the susceptibility of sperm epigenetics to environmental insults and its potential reproductive and downstream effects, we provided a comprehensive review of male preconception environment and sperm epigenetics. We found that sperm epigenome can be modified by lifestyle such as diet, and exercise with limited studies related to ubiquitous environmental endocrine disruptive compounds like phthalates. To better understand the impact of phthalate on sperm epigenome and early development, adult male mice were exposed to low and high doses of DEHP and sperm epigenome and embryonic transcriptome profiles were assessed. Consistent with previous findings in human, we found that DEHP exposure modified DNA methylomes in F0 sperm and F1 embryo; altered F1 embryonic transcriptome at developmental genes. Beyond spermatogenesis, sperm also undergo epididymal maturation which has been shown to play a central role in sperm function. This maturation is mediated by extracellular vesicles, the cargo of which has be reported to show sensitivity to nutritional factors and may convey paternal experience to subsequent generation. To evaluate the potential influence of phthalate exposures, we recruited 96 men undergoing infertility treatment as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). We found a total of 23 sncRNAs including the expression levels of microRNA (miRNA), transfer RNA fragments (tRFs) and piwi-interacting RNA (piRNA) that showed alteration due to concentrations of urinary phthalate metabolites. These sncRNAs targeted genomic regions found to be important in biological functions related to development, indicating likely role in early embryonic development. Lastly, preconception male age has been linked to a wide array of reproductive and offspring phenotypes. Recent evidence shows such phenotypes among younger men are not negligible which suggest the potential variation in underlying biological clock. Interestingly, DNA methylation-based clock has emerged as important estimator of biological aging in somatic tissues. Thus, this dissertation did not only develop sperm-based DNA methylation clock but also investigated its environmental susceptibility among the general population of men (n = 379) planning to conceive as part of the Longitudinal Investigation of Fertility and the Environment (LIFE) study. We found select metabolites were associated with ~ 4 months increase in sperm epigenetic clock which resulted in a suggestive positive trend with the total metabolite mixture, indicating younger men can now carry an older population of sperm. Overall, the evidence presented by this dissertation shows that paternal adult exposure to select phthalates and phthalate alternatives alters sperm methylome and persists through fertilization to influence genes involved in development in mice. In humans, phthalates are associated with altered sncRNA profiles in seminal plasma extracellular vesicles and with increased biological aging of sperm. This highlights the relevance of male preconception period in couple reproductive and offspring outcomes. Additional studies are required to replicate our findings across human and mice models.

Inadequate pipe borne water supply has led to rapid proliferation of sachet water companies in Nigeria. Recently, another dimension added to public health concerns on water quality is the storage and handling of sachet water by distributors and vendors. This study assessed the effect of storage and exposure to sunlight on the quality of sachet water in Ibadan, Nigeria. An experimental design was adopted. Two hundred sachets of water from ten brands were collected upon production from various factories. Water samples were divided into two groups: storage indoor (room temperature) and storage with exposure to sunlight for four weeks. Physicochemical and bacteriological analyses were carried out on the sachet water samples at baseline and after three days and weeks one to four of storage. The data obtained were analysed using SPSS (20.0). The bacteria isolated were E. coli, S. aureus, K. pneumonia and P.vulgaris. Total bacterial counts decreased in the order: 0 to 1.5x104cfu/100 mL (day 3) > 0 to 9.5x 102 cfu/100 mL (day 7) upon exposure to sunlight, however, there was continuous increase of bacteria count from day seven. Bacteria counts of water stored indoor increased throughout the study period. E. coli was present in all water samples by day 21. There was a significant difference in nitrite concentration between the two storage conditions across study period. This study revealed that storage duration and exposure conditions affect the quality of sachet water for drinking. Quality improvement of sachet water through exposure to sunlight was most effective on third day of exposure, while the maximum time of effectiveness was one week, beyond which the quality deteriorates fast irrespective of the storage condition. Hence, prolonged water storage beyond one week before drinking is discouraged.