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 1

Male LDL receptor–deficient mice fed a low-fat, high-cholesterol diet develop severe hypercholesterolemia-mediated atherosclerosis.

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Male LDL receptor–deficient mice fed a low-fat, high-cholesterol diet de...
Three-week-old male LDLR–/– mice were fed a low-cholesterol diet (LCD, 0.02% cholesterol) or high-cholesterol diet (HCD, 0.5% cholesterol) for 8 weeks before mating with female LDLR–/– mice. The F1 offspring were weaned at 3 weeks old and were fed an LCD for 16 weeks. (A) Schematic representation of experimental design and generation of F1 offspring. (B) Serum total cholesterol and triglyceride levels were measured (n = 4–6, ***P < 0.001, 2-sample, 2-tailed Student’s t test). (C) Lipoprotein fractions (VLDL-C, LDL-C, and HDL-C) were isolated from serum, and the cholesterol levels of each fraction were measured (n = 5–6, **P < 0.01, ***P < 0.001; 2-sample, 2-tailed Student’s t test). (D) Quantitative analysis of the lesion area in the aortic root of LCD- and HCD-fed LDLR–/– mice (n = 7, ***P < 0.05, 2-sample, 2-tailed Student’s t test). Representative images are shown to the right. VLDL-C, very low-density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol. All data are plotted as mean ± SEM. Scale bar: 100 μm.