Prenatal manganese biomarkers and operant test battery performance in Mexican children: Effect modification by child sex.

BACKGROUND: Manganese (Mn) is essential to healthy neurodevelopment, but both Mn deficiency and over-exposure have been linked to prefrontal cortex (PFC) impairments, the brain region that regulates cognitive and neurobehavioral processes responsible for spatial memory, learning, motivation, and time perception. These processes facilitated by attention, inhibitory control, working memory, and cognitive flexibility are often sexually dimorphic and complex, driven by multiple interconnected neurologic and cognitive domains. OBJECTIVE: We investigated the role of child sex as an effect modifier of the association between prenatal Mn exposure and performance in an operant testing battery (OTB) that assessed multiple cognitive and behavioral functional domains. METHODS: Children (N = 575) aged 6-8 years completed five OTB tasks. Blood and urinary Mn measurements were collected from mothers in the 2nd and 3rd trimesters. Multiple regression models estimated the association between Mn biomarkers at each trimester with OTB performance while adjusting for socio-demographic covariates. Covariate-adjusted weighted quantile sum (WQS) regression models were used to estimate the association of a Mn multi-media biomarker (MMB) mixture with OTB performance. Interaction terms were used to estimate modification effect by child sex. RESULTS: Higher blood Mn exposure was associated with better response rates (more motivation) on the progressive ratio task and higher overall accuracy on the delayed matching-to-sample task. In the WQS models, the MMB mixture was associated with better response rates (more motivation) on the progressive ratio task. Additionally, for the linear and WQS models, we observed a modification effect by child sex in the progressive ratio and delayed matching-to-sample tasks. Higher prenatal Mn biomarker levels were associated with improved task performance for girls and reduced performance in boys. CONCLUSION: Higher prenatal blood Mn concentrations and the MMB mixture predicted improved performance on two of five operant tasks. Higher prenatal Mn concentrations regulated executive functions in children in a sexually dimorphic manner. Higher prenatal Mn exposure is associated with improved performance on spatial memory and motivation tasks in girls, suggesting that Mn's nutritional role is sexually dimorphic, and should be considered when making dietary and/or environmental intervention recommendations.

Domain-specific effects of prenatal fluoride exposure on child IQ at 4, 5, and 6-12 years in the ELEMENT cohort.

OBJECTIVE: Prenatal exposure to fluoride has been associated with adverse neurodevelopmental outcomes. However, the neuropsychological profile of fluoride's developmental neurotoxicity at low levels and the stability of this relationship across childhood has not been characterized. We investigated the longitudinal and domain specific effect of prenatal fluoride exposure on IQ among children ages 4, 5, and 6-12 years in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort. METHODS: We measured the average of maternal urinary fluoride at each trimester of pregnancy adjusted for creatinine (MUFCRE). Children were administered the McCarthy Scales of Children's Abilities at ages 4 (N = 386) and 5 (N = 308), and the Wechsler Abbreviated Scale of Intelligence at age 6-12 (N = 278). We used generalized estimating equation (GEE) models to estimate the population averaged effect of MUFCRE concentration on longitudinal General Cognitive Index (GCI)/Full-Scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ (PIQ) scores (N = 348). We tested for possible interactions between MUFCRE and child sex as well as for MUFCRE and time point on children's IQ. All models controlled for relevant available covariates. RESULTS: The mean/median MUFCRE concentration was 0.90/0.83 mg/L (SD = 0.39; IQR, 0.64-1.11 mg/L). A 0.5 mg/L increase in MUFCRE predicted an average 2.12-point decrease in GCI/FSIQ (95% CI: -3.49, -0.75) and 2.63-point decrease in PIQ (95% CI: -3.87, -1.40). MUFCRE was marginally associated with VIQ across time (B = -1.29, 95% CI: -2.60, 0.01). No interactions between MUFCRE and child sex or MUFCRE and time were observed. CONCLUSION: The negative association between prenatal fluoride exposure and longitudinal IQ was driven by decrements in non-verbal intelligence (i.e. PIQ), suggesting that visual-spatial and perceptual reasoning abilities may be more impacted by prenatal fluoride exposure as compared to verbal abilities.

Prenatal PM2.5 exposure in the second and third trimesters predicts neurocognitive performance at age 9-10 years: A cohort study of Mexico City children.

INTRODUCTION: Prenatal exposure to fine particulate matter air pollution (PM2.5) is an important, under-studied risk factor for neurodevelopmental dysfunction. We describe the relationships between prenatal PM2.5 exposure and vigilance and inhibitory control, executive functions related to multiple health outcomes in Mexico City children. METHODS: We studied 320 children enrolled in Programming Research in Obesity, GRowth, Environment and Social Stressors, a longitudinal birth cohort study in Mexico City. We used a spatio-temporal model to estimate daily prenatal PM2.5 exposure at each participant's residential address. At age 9-10 years, children performed three Go/No-Go tasks, which measure vigilance and inhibitory control ability. We used Latent class analysis (LCA) to classify performance into subgroups that reflected neurocognitive performance and applied multivariate regression and distributed lag regression modeling (DLM) to test overall and time-dependent associations between prenatal PM2.5 exposure and Go/No-Go performance. RESULTS: LCA detected two Go/No-Go phenotypes: high performers (Class 1) and low performers (Class 2). Predicting odds of Class 1 vs Class 2 membership based on prenatal PM2.5 exposure timing, logistic regression modeling showed that average prenatal PM2.5 exposure in the second and third trimesters correlated with increased odds of membership in low-performance Class 2 (OR = 1.59 (1.16, 2.17), p = 0.004). Additionally, DLM analysis identified a critical window consisting of gestational days 103-268 (second and third trimesters) in which prenatal PM2.5 exposure predicted poorer Go/No-Go performance. DISCUSSION: Increased prenatal PM2.5 exposure predicted decreased vigilance and inhibitory control at age 9-10 years. These findings highlight the second and third trimesters of gestation as critical windows of PM2.5 exposure for the development of vigilance and inhibitory control in preadolescent children. Because childhood development of vigilance and inhibitory control informs behavior, academic performance, and self-regulation into adulthood, these results may help to describe the relationship of prenatal PM2.5 exposure to long-term health and psychosocial outcomes. The integrative methodology of this study also contributes to a shift towards more holistic analysis.

Prenatal exposure to metal mixtures and childhood temporal processing in the PROGRESS Birth Cohort Study: Modification by childhood obesity.

Children are frequently exposed to various biological trace metals, some essential for their development, while others can be potent neurotoxicants. Furthermore, the inflammatory and metabolic conditions associated with obesity may interact with and amplify the impact of metal exposure on neurodevelopment. However, few studies have assessed the potential modification effect of body mass index (BMI). As a result, we investigated the role of child BMI phenotype on the relationship between prenatal exposure to metal mixtures and temporal processing. Leveraging the PROGRESS birth cohort in Mexico City, children (N = 563) aged 6-9 years completed a Temporal Response Differentiation (TRD) task where they had to hold a lever down for 10-14 s. Blood and urinary metal (As, Pb, Cd, and Mn) measurements were collected from mothers in the 2nd and 3rd trimesters. Child BMI z-scores were dichotomized to normal (between -2 and +0.99) and high (≥1.00). Covariate-adjusted weighted quantile sum (WQS) regression models were used to estimate and examine the combined effect of metal biomarkers (i.e., blood and urine) on TRD measures. Effect modification by the child's BMI was evaluated using 2-way interaction terms. Children with a high BMI and greater exposure to the metal mixture during prenatal development exhibited significant temporal processing deficits compared to children with a normal BMI. Notably, children with increased exposure to the metal mixture and higher BMI had a decrease in the percent of tasks completed (ß = -10.13; 95 % CI: -19.84, -0.42), number of average holds (ß = -2.15; 95 % CI: -3.88, -0.41), longer latency (ß = 0.78; 95 % CI: 0.13, 1.44), and greater variability in the standard deviation of the total hold time (ß = 2.08; 95 % CI: 0.34, 3.82) compared to normal BMI children. These findings implicate that high BMI may amplify the effect of metals on children's temporal processing. Understanding the relationship between metal exposures, temporal processing, and childhood obesity can provide valuable insights for developing targeted environmental interventions.

Cesarean birth is associated with lower motor and language development scores during early childhood: a longitudinal analysis of two cohorts.

With global C-section rates rising, understanding potential consequences is imperative. Previous studies suggested links between birth mode and psychological outcomes. This study evaluates the association of birth mode and neurodevelopment in young children across two prospective cohorts, using repeated psychometric assessments. Data from the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) and PROGRESS (Programming Research in Obesity, Growth, and Environment and Social Stress) cohorts, comprising 7158 and 2202 observations of 1402 children aged 2 to 36 months, and 726 children aged 5 to 27 months, respectively, were analyzed. Exclusion criteria for the cohorts were maternal diseases such as preeclampsia, renal or heart disease, gestational diabetes, and epilepsy. Neurodevelopment was gauged via Bayley's Scales of Infant Development: 2nd edition for ELEMENT and 3rd edition for PROGRESS. Mixed-effects models longitudinally estimated associations between birth mode and neurodevelopment scores, adjusting for cofounders. In ELEMENT, psychomotor development composite scores were significantly affected by birth mode from ages 2 to 8 months; the largest estimate within this range was at 2 months (ß =-1.93; 95% CI: [-3.64, -0.22], reference: vaginal delivery). For PROGRESS, a negative association was found with motor development composite scores over all the studied age range (ß=-1.91; 95% CI: [-3.01, -0.81]). The association was stronger between ages 6 to 18 months, with the strongest estimate at 11 months (ß=-2.58; 95% CI: [-4.37, -0.74]). A negative impact of C-section on language scores in girls was estimated for the PROGRESS cohort (ß=-1.92; 95% CI: [-3.57, -0.27]), most marked in ages 22 to 25 months (largest ß at 24.5 months=-3.04; 95% CI: [-5.79, -0.30]). Children born by C-section showed lower motor and language development scores during specific age windows in the first three years of life. Further research is necessary to understand the complexities and implications of these findings.

Sex-specific association between prenatal manganese exposure and working memory in school-aged children in Mexico city: An exploratory multi-media approach.

It remains unclear whether manganese (Mn) exposure affects working memory (WM) in a sexually dimorphic manner. Further, no gold standard media exists to measure Mn, suggesting a combined blood and urinary Mn index may better capture the totality of exposure. We investigated the modification effect of child sex on the influence of prenatal Mn exposure on WM in school-age children, exploring two methodological frameworks to integrate exposure estimates across multiple exposure biomarkers. Leveraging the PROGRESS birth cohort in Mexico City, children (N = 559) ages 6-8 completed the between errors and strategy measures of the CANTAB Spatial Working Memory (SWM) task. Mn levels were assayed in blood and urine of mothers during the 2nd and 3rd trimesters and in umbilical cord blood from mothers and children at delivery. Weighted quantile sum regression estimated the association of a multi-media biomarker (MMB) mixture with SWM. We applied a confirmatory factor analysis to similarly quantify a latent blood Mn burden index. We then used an adjusted linear regression to estimate the Mn burden index with SWM measures. Interaction terms were used to estimate the modification effect by child sex for all models. Results showed that the between-errors-specific MMB mixture (i.e., this model demonstrates the impact of the MMB mixture on the between-error scores.) was associated (ß = 6.50, 95% CI: 0.91, 12.08) with fewer between errors for boys and more between errors for girls. The strategy-specific MMB mixture (i.e., this model demonstrates the impact of the MMB mixture on the strategy scores) was associated (ß = -1.36, 95% CI: 2.55, - 0.18) with less efficient strategy performance for boys and more efficient strategy performance for girls. A higher Mn burden index was associated (ß = 0.86, 95% CI: 0.00, 1.72) with more between errors in the overall sample. The vulnerability to prenatal Mn biomarkers on SWM differs in the directionality by child sex. An MMB mixture and composite index of body burden are stronger predictors than a single biomarker for Mn exposure on WM performance.

Urban Stress and its Association with Symptoms of Depression, Fatigue, and Sleep Disruption in Women in Mexico City.

Women in urban neighborhoods often face disproportionately higher levels of environmental and social stressors; however, the health effects from urban stressors remains poorly understood. We aimed to evaluate the association between urban stress and symptoms of depression, fatigue, and sleep disruption in a cohort of 460 women in Mexico City. To assess urban stress, women were administered the Urban Annoyances (Nuisances Environnementales) scale. Six constructs were summarized to create an overall index. Depressive symptoms were assessed using the Edinburgh Depression Scale; the Patient-Reported Outcomes Information System scales were used to assess sleep disruption and fatigue. Linear regression models were used to estimate the association with continuous symptoms comparing women with high urban stress to those with lower levels. Models were adjusted for socioeconomic status, education, age, social support, and previous depressive symptoms. High urban stress was associated with greater depressive symptoms (ß: 1.77; 95%CI: 0.83, 2.71), fatigue (ß: 2.47; 95%CI: 0.87, 4.07), and sleep disruption (ß: 2.14; 95%CI: 0.54, 3.73). Urban stress plays an important role in women's psychological and physical health, highlighting the importance of including these measures in environmental health studies. Urban interventions, such as promoting alternative transport options, should additionally be addressed to improve health of urban populations.

Changes in Depressive Symptoms, Stress and Social Support in Mexican Women during the COVID-19 Pandemic.

The aim of this study was to examine changes in depression, stress and social support levels before and during the COVID-19 pandemic in women living in Mexico City. We studied 466 women enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study who completed the Edinburgh Depression Scale (EDS) questionnaire prior (2018-2019) and during the lockdown period of the pandemic (May-November 2020). Psychosocial stress and social support for both time periods were ascertained using the Crisis in Family Systems (CRISYS) questionnaire and the Social Support Network (SSN) Scale, respectively. Associations between stress, social support and change in EDS score/depression were analyzed using generalized linear models adjusting for covariates. Higher stress (>median) during the pandemic was associated with an increase in EDS score (ß: 2.13; 95% CI (1.06, 3.19), p < 0.001), and higher odds of depression (OR: 3.75; 95% CI (2.17, 6.50), p < 0.001), while social support was associated with lower odds of depression (OR: 0.56, 95% CI (0.32, 0.97), p = 0.037). Higher levels of stress during the pandemic were associated with depression. Social support may act as a buffer for the effects of psychosocial stress. Future studies should examine the long-term effects of stress associated with the pandemic on mental and overall health.

Particulate air pollution exposure during pregnancy and postpartum depression symptoms in women in Mexico City.

BACKGROUND: Postpartum depression (PPD), which affects up to 1 in 5 mothers globally, negatively impacts the health of both mothers and children. Exposure to ambient air pollution has been linked to depressive symptoms in animal models and human studies, but the relationship between air pollution and PPD has not been widely studied. METHODS: In a birth cohort in Mexico City (509 mothers with available data), we examined the association between exposure to particulate matter ≤2.5 µm in diameter (PM2.5) with symptoms of psychological dysfunction at 1 and 6 months postpartum. Daily PM2.5 estimates were derived from a hybrid satellite-based spatio-temporally resolved model and averaged over pregnancy and the first year postpartum. Edinburgh Postnatal Depression Scale (EPDS) scores at 1 and 6 months were used to assess the relationship between PM2.5 exposure and probable PPD (EPDS score ≥13) using relative risk regression and symptoms of anhedonia, depression, and anxiety (derived from EPDS subscales) using negative binomial regression. RESULTS: A 5-µg/m3 increase in average PM2.5 exposure during pregnancy was associated with an increased risk of PPD at 6 months (RR = 1.59; 95% CI: 1.11 to 2.28) and of late-onset PPD (no PPD at 1 month, PPD at 6 months) (RR = 2.58; 95% CI: 1.40 to 4.73) in covariate-adjusted models. No association was observed between PM2.5 exposure in the first year postpartum and PPD. Average PM2.5 exposure during pregnancy was also associated with increased 6-month EPDS subscale symptom scores for anhedonia (p = 0.03) and depression (p = 0.04). CONCLUSION: Our results suggest that in women in Mexico City, particulate matter exposure during pregnancy is positively associated with PPD and symptoms of anhedonia and depression at 6 months postpartum. Future studies should examine mechanisms linking air pollution and other environmental exposures during pregnancy with postpartum psychological functioning.