Sala-Hamrick Kimberley E, Wang Kai, Perera Bambarendage P U, Sartor Maureen A, Svoboda Laurie K, Dolinoy Dana C
Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
Epigenetics. 2025 Dec;20(1):2542879. doi: 10.1080/15592294.2025.2542879. Epub 2025 Aug 10.
The landscape of PIWI-interacting RNA (piRNA) expression in the heart is poorly understood, particularly regarding sex differences. Altered piRNA expression has been reported in cardiovascular disease (CVD), and although exposure to the metal lead (Pb) is strongly associated with CVD risk, no studies have investigated Pb's effects on cardiac piRNAs. This study aimed to characterize piRNA expression in the murine heart and assess sex-specific effects of human-relevant maternal Pb exposure on adult offspring cardiac piRNA expression. piRNAs were identified from whole mouse hearts using sodium periodate exclusion of small RNA and subsequent sequencing. Control mice expressed 18,956 piRNAs in combined-sex analysis; sex-specific analyses revealed 9,231 piRNAs in female hearts and 5,972 piRNAs in male hearts. Genomic mapping showed 28-41% aligned to introns, while 12-28% mapped to exons. Comparing control and Pb-exposed hearts, we found more potential Pb-induced expression changes in females (847) compared to males (187) (p-value < 0.05 and |logFC| > 1). These piRNAs were significantly enriched near genes involved in biological processes related to heart function and CVD development, including mitochondrial function, energy metabolism, and cardiac muscle structure (FDR < 0.05). Overall, we characterized combined and sex-stratified piRNA expression in both control and Pb-exposed murine hearts. In addition to providing a foundation for sex-specific piRNA expression in the heart, these findings suggest a novel epigenetic mechanism by which developmental Pb exposure may impact CVD risk later in life. Future studies will link these sex-specific molecular changes to Pb-induced alterations in cardiac function.
人们对心脏中与PIWI相互作用RNA（piRNA）表达的情况了解甚少，尤其是关于性别差异方面。已有报道称心血管疾病（CVD）中piRNA表达发生改变，尽管接触金属铅（Pb）与CVD风险密切相关，但尚无研究调查铅对心脏piRNA的影响。本研究旨在描述小鼠心脏中piRNA的表达特征，并评估与人类相关的母体铅暴露对成年后代心脏piRNA表达的性别特异性影响。使用高碘酸钠排除小RNA并随后进行测序，从小鼠全心脏中鉴定出piRNA。在综合性别分析中，对照小鼠表达了18,956种piRNA；性别特异性分析显示，雌性心脏中有9,231种piRNA，雄性心脏中有5,972种piRNA。基因组定位显示，28% - 41%的piRNA与内含子对齐，而12% - 28%的piRNA定位在外显子上。比较对照心脏和铅暴露心脏，我们发现与雄性（187种）相比，雌性中潜在的铅诱导表达变化更多（847种）（p值<0.05且|logFC|>1）。这些piRNA在与心脏功能和CVD发展相关的生物学过程（包括线粒体功能、能量代谢和心肌结构）相关的基因附近显著富集（FDR<0.05）。总体而言，我们描述了对照和铅暴露小鼠心脏中综合及性别分层的piRNA表达情况。除了为心脏中性别特异性piRNA表达提供基础外，这些发现还提示了一种新的表观遗传机制，即发育过程中的铅暴露可能在以后的生活中影响CVD风险。未来的研究将把这些性别特异性分子变化与铅诱导的心脏功能改变联系起来。
