人类接触多环芳烃 (PAH) 是一个严重且日益严重的公共卫生问题。由于气候变暖和大规模野火发生频率的增加，频繁的高剂量暴露可能会增加。在这里，我们描述了已经适应慢性、极端多环芳烃污染的野生异斜眼底种群中细胞色素 P450 1A ( CYP1A ) 基因的表观遗传记忆。在野生型鱼类中，PAH 高度诱导 CYP1A。在耐受 PAH 的鱼类中，CYP1A 的诱导作用减弱。由于 CYP1A 通过代谢激活 PAH，这种记忆可以保护这些鱼免受 PAH 介导的癌症。然而，在清洁水中饲养的耐受 PAH 的鱼恢复了 CYP1A 诱导能力，这表明诱导迟缓是先前接触的非遗传记忆。为了探索这种可能性，我们从对多环芳烃敏感和耐受的种群中培育纯化的野生鱼，对未接触过暴露的胚胎进行人工受精，并用多环芳烃挑战它们。我们观察到 F 1 PAH 耐受胚胎中世代 PAH 应激可逆记忆的表观遗传控制。具体来说，我们观察到 CYP1A 启动子增强子中的二价结构域包含激活和抑制组蛋白翻译后修饰。相对于抑制性修饰，激活性修饰在敏感胚胎中显示出对 PAH 的反应更大的增加，相对于耐受性，这与更大的基因激活一致。此外，耐受 PAH 的成年鱼在停止接触后很长一段时间内表现出 CYP1A 的持续诱导，这与有缺陷的 CYP1A 关闭和恢复到基线一致。由于 CYP1A 表达与癌症风险呈负相关，这些结果表明，耐 PAH 的鱼类在生命早期具有针对 PAH 诱发的癌症的表观遗传保护，这种保护会随着持续的基因激活而降解。表观遗传记忆，或生物体内跨细胞分裂的遗传或跨越几代人，环境暴露反应是一个引人注目的现象，但对机制的了解有限。在这里，我们表征了污染适应的异斜眼底 CYP1A 基因的表观遗传记忆。我们发现 CYP1A 启动子增强子包含一个二价结构域，包含活性和抑制性组蛋白修饰，该结构域显示出与污染物激活剂基因诱导减少相关的功能减少。在生命早期，这种记忆可以保护鱼类免受污染诱发的癌症。然而，这种减少的功能是有代价的；成年鱼的 CYP1A 转录恢复有缺陷，这会增加以后的癌症风险。这些结果为表观遗传记忆模型提供了初始机制，并强调了潜在的成本。

Human exposure to polycyclic aromatic hydrocarbons (PAH) is a significant and growing public health problem. Frequent, high dose exposures are likely to increase due to a warming climate and increased frequency of large-scale wildfires. Here, we characterize an epigenetic memory at the cytochrome P450 1A ( CYP1A ) gene in a population of wild Fundulus heteroclitus that has adapted to chronic, extreme PAH pollution. In wild-type fish, CYP1A is highly induced by PAH. In PAH-tolerant fish, CYP1A induction is blunted. Since CYP1A metabolically activates PAH, this memory protects these fish from PAH-mediated cancer. However, PAH-tolerant fish reared in clean water recover CYP1A inducibility, indicating that blunted induction is a non-genetic memory of prior exposure. To explore this possibility, we bred depurated wild fish from PAH-sensitive and -tolerant populations, manually fertilized exposure-naïve embryos, and challenged them with PAH. We observed epigenetic control of the reversible memory of generational PAH stress in F 1 PAH-tolerant embryos. Specifically, we observed a bivalent domain in the CYP1A promoter enhancer comprising both activating and repressive histone post-translational modifications. Activating modifications, relative to repressive ones, showed greater increases in response to PAH in sensitive embryos, relative to tolerant, consistent with greater gene activation. Also, PAH-tolerant adult fish showed persistent induction of CYP1A long after exposure cessation, which is consistent with defective CYP1A shutoff and recovery to baseline. Since CYP1A expression is inversely correlated with cancer risk, these results indicate that PAH-tolerant fish have epigenetic protection against PAH-induced cancer in early life that degrades in response to continuous gene activation.Epigenetic memory, or the inheritance across cell division within an organism or across generations, of environmental exposure response is a compelling phenomenon with limited understanding of mechanism. Here, we characterized an epigenetic memory at the CYP1A gene in pollution-adapted Fundulus heteroclitus . We found that the CYP1A promoter enhancer contains a bivalent domain, comprising both active and repressive histone modifications, that shows reduced function correlating with reduced gene induction by its pollutant activator. In early life, this memory protects fish against pollution-induced cancer. However, this reduced function carries a cost; adult fish show defective transcriptional recovery of CYP1A , which increases cancer risk later in life. These results provide an initial mechanism for a model epigenetic memory and highlight potential costs.