Critical windows of susceptibility in the association between manganese and neurocognition in Italian adolescents living near ferro-manganese industry,NeuroToxicology

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Critical windows of susceptibility in the association between manganese and neurocognition in Italian adolescents living near ferro-manganese industry
NeuroToxicology ( IF 3.4 ) Pub Date : 2021-08-31 , DOI: 10.1016/j.neuro.2021.08.014
Julia Anglen Bauer ₁ , Roberta F White ₂ , Brent A Coull ₃ , Christine Austin ₄ , Manuela Oppini ₅ , Silvia Zoni ₅ , Chiara Fedrighi ₅ , Giuseppa Cagna ₅ , Donatella Placidi ₅ , Stefano Guazzetti ₆ , Qiong Yang ₇ , David C Bellinger ₈ , Thomas F Webster ₁ , Robert O Wright ₄ , Donald Smith ₉ , Megan Horton ₄ , Roberto G Lucchini ₁₀ , Manish Arora ₄ , Birgit Claus Henn ₁

Affiliation

Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA.
Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy.
Azienda USL - IRCCS - di Reggio Emilia, Italy.
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Departments of Neurology and Psychiatry, Boston Children's Hospital, Boston, MA, USA; Departments of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA.
Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, CA, USA.
Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy; School of Public Health, Florida International University, Miami, FL, USA.

Introduction

Understanding the neurodevelopmental effects of manganese (Mn) is complicated due to its essentiality for growth and development. While evidence exists for the harmful effects of excess Mn, pediatric epidemiologic studies have observed inconsistent associations between Mn and child cognition.

Objective

We sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers.

Methods

Deciduous teeth were collected from 195 participants (ages 10–14 years) of the Public Health Impact of Manganese Exposure (PHIME) study in Brescia, Italy. Measurements of tooth Mn represented prenatal (∼14 weeks gestation – birth), early postnatal (birth – 1.5 years) and childhood (∼1.5 – 6 years) time windows. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), to obtain composite IQ and subtest scores. Associations between tooth Mn at each time window and adolescent WISC-III scores were estimated using multivariable linear regression. We tested differences in associations between Mn and outcomes across time windows using multiple informant models. Sex-specific associations were explored in stratified models.

Results

Adjusted associations between tooth Mn and composite IQ scores were positive in the prenatal period and negative in the childhood period. Associations were strongest for subtest scores that reflect working memory, problem solving, visuospatial ability and attention: prenatal Mn was positively associated with Digits backward [SD change in score per interquartile range increase in Mn: β = 0.20 (95 % CI: 0.02, 0.38)] and Block design [β = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [β = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [β = -0.14 (-0.28, -0.001)]. Sex-stratified analyses suggested different Mn-cognition associations for boys and girls and was also dependent on the time window of exposure.

Conclusion

Our results suggest that exposure timing is critical when evaluating Mn associations between Mn and cognition. Higher prenatal Mn was beneficial for adolescent cognition; however, these beneficial associations shifted towards harmful effects in later time windows. Cognitive domains most sensitive to Mn across time windows included visuospatial ability, working memory, attention and problem-solving.

中文翻译：

生活在锰铁工业附近的意大利青少年锰与神经认知之间关联的关键易感性窗口

介绍

了解锰 (Mn) 对神经发育的影响是复杂的，因为它对生长和发育至关重要。虽然存在过量锰有害影响的证据，但儿科流行病学研究发现锰与儿童认知之间存在不一致的关联。

客观的

我们试图使用乳牙生物标志物来估计在三个不同的生命早期时间窗口测量的 Mn 与青少年认知之间的前瞻性关联。

方法

从意大利布雷西亚的锰暴露 (PHIME) 公共卫生影响研究的 195 名参与者（年龄 10-14 岁）中收集乳牙。牙齿 Mn 的测量代表产前（~14 周妊娠 - 出生）、产后早期（出生 - 1.5 岁）和儿童期（~1.5 - 6 岁）时间窗。神经心理学家管理韦氏儿童智力量表第三版 (WISC-III)，以获得综合智商和分测验分数。使用多变量线性回归估计每个时间窗的牙齿 Mn 与青少年 WISC-III 评分之间的关联。我们使用多个线人模型测试了跨时间窗口的 Mn 与结果之间关联的差异。在分层模型中探索了特定性别的关联。

结果

调整后的牙齿锰与综合智商得分之间的关联在产前呈正相关，而在儿童时期呈负相关。反映工作记忆、解决问题、视觉空间能力和注意力的子测验分数之间的关联最强：产前 Mn 与数字向后呈正相关 [Mn 每四分位数范围增加的分数变化标准差：β = 0.20（95% CI：0.02、0.38 )] 和 Block design [β = 0.21 (0.01, 0.41)] 并且出生后早期 Mn 与数字正向正相关 [β = 0.24 (0.09, 0.40)]，而儿童期 Mn 与编码呈负相关 [β = -0.14 ( -0.28, -0.001)]。性别分层分析表明男孩和女孩的锰认知关联不同，并且还取决于暴露的时间窗口。