Paternal hypercholesterolemia elicits sex-specific exacerbation of atherosclerosis in offspring
Rebecca Hernandez, Xiuchun Li, Junchao Shi, Tejasvi R. Dave, Tong Zhou, Qi Chen, Changcheng Zhou
Rebecca Hernandez, Xiuchun Li, Junchao Shi, Tejasvi R. Dave, Tong Zhou, Qi Chen, Changcheng Zhou
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Research Article Cell biology Vascular biology

Paternal hypercholesterolemia elicits sex-specific exacerbation of atherosclerosis in offspring

Abstract

Emerging studies suggest that various parental exposures affect offspring cardiovascular health, yet the specific mechanisms, particularly the influence of paternal cardiovascular disease (CVD) risk factors on offspring cardiovascular health, remain elusive. The present study explores how paternal hypercholesterolemia affects offspring atherosclerosis development using the LDL receptor-deficient (LDLR–/–) mouse model. We found that paternal high-cholesterol diet feeding led to significantly increased atherosclerosis in F1 female, but not male, LDLR–/– offspring. Transcriptomic analysis highlighted that paternal hypercholesterolemia stimulated proatherogenic genes, including Ccn1 and Ccn2, in the intima of female offspring. Sperm small noncoding RNAs (sncRNAs), particularly transfer RNA–derived (tRNA-derived) small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), contribute to the intergenerational transmission of paternally acquired metabolic phenotypes. Using a newly developed PANDORA-Seq method, we identified that high-cholesterol feeding elicited changes in sperm tsRNA/rsRNA profiles that were undetectable by traditional RNA-Seq, and these altered sperm sncRNAs were potentially key factors mediating paternal hypercholesterolemia-elicited atherogenesis in offspring. Interestingly, high-cholesterol feeding altered sncRNA biogenesis–related gene expression in the epididymis but not testis of LDLR–/– sires; this may have led to the modified sperm sncRNA landscape. Our results underscore the sex-specific intergenerational effect of paternal hypercholesterolemia on offspring cardiovascular health and contribute to the understanding of chronic disease etiology originating from parental exposures.

Authors

Rebecca Hernandez, Xiuchun Li, Junchao Shi, Tejasvi R. Dave, Tong Zhou, Qi Chen, Changcheng Zhou

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Figure 9

PANDORA-Seq reveals significantly changed sperm tsRNAs and rsRNAs induced by high-cholesterol diet feeding in male LDL receptor–deficient mice.

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PANDORA-Seq reveals significantly changed sperm tsRNAs and rsRNAs induce...
Three-week-old male LDLR–/– mice were fed an LCD or HCD for 9 weeks. Total RNAs were isolated from the sperm and used for PANDORA-Seq and traditional small RNA sequencing. (A) Sperm tsRNA and rsRNA relative expression (normalized to miRNAs) under traditional sequencing and PANDORA-Seq protocols. (B) Sperm tsRNA responses to traditional sequencing and PANDORA-Seq in regard to different genomic or mitochondria tRNA origins (5′tsRNA, 3′tsRNA, 3′tsRNA-CCA end, and internal tsRNAs). The y axes represent the relative expression levels compared with total reads of miRNA. Different letters above the bars indicate statistically significant differences (P < 0.05). Same letters indicate P > 0.05. Statistical significance was determined by 2-sided 1-way ANOVA with uncorrected Fisher’s least significant difference test. All data are plotted as mean ± SEM. (C) Heatmap representation of differentially expressed sperm tsRNAs detected by PANDORA-Seq. Biological replicates are represented in each row. Red represents relatively increased expression, whereas blue represents decreased expression with adjusted P < 0.05 and FC > 2 as the cutoff threshold. (D and E) Dynamic responses to LCD or HCD of representative sperm tsRNAs (D) and rsRNAs (E) detected by PADNORA-Seq. Mapping plots are presented as mean ± SEM (n = 3 in each group).