TABLE 2.

Key studies for genetic, epigenetic, and transgenerational of male reproductive impairment.

Study	Year	Study cohort	Findings	Key findings for future studies	Future integration
Genetics Aston et al. (73)	2009	52 oligozoospermic men and 40 azoospermic men.	Identification of 21 SNPs associated with oligozoospermia and azoospermia.	Pilot GWAS for future studies linking SNPs with male infertility.	Identification of unique SNPs associated with male infertility.
Lopes et al. (74) Epigenetics	2013	Sample 1: 323 Caucasian men with spermatogenic impairment + 1,100 controls. Sample 2: 979 Han Chinese men with azoospermia + 6,253 controls.	Rare autosomal deletions, rare X-linked CNVs, and rare Y-linked duplications increase an individual’s risk of spermatogenic impairment by 10%, 29%, and 88%, respectively. DMRT1 loss of function mutations are rare risk factors for spermatogenic failure.	Hypothesis generating data to direct future studies linking CNVs to azoospermia.	Identification of unique CNVs associated with male infertility.
Hammoud et al. (31)	2009	Semen samples from four men with known fertility.	Enrichment of modified nucleosomes among genes for embryonic development in sperm may provide instruction for regulation of developmental gene, noncoding RNA, and imprinted loci.	Highlight sperm epigenetic markings and links to developmental regulation.	Determination of specific epigenetic signatures associated with male infertility.
Aston et al. (41)	2015	127 men with male factor infertility undergoing IVF and 54 normospermic controls.	Significant difference in sperm DNA methylation between men with male factor infertility undergoing IVF compared with fertile men, which was predictive of poor embryo quality.	Understand what impacts sperm DNA methylation signatures.	Use of specific epigenetic signatures to help guide treatment with ART.
Jenkins et al. (46) Transgenerational/familial fertility and somatic health assessments	2018	329 semen samples from fertile and infertile men.	Predictive model incorporating sperm DNA methylation signatures can predict an individual’s age with >94% accuracy.	Drive investigation on the potential impacts of epigenetic signatures on aging, fertility, and somatic health.	Use of sperm DNA methylation signatures to understand environmental effects.
Guo et al. (54)	2018	Single-cell RNA sequencing of 6,500 testicular cells.	Description of key transcription and epigenetic signatures in the normal adult human testis. Suggested developmental plasticity between five transcriptional/ developmental state (including unique state 0, a novel early hSSC state).	Highlight new areas into germ cell development transitions and plasticity.	Contribute to development of hSSC for diagnostic and therapeutic uses.

Note: ART = artificial reproductive technologies; CI = confidence interval; CNV = copy number variants; GWAS = genomewide association study; HR = hazard ratio; hSSC = human spermatogonial stem cell; IVF = in vitro fertilization; SNP = single-nucleotide polymorphism.