Chemicals found in plastics and personal-care products like shaving cream have been known to alter men’s hormone levels and diminish semen quality. Now these chemicals, additives called phthalates, have been found to modify sperm epigenetics. Specifically, phthalates have been linked with altered DNA methylation patterns.

Although the phthalate-induced epigenetic changes don’t disrupt DNA at the sequence level, they may skew gene expression—not just in sperm, but also in developing embryos. By altering the expression of genes related to growth, cell movement, and cytoskeleton structure, phthalates—or, more precisely, phthalate metabolites—may influence couples’ prospects for reproductive success.

The new findings come from an ongoing study led by environmental health scientist Richard Pilsner, Ph.D., at the University of Massachusetts Amherst. As part of this study, researchers recruited 48 couples at an in vitro fertilization (IVF) clinic and took a single urine sample from the men on the same day they donated sperm. The researchers measured 17 metabolites from eight different phthalate parent compounds in that sample, then performed DNA methylation analyses on sperm cells to examine statistical associations.

After receiving sperm cells from the IVF clinic, the UMass team extracted and analyzed DNA samples. Using a genomics system to examine approximately 485,000 sites for DNA methylation, the researchers identified 6479 regions of interest in assessing a possible correlation between phthalate metabolite exposure and DNA methylation.

“Rather than looking for methylation changes at individual sites on the DNA, we looked at DNA regions or clusters on genes that might be more biologically meaningful than individual sites,” explained Haotian “Howie” Wu, a graduate student and member of Dr. Pilsner’s team. “It's not just numbers we were interested in. We wanted to pay attention not only to the statistical relationships, but also the biology.”

Details of the researchers’ work appeared September 12 in the journal Human Reproduction, in an article entitled “Preconception Urinary Phthalate Concentrations and Sperm DNA Methylation Profiles among Men Undergoing IVF Treatment: A Cross-Sectional Study.” This article indicated that 131 differentially methylated regions (DMRs) were associated with at least one urinary metabolite, and that most sperm DMRs were associated with antiandrogenic metabolites.

“The DMRs were enriched in lincRNAs [long intergenic noncoding RNAs] as well as in regions near coding regions,” the article stated. “Functional analyses of DMRs revealed enrichment of genes related to growth and development as well as cellular function and maintenance.”

In addition, the article indicated that 13% of sperm DMRs were inversely associated with high-quality blastocyst-stage embryos after IVF.

Although phthalates are estimated to be detectable in nearly 100% of the U.S. population, the influence of preconception phthalate exposure on sperm DNA methylation in humans had not been studied before, noted the authors of the current study.

“To our knowledge, this is the first study to report that preconception urinary phthalate metabolite concentrations are associated with sperm DNA methylation in humans,” the authors asserted. “These results suggest that paternal adult environmental conditions may influence epigenetic reprogramming during spermatogenesis, and in turn, influence early-life development.”

Dr. Pilsner explains, “There has always been this heavy concern in the past with expectant moms not smoking and not drinking, for example, to protect the fetus. In this study, we see that dad's environmental health contributes to reproductive success. For sperm to mature is a 72-day process, almost three months, and our study shows that this preconception time period may represent an important developmental window by which environmental exposures may influence sperm epigenetics, and in turn, early life development. So, in the same way mom needs to be careful, dad also needs to.”

“We examined the biological pathways, or common links between genes, that might be affected in these 131 regions that were identified,” he added. “The next step, after identifying associated regions, is to try to determine the possible biological meaning.”

The researchers stress that these early results represent a small sample, and note that it is unclear from this study if these methylated changes are inherited and persist during prenatal and postnatal development. Wu adds, “We are finding interesting things and raising interesting questions, and we will certainly want to explore further.”

Dr. Pilsner has recently received a multi-million-dollar grant to replicate and validate the findings with a dose-dependent experiment in mice. He adds, “It doesn't surprise me that sperm carry some sort of environmental legacy to the next generation. What the sperm cell encounters during its development can influence these chemical tags or DNA methylated, and it may well have an effect on the developing embryo and offspring.”

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