Table 1:
Selected studies on paternal preconception exposures and sperm epigenetic aberrations.
| Exposure | Species | Method | Sperm epigenetic aberrations | Implications | References |
|---|---|---|---|---|---|
| Endocrine-disrupting compounds | |||||
| Phthalates | Human | 450K Array MassArray | Environmental relevant levels of anti-androgenic urinary phthalate metabolites (MEHP, MBP and MCOCH) were associated with the majority of sperm DMRs, which were enriched in genes associated with blastocyst quality, growth and development, and cellular function and maintenance. Additionally, 17 DMRs were associated with diminished blastocyst quality. | Spermatogenesis/embryo quality | Wu et al. 2017b |
| DEHP | Human | HRM-PCR | Occupational exposure to DEHP exposure was inversely associated with LINE-1 DNA methylation. | Infertility | Tian et al. 2019 |
| Bisphenol A(BPA) | Human | 5-hMeDIP-seq | 9,610 sperm DMRs were identified in occupationally exposed men compared to controls. Correlation between urinary BPA levels and 5hmC was not examined. | Spermatogenesis | Zheng et al, 2017 |
| BPA | Human | qPCR | Higher sperm 5hmC at the ACHE gene locus was found among factory workers with BPA exposure compared to unexposed factory workers. However, no significant correlation between urinary BPA and ACHE 5hmC was found among all subjects. | Sperm quality | Song et al., 2019 |
| Dioxins | Human | WGBS | 52 sperm DMRs were identified in young adults who had high peripubertal (8–9 years of age) blood dioxin (TCDD) levels compared to those with low peripubertal blood dioxin levels. Enrichment of DMRs occurred at loci functionally relevant for development and cellular functions. | Embryo development/sperm functions | Pilsner et al. 2018 |
| Dioxins | Human | 450K Array | High serum level TCDD among Operation Ranch Hand Veterans was associated with methylation alterations at 36 sperm gene regions that included H19, compared to control. Data comparison with previous study (Pilsner et al. 2018) showed 5 significant overlapping loci with consistent methylation directionality. | Embryo development/sperm quality | Kelsey et al. 2019 |
| Drug use | |||||
| Chemotherapy | Human | MeDIP-seq | Chemotherapy was significantly associated with over 2,000 DMRs mostly within the CpG desert regions of exposed sperm compared to control. | Inheritance | Shnorhavorian et al. 2017 |
| Chemotherapy (BEP) | Rat | RLGS | A total 143 loci were reported to be significantly altered in both spermatids and mature spermatozoa of exposed rat relative to controls with methylation. | Spermatogenesis | Chan et al. 2012 |
| Cigarettes | Human | 450K Array | 141 CpGs were associated with smoking, 74% of which were hypomethylated and occurred most frequently at regions previously reported to display H3K4 and H3K27 methylation in mature sperm. | Spermatogenesis | Jenkins et al. 2017 |
| Cigarettes | Human | Pyrosequencing | Cigarette smoking altered sperm methylation of H19 and SNRPN and was found to be associated with increased risk of poor sperm motility and morphology. | Sperm quality | Dong et al. 2017 |
| Cigarettes | Human | 450K Array | Current smokers exhibited differential methylation at 7 CpG sites related to MAPK8IP3 and TKR genes, important for capacitation and spermatogenesis respectively. | Sperm function/spermatogenesis | Laqqan et al. 2017 |
| Cigarettes | Human | 450K Array | Cigarette smoking was associated with 11 CpG loci in sperm within PGAM5, PTPRN2 and TYRO3, the latter is important for spermatogenesis. | Spermatogenesis | Alkhaled et al. 2018 |
| Nicotine | Mice | MeDIP; qPCR | Nicotine exposure induced changes in global and dopamine-specific sperm DNA methylation with inter- and transgenerational adverse health effects. | Inheritance | McCarthy et al. 2018 |
| Cannabis THC | Human and Rat | RRBS; Pyrosequencing | Cannabis use was associated with 3,979 sperm DMRs including genes, PTPRN2 and MAPK8IP3, previously found to be sensitive to tobacco exposure. There was substantial overlap in DMRs between rat (THC-exposure) and human sperm. | Spermatogenesis | Murphy et al. 2018 |
| Cannabis THC | Human and Rat | Pyrosequencing | This study validated the sensitivity (hypomethylation) of specific loci found within intronic region of DLGAP2, a gene strongly implicated in autism. | Inheritance | Schrott et al. 2019 |
| Ethanol | Mice | RT-qPCR | Ethanol exposure resulted in hypomethylation of Bdnf promoter of sperm, which was maintained in the ventral tegmental area of offspring. | Inheritance | Finegersh and Homanics 2014 |
| Ethanol | Mice | RT-qPCR | Ethanol exposure was associated with altered expression of sperm small RNAs (tRNA, mitochondrial small RNA, and microRNA) and epididymosomal tRNA. | Inheritance | Rompala et al. 2018 |
| Diet | |||||
| Low protein diet (LPD) | Mice | RRBS; MeDIP | LPD induced depletion of gene promoter H3K27me3 in F0 sperm compared to control. Offspring of LPD sires exhibited altered methylation at promoters of liver PPARa gene relative to control. | Inheritance | Carone et al. 2010 |
| LPD | Mice | RT-qPCR; RNA-seq | LPD was associated with downregulation of let-7 miRNA and upregulation of 5’ tRFs in sperm, a profile that matched LPD-induced sRNA alterations in epididymosomes. | Embryo development | Sharma et al. 2016 |
| LPD | Mice | MBD2-seq; RT-qPCR | LPD induced global hypomethylation and reduced expression of Dnmt1 and Dnmt4l in sperm. Offspring of LPD fathers gained more weight compared to offspring of controls. | Inheritance | Watkins et al. 2018 |
| High fat diet (HFD) | Mice | Microarray; RT-qPCR; ELISA | HFD caused differential expression of 4 miRNAs in sperm as well as global hypomethylation in late elongating spermatids. | Inheritance | Fullston et al. 2013 |
| HFD + STZ | Mice | Microarray; MeDIP-seq; | HFD & STZ-induced paternal prediabetes altered overall sperm methylome and was associated with genes largely overlapping with offspring’s pancreatic islets. | Inheritance | Wei et al. 2014 |
| HFD + high sugar | Mice | RT-qPCR, RNA‐seq | Western-like diet, characterized with high HFD and/or high sugar, altered sperm RNA population, predominantly miRNA. Injection of miR-19b into naive embryo produced offspring with metabolic disorder similar to F0 phenotypes. | Embryo development/Offspring diseases | Grandjean et al. 2015 |
| HFD | Mice | RT-qPCR; ELISA | No differential global methylation was observed in sperm of HFD-induced obese mice group relative to control. | Sperm function | Binder et al. 2015 |
| HFD | Rat | MBD; RT-qPCR; RNA-seq | HFD altered sperm DNA methylation profile and differential expression of sncRNAs (piRNAs and miRNA let-7c). Similar sperm epigenetic profile observed in male F1 generation. | Inheritance | De Castro Barbosa et al. 2016 |
| HFD | Mice | RT-qPCR, RNA‐Seq | HFD altered sperm tRNA and was associated with F1 metabolic disorder. Zygotic injection of sperm tRNA fraction from HFD males produced metabolic disorders in F1 offspring. | Inheritance | Chen et al. 2016 |
| HFD | Mice | RT-qPCR, RNA‐seq | Dnmt2 knock out reduced sperm tRNA and nullified metabolic disorders effect of HFD in offspring. | Inheritance | Zhang et al. 2018 |
| Folic acid | Human | RRBS | Long-term exposure to high level of folic acid resulted in global sperm hypomethylation predominantly at low CpG density and DNA repeats regions. | Infertility | Aarabi et al. 2015 |
| Folic acid | Human | 450K Array | Sperm DNA methylation was not altered from short-term supplementation with low dose folic acid. | - | Chan et al. 2017 |
| Folic acid | Mice | RRBS | At high dose folic acid, sperm hypomethylation occurred in heterozygous Mthfr genotype mice but not in wildtype. Hypomethylation in wild type sperm was only observed at extremely high dose with deficiency in Mthfr expression. | Infertility | Aarabi et al. 2018 |
| Obesity | |||||
| Obesity/weight loss | Human | MNase-seq; RRBS; RNA-seq | Obese men had altered sperm piRNAs compared to lean men. Sperm DNA methylation was remodeled after gastric-bypass surgery-induced weight loss. | Sperm quality | Donkin et al. 2016 |
| Obesity | Human | Pyrosequencing | Obese men had significantly altered methylation at imprinted loci of sperm compared to lean men. | Sperm quality | Soubry et al. 2016 |
| BMI | Human | RNA-seq | Male BMI was associated with 421 short exon sized RNA elements, which were related to epigenetic processes that regulate chromatin organization. | Sperm quality | Swanson et al. 2019 |
| Exercise | |||||
| Long-term exercise | Mice | MBD; RT-qPCR | Mice subjected to 12 weeks exercise had altered sperm DNA methylation in metabolic genes and miRNA profiles. | Inheritance | Murashov et al. 2016 |
| Voluntary wheel running | Mice | RNAseq; RT-qPCR | Mice that experienced voluntary wheel-running exercise exhibited altered sperm miRNA and tRNA expression. Also, male offspring of runners had suppressed juvenile fear memory and reduced anxiety. | Inheritance | Short et al. 2017 |
| Short term training/detraining | Human | RNA-seq; RRBS | Exercise reversed alteration in sperm piRNA expression. Training and detraining induced methylation alterations at regions functionally related to neurogenesis, neuron differentiation, and axon guidance. | Development | Ingerslev et al. 2018 |
| Environmental stress | |||||
| Peripubertal/adult trauma | Mice | RT-qPCR | Pubertal or adult-exposure to chronic variable stress altered sperm miRNA profiles, which was associated with dysregulation of HPA stress axis in both male and female offspring. | Inheritance | Rodgers et al. 2013 |
| Odor | Mice | ChIP; RT-qPCR | Compared to control, odor fear conditioned F0 mice displayed CpG hypomethylation of sperm Olfr151 gene with similar methylome alteration in F1 sperm. | Inheritance | Dias & Ressler 2014 |
| Cold | Mice | Pyrosequencing; WGBS | Cold exposed mice had significant sperm global CpG methylation alteration and DMRs (2,341) within or downstream of genes important for neurogenesis relative to control. | Development/inheritance | Sun et al. 2018 |
Abbreviations: HRM: High-melting resolution; MBD: Methyl Binding Domain; MeDIP: Methylated DNA immunoprecipitation; 5-hMeDIP-seq: 5-hyroxymethyl cytosine DNA immunoprecipitation (hMeDIP) Sequencing; RRBS: Reduced representation bisulfite sequencing; WGBS: Whole genome bisulfite sequencing; RLGS: Restriction landmark genomic scanning; MNase-seq: Micrococcal nuclease-sequencing; ChIP: Chromatin immunoprecipitation; SMART-seq: Switch Mechanism at the 5′ End of RNA Templates-sequencing; ELISA: Enzyme-linked immunosorbent assay; STZ: Streptozotocin; HFD: High fat diet; LPD: Low protein diet; BEP : bleomycin, etoposide, and cis-platinum