School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, Australia; Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, Sydney, NSW 2037, Australia.
Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
Environ Int. 2024 Sep;191:108971. doi: 10.1016/j.envint.2024.108971. Epub 2024 Aug 20.
There is no safe level of air pollution for human health. Traffic-related particulate matter (PM) is a major in-utero toxin, mechanisms of action of which are not fully understood. BALB/c dams were exposed to an Australian level of traffic PM (5 µg/mouse/day, intranasal, 6 weeks before mating, during gestation and lactation). Male offspring had reduced memory in adulthood, whereas memory was normal in female littermates, similar to human responses. Maternal PM exposure resulted in oxidative stress and abnormal mitochondria in male, but not female, brains. RNA-sequencing analysis showed unique sex-related changes in newborn brains. Two X-chromosome-linked histone lysine demethylases, Kdm6a and Kdm5c, demonstrated higher expression in female compared to male littermates, in addition to upregulated genes with known functions to support mitochondrial function, synapse growth and maturation, cognitive function, and neuroprotection. No significant changes in Kdm6a and Kdm5c were found in male littermates, nor other genes, albeit significantly impaired memory function after birth. In primary foetal cortical neurons, PM exposure suppressed neuron and synaptic numbers and induced oxidative stress, which was prevented by upregulation of Kdm6a or Kdm5c. Therefore, timely epigenetic adaptation by histone demethylation to open DNA for translation before birth may be the key to protecting females against prenatal PM exposure-induced neurological disorders, which fail to occur in males associated with their poor cognitive outcomes.
对于人类健康而言，空气污染不存在安全水平。交通相关的颗粒物（PM）是一种主要的宫内毒素，其作用机制尚未完全阐明。BALB/c 孕鼠在受孕前 6 周、妊娠期和哺乳期经鼻腔每天接受相当于澳大利亚交通水平的 PM（5μg/只）暴露。雄性后代在成年后记忆力下降，而雌性同窝仔则记忆力正常，这与人类的反应相似。母体 PM 暴露导致雄性而非雌性大脑中的氧化应激和异常线粒体。RNA 测序分析显示新生大脑存在独特的性别相关变化。两个 X 染色体连锁的组蛋白赖氨酸去甲基酶 Kdm6a 和 Kdm5c 在雌性中比雄性同窝仔的表达更高，除了已知具有支持线粒体功能、突触生长和成熟、认知功能和神经保护作用的上调基因。尽管出生后记忆功能明显受损，但雄性同窝仔中 Kdm6a 和 Kdm5c 以及其他基因均未发生显著变化。在原代胎儿皮质神经元中，PM 暴露抑制神经元和突触数量，并诱导氧化应激，而 Kdm6a 或 Kdm5c 的上调可预防这种应激。因此，在出生前通过组蛋白去甲基化及时进行表观遗传适应，打开 DNA 进行翻译，可能是保护女性免受产前 PM 暴露引起的神经紊乱的关键，而男性则不会出现这种紊乱，这与他们认知能力较差有关。
