Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, 1719 6th Ave South, CIRC 560, Birmingham, AL, 35294, USA.
Center for Neuroscience, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Curr Environ Health Rep. 2022 Dec;9(4):563-573. doi: 10.1007/s40572-022-00380-6. Epub 2022 Oct 6.
Sex dimorphism in Parkinson's disease (PD) is an ostensible feature of the neurological disorder, particularly as men are 1.5-2 times more likely to develop PD than women. Clinical features of the disease, such as presentation at onset, most prevalent symptoms, and response to treatment, are also affected by sex. Despite these well-known sex differences in PD risk and phenotype, the mechanisms that impart sex dimorphisms in PD remain poorly understood.
As PD incidence is influenced by environmental factors, an intriguing pattern has recently emerged in research studies suggesting a male-specific vulnerability to dopaminergic neurodegeneration caused by neurotoxicant exposure, with relative protection in females. These new experimental data have uncovered potential mechanisms that provide clues to the source of sex differences in dopaminergic neurodegeneration and other PD pathology such as alpha-synuclein toxicity. In this review, we discuss the emerging evidence of increased male sensitivity to neurodegeneration from environmental exposures. We examine mechanisms underlying dopaminergic neurodegeneration and PD-related pathologies with evidence supporting the roles of estrogen, SRY expression, the vesicular glutamate transporter VGLUT2, and the microbiome as prospective catalysts for male vulnerability. We also highlight the importance of including sex as a biological variable, particularly when evaluating dopaminergic neurotoxicity in the context of PD.
帕金森病（PD）的性别二态性是该神经退行性疾病的一个明显特征，男性患 PD 的可能性比女性高 1.5-2 倍。疾病的临床特征，如发病时的表现、最常见的症状以及对治疗的反应，也受到性别的影响。尽管 PD 风险和表型存在这些众所周知的性别差异，但赋予 PD 性别二态性的机制仍知之甚少。
由于 PD 的发病率受环境因素的影响，最近的研究表明，一种有趣的模式已经出现，即男性对神经毒性暴露引起的多巴胺能神经退行性变特别敏感，而女性则相对受到保护。这些新的实验数据揭示了潜在的机制，为多巴胺能神经退行性变和其他 PD 病理学（如α-突触核蛋白毒性）中性别差异的来源提供了线索。在这篇综述中，我们讨论了环境暴露导致男性对神经退行性变敏感性增加的新证据。我们研究了多巴胺能神经退行性变和与 PD 相关的病理学的潜在机制，有证据表明雌激素、SRY 表达、囊泡谷氨酸转运体 VGLUT2 和微生物组作为男性易感性的潜在催化剂的作用。我们还强调了将性别作为生物学变量纳入研究的重要性，特别是在评估 PD 背景下的多巴胺能神经毒性时。
