Sperm production is comprised in mice exposed to environmentally relevant per- and polyfluoroalkyl substances (PFAS)

Per- and polyfluoroalkyl substances (PFAS) are a large group of persistent synthetic chemicals that are ubiquitous environmental contaminants. Mounting evidence demonstrates that PFAS can bioaccumulate and induce a suite of adverse health outcomes, including compromise of male reproduction. Despite this knowledge, there remains no clear consensus as to how PFAS elicit these responses. Accordingly, here we aimed to determine how an environmentally relevant cocktail of PFAS impact the fertility of male mice. After twelve weeks of continuous PFAS exposure, blood plasma was isolated for hormone and PFAS profiling and reproductive tissues and spermatozoa were subjected to a comprehensive battery of histological and functional analyses. These analyses revealed that PFAS exposure significantly reduced the rate of daily sperm production linked with reduced levels of circulating testosterone and dihydrotestosterone. Functional profiling of mature spermatozoa from PFAS exposed males failed to identify any overt changes in sperm viability, motility, DNA integrity, or ability to undergo capacitation and support in vitro fertilization and early embryonic development. PFAS exposed spermatozoa did, however, present with pronounced changes in their small non-coding RNA profile and were linked with significant dysregulation of early embryonic gene expression. These observations afford new mechanistic insight into how PFAS exposure impacts male reproductive health. Overall design: Male mice were exposed to a cocktail of PFAS chemicals for 12 weeks at two different doses (low and high). Following exposure, mice were euthanized and sperm was isolated from the cauda epididymis. Preparations of sperm were either snap frozen for subsequent small RNA-sequenicng or used as donors to fertilize eggs from control females to collect developmentall staged embryos (4-cell stage) for embryo RNA-sequencing.

全氟和多氟烷基物质（Per- and polyfluoroalkyl substances, PFAS）是一类分布广泛的持久性合成化学污染物。越来越多的研究证据表明，PFAS可在生物体内富集，并引发一系列不良健康效应，其中包括雄性生殖功能受损。尽管已有上述认知，但目前学界对于PFAS引发此类效应的具体机制仍未达成明确共识。有鉴于此，本研究旨在探究环境相关浓度的PFAS混合物对雄性小鼠生育能力的影响。在持续12周PFAS暴露后，研究人员采集小鼠血浆以进行激素与PFAS谱分析，并对生殖组织及精子开展了一套全面的组织学与功能学检测。分析结果显示，PFAS暴露显著降低了每日精子生成速率，且这一变化与循环中睾酮及二氢睾酮水平降低密切相关。对PFAS暴露雄性个体的成熟精子进行功能谱分析后，未发现精子活力、运动能力、DNA完整性，或获能、支持体外受精及早期胚胎发育的能力存在显著异常。但经PFAS暴露的精子，其小非编码RNA（small non-coding RNA）谱发生了显著改变，且与早期胚胎基因表达的显著失调相关。上述发现为理解PFAS暴露影响雄性生殖健康的具体机制提供了全新视角。整体实验设计：雄性小鼠以两种不同剂量（低剂量与高剂量）暴露于PFAS混合物，时长为12周。暴露结束后，对小鼠实施安乐死，从附睾尾分离精子。部分精子样本经快速冷冻后用于后续小RNA测序（small RNA-sequencing）；其余精子则作为受精供体，与对照雌性小鼠的卵子进行体外受精，以收集发育至4细胞期的胚胎，用于胚胎RNA测序。