Secondhand smoke affects reproductive functions by altering the mouse testis transcriptome, and leads to select intron retention in Pde1a

• Published in: Environment international Vol. 161; p. 107086
• Main Authors: Tommasi, Stella, Kitapci, Tevfik H., Blumenfeld, Hannah, Besaratinia, Ahmad
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.03.2022; Elsevier
• Subjects: Animals; Cyclic Nucleotide Phosphodiesterases, Type 1; Gene expression; Introns; Male; Male reproductive system; Mice; RNA-seq; Secondhand smoke; Spermatozoa; Testis; Tobacco Smoke Pollution - adverse effects; Transcriptome; Variant; BH; PDE1A; PTEN; HEPA; DEGs; RNA-seq; FDR; SNPs; IACUC; Neat1; RT-qPCR; SHS; WHO; Secondhand smoke; Klk1b21; SV; Tbp; TGFB1; NMD; UTRs; IR; Steap1; HNF1A; IGF1; Gene expression; Ints6l; MSS; Actb; PCA; Variant; GATK; TSP; SSS; TEC; Gadph; Male reproductive system; IPA; FC; PTC
• ISSN: 0160-4120; 1873-6750; 1873-6750
• DOI: 10.1016/j.envint.2022.107086

[Display omitted] •There is a paucity of data on the effects of SHS on the male reproductive system.•We investigated the effects of SHS on the testis transcriptome in a mouse model.•Testis development & function-specific genes were dysregulated in SHS-exposed mice.•SHS-exposed mice showed a novel intron variant in a key regulator of spermatogenesis.•SHS exposure adversely affects reproductive system-related genes and pathways in mice. Human exposure to secondhand smoke (SHS) is known to result in adverse effects in multiple organ systems. However, the impact of SHS on the male reproductive system, particularly on the regulation of genes and molecular pathways that govern sperm production, maturation, and functions remains largely understudied. We investigated the effects of SHS on the testis transcriptome in a validated mouse model. Adult male mice were exposed to SHS (5 h/day, 5 days/week for 4 months) as compared to controls (clean air-exposed). RNA-seq analysis was performed on the testis of SHS-exposed mice and controls. Variant discovery and plink association analyses were also conducted to detect exposure-related transcript variants in SHS-treated mice. Exposure of mice to SHS resulted in the aberrant expression of 131 testicular genes. Whilst approximately two thirds of the differentially expressed genes were protein-coding, the remaining (30.5%) comprised noncoding elements, mostly lncRNAs (19.1%). Variant discovery analysis identified a homozygous frameshift variant that is statistically significantly associated with SHS exposure (P = 7.744e-06) and is generated by retention of a short intron within Pde1a, a key regulator of spermatogenesis. Notably, this SHS-associated intron variant harbors an evolutionarily conserved, premature termination codon (PTC) that disrupts the open reading frame of Pde1a, presumably leading to its degradation via nonsense-mediated decay. SHS alters the expression of genes involved in molecular pathways that are crucial for normal testis development and function. Preferential targeting of lncRNAs in the testis of SHS-exposed mice is especially significant considering their crucial role in the spatial and temporal modulation of spermatogenesis. Equally important is our discovery of a novel homozygous frameshift variant that is exclusively and significantly associated with SHS-exposure and is likely to represent a safeguard mechanism to regulate transcription of Pde1a and preserve normal testis function during harmful exposure to environmental agents.