Peripubertal serum dioxin concentrations and subsequent sperm methylome profiles of young Russian adults

Pilsner, J. Richard; Shershebnev, Alex; Medvedeva, Yulia A.; Suvorov, Alexander; Wu, Haotian; Goltsov, Alexei A.; Loukianov, Evgeny; Andreeva, Tatiana V.; Gusev, Fedor; Manakhov, Andrey D.; Smigulina, Luidmila; Logacheva, Maria D.; Shtratnikova, Victoria; Kuznetsova, Irina; Speranskiy-Podobed, Peter; Burns, Jane S.; Williams, Paige L.; Korrick, Susan A.; Lee, Mary; Rogaev, Evgeny I.; Hauser, Russ; Sergeyev, Oleg

doi:10.1016/j.reprotox.2018.03.007

Cited by 24 publications

(20 citation statements)

References 68 publications

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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: 85%

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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Section: Discussionmentioning

confidence: 85%

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

et al. 2018

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“…This observation might partially be explained by the sequencing technique and source of DNA. Although according to manufacture recommendation, Ovation method is compatible with paired-end sequencing, previous results employing this method, sequenced the libraries in a single-end mode, and not paired-end, mode (Pilsner et al, 2018;Chen et al, 2019;Paul et al, 2019;Rashid et al, 2020). The same studies applied this method to study DNA methylome in rat, mice and humans brain/sperm cells while, according to manufacturer's recommendation, the Ovation method is designed to generate RRBS libraries from human genomic DNA (NuGEN, 2020).…”

Section: Discussionmentioning

confidence: 99%

Sperm DNA Hypomethylation Proximal to Reproduction Pathway Genes in Maturing Elite Norwegian Red Bulls

et al. 2020

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Genomic selection in modern farming demands sufficient semen production in young bulls. Factors affecting semen quality and production capacity in young bulls are not well understood; DNA methylation, a complicated phenomenon in sperm cells, is one such factors. In this study, fresh and frozen-thawed semen samples from the same Norwegian Red (NR) bulls at both 14 and 17 months of age were examined for sperm chromatin integrity parameters, ATP content, viability, and motility. Furthermore, reduced representation bisulfite libraries constructed according to two protocols, the Ovation R RRBS Methyl-Seq System (Ovation method) and a previously optimized gel-free method and were sequenced to study the sperm DNA methylome in frozen-thawed semen samples. Sperm quality analyses indicated that sperm concentration, total motility and progressivity in fresh semen from 17 months old NR bulls were significantly higher compared to individuals at 14 months of age. The percentage of DNA fragmented sperm cells significantly decreased in both fresh and frozen-thawed semen samples in bulls with increasing age. Libraries from the Ovation method exhibited a greater percentage of read loss and shorter read size following trimming. Downstream analyses for reads obtained from the gel-free method revealed similar global sperm DNA methylation but differentially methylated regions (DMRs) between 14-and 17 months old NR bulls. The majority of identified DMRs were hypomethylated in 14 months old bulls. Most of the identified DMRs (69%) exhibited a less than 10% methylation difference while only 1.5% of DMRs exceeded a 25% methylation difference. Pathway analysis showed that genes annotated with DMRs having low methylation differences (less than 10%) and DMRs having between 10 and 25% methylation differences, could be associated with important hormonal signaling and sperm function relevant pathways, respectively. The current research shows that RRBS in parallel with routine sperm quality analyses could be informative in reproductive capacity of young NR bulls. Although global sperm DNA methylation levels in 14 and 17 months old NR bulls were similar, regions with low and varying levels of DNA methylation differences can be identified and linked with important sperm function and hormonal pathways.

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“…While these associations are well established, the molecular mechanisms involved remain elusive, especially for paternal transmission. Recent studies focusing on the influence of preconception paternal insults implicate epigenetic processes important for germ cell development and maturation 17 – 46 . Advances in high-throughput next-generation sequencing have revealed highly complex populations of RNA in sperm, and in animal studies, small noncoding RNA (sncRNA) populations have emerged as causal agents in the germline transmission of paternal experience 44 , 47 – 51 .…”

Section: Introductionmentioning

confidence: 99%

Repeated sampling facilitates within- and between-subject modeling of the human sperm transcriptome to identify dynamic and stress-responsive sncRNAs

Morgan

Shetty

Chan

et al. 2020

Sci Rep

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Epidemiological studies from the last century have drawn strong associations between paternal life experiences and offspring health and disease outcomes. Recent studies have demonstrated sperm small non-coding RNA (sncRNA) populations vary in response to diverse paternal insults. However, for studies in retrospective or prospective human cohorts to identify changes in paternal germ cell epigenetics in association with offspring disease risk, a framework must first be built with insight into the expected biological variation inherent in human populations. In other words, how will we know what to look for if we don’t first know what is stable and what is dynamic, and what is consistent within and between men over time? From sperm samples from a ‘normative’ cohort of healthy human subjects collected repeatedly from each subject over 6 months, 17 healthy male participants met inclusion criteria and completed donations and psychological evaluations of perceived stress monthly. sncRNAs (including miRNA, piRNA, and tRNA) isolated from mature sperm from these samples were subjected to Illumina small RNA sequencing, aligned to subtype-specific reference transcriptomes, and quantified. The repeated measures design allowed us to define both within- and between-subject variation in the expression of 254 miRNA, 194 tRNA, and 937 piRNA in sperm over time. We developed screening criteria to identify a subset of potential environmentally responsive ‘dynamic’ sperm sncRNA. Implementing complex modeling of the relationships between individual dynamic sncRNA and perceived stress states in these data, we identified 5 miRNA (including let-7f-5p and miR-181a-5p) and 4 tRNA that are responsive to the dynamics of prior stress experience and fit our established mouse model. In the current study, we aligned repeated sampling of human sperm sncRNA expression data with concurrent measures of perceived stress as a novel framework that can now be applied across a range of studies focused on diverse environmental factors able to influence germ cell programming and potentially impact offspring development.

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Peripubertal serum dioxin concentrations and subsequent sperm methylome profiles of young Russian adults

Abstract: Findings from our limited sample size suggest that peripubertal environmental exposures are associated with sperm DNA methylation in young adults.

Cited by 24 publications

References 68 publications

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

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

Sperm DNA Hypomethylation Proximal to Reproduction Pathway Genes in Maturing Elite Norwegian Red Bulls

Repeated sampling facilitates within- and between-subject modeling of the human sperm transcriptome to identify dynamic and stress-responsive sncRNAs

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