Preconception urinary phthalate concentrations and sperm DNA methylation profiles among men undergoing IVF treatment: a cross-sectional study

Wu, Haotian; Estill, Molly; Shershebnev, Alexander; Suvorov, Alexander; Krawetz, Stephen A.; Whitcomb, Brian W.; Dinnie, H.; Rahil, Tayyab; Sites, Cynthia K.; Pilsner, J. Richard

doi:10.1093/humrep/dex283

Cited by 97 publications

(55 citation statements)

References 53 publications

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“…Twelve of the fifteen phthalate metabolites were measured above the LOD in more than 90% of samples (MEOHP, MEHHP, MECPP, MBzP, MBP, MHBP, MHiBP, MMP, MCOP, MEP, MCPP, and MCNP). Urinary phthalate concentrations in the current study are in line with those reported previously by our group (Wu et al, 2017b, 2017c) and others (CDC, 2010; Dodge et al, 2015). Lower urinary concentrations were observed for the two metabolites of DINCH, a phthalate alternative, with 38% > LOD for MCOCH and 63.1% > LOD for MHINCH.…”

Section: Resultssupporting

confidence: 93%

Associations of urinary phthalate metabolites and lipid peroxidation with sperm mitochondrial DNA copy number and deletions

Huffman

Rosati

et al. 2018

Environmental Research

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Background: Phthalates, a chemical class of plasticizers, are ubiquitous environmental contaminants that have been associated with oxidative stress. Mitochondria DNA copy number (mtDNAcn) and DNA deletions (mtDNAdel) are emerging biomarkers for cellular oxidative stress and environment exposures. Objectives: To examine associations of urinary phthalate metabolite and isoprostane concentrations on sperm mtDNAcn and mtDNAdel in male partners undergoing assisted reproductive technologies (ART). Methods: Ninety-nine sperm samples were collected from male partners undergoing ART at Baystate Medical Center in Springfield, MA as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Seventeen urinary phthalate metabolite concentrations were analyzed by the Centers for Disease Control using tandem mass spectrometry. Urinary 15-F2t-isoprostane concentrations, a biomarker of lipid peroxidation, were measured using a competitive enzyme-linked immunosorbent assay. A triplex qPCR method was used to determine the relative quantification of mtDNAcn and mtDNAdel. Results: Sperm mtDNAcn and mtDNAdel were positively correlated (Spearman rho = 0.31; p = .002). Adjusting for age, BMI, current smoking, race, and measurement batch, urinary monocarboxy-isononyl phthalate (MCNP) concentrations were positively associated with mtDNAcn (β = 1.63, 95% CI: 0.14, 3.11). Other urinary phthalate metabolite and isoprostane concentrations were not associated with sperm mtDNAcn or mtDNAdel. Conclusions: Among this cohort of male ART participants, those with higher MCNP had higher mtDNAcn; other phthalate metabolites and isoprostane were not associated with mtDNAcn and mtDNAdel. Given our relatively small sample size, our results should be interpreted with caution. Future research is needed to replicate the findings in larger studies and among sperm samples obtained from the general population.

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Section: Resultssupporting

confidence: 93%

Associations of urinary phthalate metabolites and lipid peroxidation with sperm mitochondrial DNA copy number and deletions

Huffman

Rosati

et al. 2018

Environmental Research

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“…Collectively, our findings demonstrate that two common endocrine disruptors are capable of causing aberrant DNA methylation of CpG islands in sperm and the brain and that a few of these sites are faithfully transmitted for multiple generations. EDC exposure has been shown to be associated with altered DNA methylation in humans for dioxins [78], flame retardants like organophosphates [44] and polybrominated diphenyl ethers [79], phthalates [80], and PCBs [81]. To our knowledge, a similar study has not been performed for VIN in humans.…”

Section: Discussionmentioning

confidence: 84%

Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm

et al. 2018

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All animals have body burdens of polychlorinated biphenyls (PCBs) despite their ban decades ago. These and modern endocrine-disrupting chemicals (EDCs) such as the fungicide vinclozolin (VIN) perturb hormone signaling and lead to dysfunctions following prenatal exposures. Beyond direct exposures, transgenerational disease phenotypes can persist for multiple generations without subsequent exposure. The mechanisms of action of these EDCs differ: VIN is anti-androgenic while the PCB mixture Aroclor 1221 (A1221) is weakly estrogenic. Based on limited evidence for the inheritance of epimutations in germline, we measured DNA methylation in brain and sperm of rats. Pregnant dams were exposed from day 8-18 of gestation to low dosages of VIN, A1221, or the vehicle. To produce paternal lineages, exposed F1 males were bred with untreated females, creating the F2 and subsequently F3 generations. In adult F1 and F3 males, mature sperm was collected, and brain nuclei involved in anxiety and social behaviors (CA3 of the hippocampus; central amygdala) were selected for assays of epimutations in CpG islands using reduced representation bisulfite sequencing. In F1 sperm, VIN and PCBs induced differential methylation in 215 and 284 CpG islands, respectively, compared to vehicle. The majority of effects were associated with hypermethylation. Fewer epimutations were detected in the brain. A subset of differentially methylated regions were retained from the F1 to the F3 generation, suggesting a common mechanism of EDC and germline epigenome interaction. Thus, EDCs can cause heritable epimutations in the sperm that may embody the future phenotype of brain-behavior disorders caused by direct or transgenerational exposures. ARTICLE HISTORY

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“…Mechanistically, it is thought that germ cells and preimplantation embryos are most susceptible to endogenous and exogenous environmental factors because the epigenome in these cells undergoes dramatic reprogramming [92,93]. While causal links have not been established between individuals' exposures, epigenetic alterations in germ cells and cancer risk in their children, factors such as dietary folate, alcohol, obesity, smoking, endocrine disrupters, and phthalates have been shown to alter epigenetic marks in germ cells [94][95][96][97][98][99][100]. Animal studies have shown some provocative findings.…”

Section: Towards a Better Understanding Of How Exposures Affect Breasmentioning

confidence: 99%

Epigenetic Biomarkers for Environmental Exposures and Personalized Breast Cancer Prevention

Park

2020

IJERPH

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Environmental and lifestyle factors are believed to account for >80% of breast cancers; however, it is not well understood how and when these factors affect risk and which exposed individuals will actually develop the disease. While alcohol consumption, obesity, and hormone therapy are some known risk factors for breast cancer, other exposures associated with breast cancer risk have not yet been identified or well characterized. In this paper, it is proposed that the identification of blood epigenetic markers for personal, in utero, and ancestral environmental exposures can help researchers better understand known and potential relationships between exposures and breast cancer risk and may enable personalized prevention strategies.

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Preconception urinary phthalate concentrations and sperm DNA methylation profiles among men undergoing IVF treatment: a cross-sectional study

Abstract: This work was supported by grant K22-ES023085 from the National Institute of Environmental Health Sciences. The authors declare no competing interests.

Cited by 97 publications

References 53 publications

Associations of urinary phthalate metabolites and lipid peroxidation with sperm mitochondrial DNA copy number and deletions

Associations of urinary phthalate metabolites and lipid peroxidation with sperm mitochondrial DNA copy number and deletions

Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm

Epigenetic Biomarkers for Environmental Exposures and Personalized Breast Cancer Prevention

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