Abstract：
Air pollution (AP) exposures have been associated with numerous neurodevelopmental and psychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia, all male-biased disorders with onsets from early life to late adolescence/early adulthood. While prior experimental studies have focused on effects of AP exposures during early brain development, brain development actually extends well into early adulthood. The current study in mice sought to extend the understanding of developmental brain vulnerability during adolescence, a later but significant period of brain development and maturation to the ultrafine particulate (UFPs) component of AP, considered its most reactive component. Additionally, it examined adolescent response to UFPs when preceded by earlier developmental exposures, to ascertain the trajectory of effects and potential enhancement or mitigation of adverse consequences. Outcomes focused on shared features associated with multiple neurodevelopmental disorders. For this purpose, C57Bl/6 J mice of both sexes were exposed to ambient concentrated UFPs or filtered air from PND (postnatal day) 4-7 and PND10-13, and again at PND39-42 and 45-49, resulting in 3 exposure postnatal/adolescent treatment groups per sex: Air/Air, Air/UFP, and UFP/UFP. Features common to neurodevelopmental disorders were examined at PND50. Mass exposure concentration from postnatal exposure averaged 44.34 μg/m3 and the adolescent exposure averaged 49.18 μg/m3. Male brain showed particular vulnerability to UFP exposures in adolescence, with alterations in frontal cortical and striatal glutamatergic and tryptophan/serotonergic neurotransmitters and concurrent reductions in levels of astrocytes in corpus callosum and in serum cytokine levels, with combined exposures resulting in significant reductions in corpus callosum myelination and serum corticosterone. Reductions in serum corticosterone in males correlated with reductions in neurotransmitter levels, and reductions in striatal glutamatergic function specifically correlated with reductions in corpus callosum astrocytes. UFP-induced changes in neurotransmitter levels in males were mitigated by prior postnatal exposure, suggesting potential adaptation, whereas reductions in corticosterone and in corpus callosum neuropathological effects were further strengthened by combined postnatal and adolescent exposures. UFP-induced changes in females occurred primarily in striatal dopamine systems and as reductions in serum cytokines only in response to combined postnatal and adolescent exposures. Findings in males underscore the importance of more integrated physiological assessments of mechanisms of neurotoxicity. Further, these findings provide biological plausibility for an accumulating epidemiologic literature linking air pollution to neurodevelopmental and psychiatric disorders. As such, they support a need for consideration of the regulation of the UFP component of air pollution.
摘要：
空气污染（AP）暴露与许多神经发育和精神疾病有关，包括自闭症谱系障碍,注意缺陷多动障碍和精神分裂症，从生命早期到青春期后期/成年早期的所有男性偏见疾病。虽然先前的实验研究集中在早期大脑发育过程中AP暴露的影响，大脑发育实际上一直延伸到成年早期。目前对小鼠的研究试图扩大对青春期发育大脑脆弱性的理解，大脑发育和成熟到AP的超细颗粒（UFP）成分的后期但重要的时期，被认为是其最具反应性的成分。此外,它检查了青少年对UFP的反应，确定影响的轨迹和潜在的增强或缓解不利后果。结果集中在与多种神经发育障碍相关的共同特征上。为此,将两种性别的C57Bl/6J小鼠暴露于环境浓缩的UFP或来自PND（出生后第4-7天）和PND10-13的过滤空气，并再次暴露于PND39-42和45-49，导致每个性别3个暴露于出生后/青少年治疗组：空气/空气，空气/UFP,和UFP/UFP。在PND50检查了神经发育障碍的常见特征。出生后暴露的质量暴露浓度平均为44.34μg/m3，青少年暴露平均为49.18μg/m3。男性大脑在青春期对UFP暴露表现出特别的脆弱性，额叶皮质和纹状体谷氨酸能和色氨酸/5-羟色氨酸能神经递质的改变，以及call体星形胶质细胞水平和血清细胞因子水平的同时降低，联合暴露导致call体髓鞘形成和血清皮质酮显著减少。男性血清皮质酮的降低与神经递质水平的降低相关，纹状体谷氨酸能功能的减少与call体星形胶质细胞的减少特别相关。UFP诱导的男性神经递质水平的变化通过先前的产后暴露得到缓解，暗示潜在的适应性，而出生后和青少年联合暴露进一步加强了皮质酮和call体神经病理效应的降低。UFP引起的女性变化主要发生在纹状体多巴胺系统中，而血清细胞因子的减少仅是对产后和青少年联合暴露的反应。男性的研究结果强调了对神经毒性机制进行更综合的生理评估的重要性。Further,这些发现为越来越多的将空气污染与神经发育和精神疾病联系起来的流行病学文献提供了生物学上的合理性.因此，他们支持需要考虑对UFP空气污染组成部分的监管。
