Early pregnancy essential and non-essential metal mixtures and maternal antepartum and postpartum depressive symptoms.

BACKGROUND: Mood disorders are common during and after pregnancy, and environmental metals may contribute to increased risk. Antepartum metal exposures have not been well characterized in relation to maternal depression. We evaluated the extent to which early pregnancy erythrocyte concentrations of essential and non-essential metals were prospectively associated with antepartum and postpartum depressive symptoms. METHODS: Participants were 1226 women in Project Viva, a longitudinal cohort recruited during pregnancy (1999-2002). We measured concentrations of 11 metals in maternal first trimester erythrocytes (arsenic, barium, cadmium, cesium, copper, mercury, magnesium, manganese, lead, selenium, zinc). Using the Edinburgh Postnatal Depression Scale (EPDS), we assessed elevated depressive symptoms (≥13; 0-30 scale) at mid-pregnancy and at 6 and 12 months postpartum. We applied latent class mixed modeling to identify symptom trajectories. Adjusting for maternal sociodemographics and co-exposures, we examined associations between the metal mixture and depressive symptoms using logistic (for EPDS≥13)/multinomial (for symptom trajectories) regression and quantile g-computation. RESULTS: In this cohort of moderately high socioeconomic status participants (e.g., 72 % college graduate), low-level metal concentrations were weakly to moderately correlated (Spearman: -0.24 to 0.59); the prevalence of depressive symptoms ranged from 9 % (mid-pregnancy) to 6 % (12 months postpartum); and three trajectories (stable low; elevated mid-pregnancy, then decreasing; moderate mid-pregnancy, then increasing) best fit the EPDS data. The early pregnancy erythrocyte metal mixture was not associated with maternal depressive symptoms in logistic, multinomial, or mixture models. For individual metals, most confidence intervals (CI) included the null. There was weak evidence that arsenic, lead, and selenium were moderately associated with elevated odds of depressive symptoms and/or trajectories. However, the odds ratios (95 % CI) per doubling of these three metals were imprecise [e.g., arsenic: 1.13 (0.94, 1.40) for EPDS≥13 at six months postpartum; lead: 1.19 (0.80, 1.77) for EPDS≥13 at mid-pregnancy; selenium: 2.35 (0.84, 6.57) for elevated mid-pregnancy, then decreasing versus stable low trajectory]. DISCUSSION: We did not observe strong, consistent evidence of associations between early pregnancy erythrocyte metal concentrations and subsequent maternal antepartum and postpartum depressive symptoms.

Environmental Metal Exposure, Neurodevelopment, and the Role of Iron Status: a Review.

PURPOSE OF REVIEW: Exposure to environmental metals, like lead (Pb), manganese (Mn), and methylmercury (Me-Hg), has consistently been implicated in neurodevelopmental dysfunction. Recent research has focused on identifying modifying factors of metal neurotoxicity in childhood, such as age, sex, and co-exposures. Iron (Fe) status is critical for normal cognitive development during childhood, and current mechanistic, animal, and human evidence suggests that Fe status may be a modifier or mediator of associations between environmental metals and neurodevelopment. The goals of this review are to describe the current state of the epidemiologic literature on the role of Fe status (i.e., hemoglobin, ferritin, blood Fe concentrations) and Fe supplementation in the relationship between metals and children's neurodevelopment, and to identify research gaps. RECENT FINDINGS: We identified 30 studies in PubMed and EMBASE that assessed Fe status as a modifier, mediator, or co-exposure of associations of Pb, Me-Hg, Mn, copper (Cu), zinc (Zn), arsenic (As), or metal mixtures measured in early life (prenatal period through 8 years of age) with cognition in children. In experimental studies, co-supplementation of Fe and Zn was associated with better memory and cognition than supplementation with either metal alone. Several observational studies reported interactions between Fe status and Pb, Mn, Zn, or As in relation to developmental indices, memory, attention, and behavior, whereby adverse associations of metals with cognition were worse among Fe-deficient children compared to Fe-sufficient children. Only two studies quantified joint associations of complex metal mixtures that included Fe with neurodevelopment, though findings from these studies were not consistent. Findings support memory and attention as two possible cognitive domains that may be both vulnerable to Fe deficiency and a target of metals toxicity. Major gaps in the literature remain, including evaluating Fe status as a modifier or mediator of metal mixtures and cognition. Given that Fe deficiency is the most common nutritional deficiency worldwide, characterizing Fe status in studies of metals toxicity is important for informing public health interventions.

Prenatal metal mixture concentrations and reward motivation in children.

Reward motivation is a complex umbrella term encompassing the cognitions, emotions, and behaviors involved in the activation, execution, and persistence of goal-directed behavior. Altered reward motivation in children is characteristic of many neurodevelopmental and psychiatric disorders. Previously difficult to operationalize, the Progressive Ratio (PR) task has been widely used to assess reward motivation in animal and human studies, including children. Because the neural circuitry supporting reward motivation starts developing during pregnancy, and is sensitive to disruption by environmental toxicants, including metals, the goal of this study was to examine the association between prenatal concentrations of a mixture of neurotoxic metals and reward motivation in children. We measured reward motivation by administering a PR test to 373 children ages 6-8 years enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) Study in Mexico City. Children were asked to press a response lever for a token reward; one press on the response lever was required to earn the first token and each subsequent token required an additional 10 lever presses. Maternal blood concentrations of lead, manganese, zinc, arsenic, cadmium, and selenium were measured using inductively-coupled plasma mass spectrometry during the 2nd and 3rd trimesters of pregnancy. We performed generalized Weighted Quantile Sum (gWQS) regression analyses to examine associations between the prenatal metal mixture and reward motivation; adjusting for child sex, birthweight and age; and maternal IQ, education, and socioeconomic status. The prenatal metal mixture was significantly associated with higher motivation as indicated by more lever presses (ß = 0.02, p < 0.001) and a shorter time between receiving the reinforcer and the first press (ß = 0.23, p = 0.01), and between subsequent presses (ß = 0.07, p = 0.005). Contributions of different metals to this association differed by trimester and child sex. These findings suggest that children with increased exposure to metal during the 2nd and 3rd trimesters of gestation demonstrate increased reward motivation, which may reflect a tendency to perseverate or hypersensitivity to positive reinforcement.

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.

Environmental exposure to metal mixtures and linear growth in healthy Ugandan children.

BACKGROUND: Stunting is an indicator of poor linear growth in children and is an important public health problem in many countries. Both nutritional deficits and toxic exposures can contribute to lower height-for-age Z-score (HAZ) and stunting (HAZ < -2). OBJECTIVES: In a community-based cross-sectional sample of 97 healthy children ages 6-59 months in Kampala, Uganda, we examined whether exposure to Pb, As, Cd, Se, or Zn were associated with HAZ individually or as a mixture. METHODS: Blood samples were analyzed for a mixture of metals, which represent both toxins and essential nutrients. The association between HAZ and metal exposure was tested using multivariable linear regression and Weighted Quantile Sum (WQS) regression, which uses mixtures of correlated exposures as a predictor. RESULTS: There were 22 stunted children in the sample, mean HAZ was -0.74 (SD = 1.84). Linear regression showed that Pb (ß = -0.80, p = 0.021) and Se (ß = 1.92, p = 0.005) were significantly associated with HAZ. The WQS models separated toxic elements with a presumed negative effect on HAZ (Pb, As, Cd) from essential nutrients with presumed positive effect on HAZ (Se and Zn). The toxic mixture was significantly associated with lower HAZ (ß = -0.47, p = 0.03), with 62% of the effect from Pb. The nutrient WQS index did not reach statistical significance (ß = -0.47, p = 0.16). DISCUSSION: Higher blood lead and lower blood selenium level were both associated with lower HAZ. The significant associations by linear regression were reinforced by the WQS models, although not all associations reached statistical significance. These findings suggest that healthy children in this neighborhood of Kampala, Uganda, who have a high burden of toxic exposures, may experience detrimental health effects associated with these exposures in an environment where exposure sources are not well characterized.

Maternal Prenatal Psychosocial Stress and Prepregnancy BMI Associations with Fetal Iron Status.

BACKGROUND: Iron accrued in utero is critical for fetal and infant neurocognitive development. Psychosocial stress and obesity can each suppress fetal iron accrual. Their combined effects and differences by fetal sex are not known. In an observational pregnancy cohort study in Mexico City, we investigated associations of maternal prenatal life stressors, psychological dysfunction, and prepregnancy BMI with fetal iron status at delivery. OBJECTIVES: We hypothesized that greater maternal prenatal psychosocial stress and prepregnancy overweight and obesity are associated with lower cord blood ferritin and hemoglobin (Hb), with stronger associations in boys than girls. METHODS: Psychosocial stress in multiple domains of life stress (negative life events, perceived stress, exposure to violence) and psychological dysfunction symptoms (depression, generalized anxiety, and pregnancy-specific anxiety) were assessed with validated questionnaires during pregnancy. Prepregnancy BMI was predicted with a validated equation and categorized as normal/overweight/obese. Cord blood ferritin and Hb associations with prenatal psychosocial stress and BMI were modeled in multivariable linear regressions adjusted for maternal age, socioeconomic status, child sex, and prenatal iron supplementation. Interactions with child sex and 3-way stress-overweight/obesity-sex interactions were tested with product terms and likelihood ratio tests. RESULTS: In 493 dyads, median (IQR) cord blood ferritin and Hb concentrations were 185 µg/L (126-263 g/dL) and 16 g/dL (14.7-17.1 g/dL), respectively. Ferritin was lower in infants of mothers with higher prenatal perceived stress (-23%; 95% CI: -35%, -9%), violence exposure (-28%; 95% CI: -42%, -12%), anxiety symptoms (-16%; 95% CI: -27%, -4%), and obesity (-17%; 95% CI: -31%, 0.2%). Interaction models suggested sex differences and synergism between maternal stress and overweight/obesity. No associations were observed between stress or BMI and Hb. CONCLUSIONS: Multiple prenatal psychosocial stressors and excess prepregnancy BMI were each inversely associated with fetal iron status at birth. Pregnancies and infants at elevated risk of impaired fetal iron accrual may be identifiable according to observed synergism between maternal stress and obesity and differential associations with fetal iron status by infant sex.

Maternal prenatal fish consumption and cognition in mid childhood: Mercury, fatty acids, and selenium.

BACKGROUND: Few studies of maternal prenatal fish intake have included biomarkers of exposure to mercury, long-chain n-3 fatty acids, and selenium, which are hypothesized to mediate associations with child neurodevelopment. OBJECTIVES: Examine associations of maternal prenatal fish intake with child neurodevelopment accounting for biomarkers. METHODS: In 1999-2002 we enrolled pregnant women into the Project Viva cohort. At median 27.9weeks gestation, we estimated maternal fish intake using food frequency questionnaires, and collected blood. We assayed erythrocytes for total mercury and selenium, and plasma for fatty acids including n-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). In mid-childhood (median 7.7years), we administered cognitive tests including the Kauffman Brief Intelligence Test (KBIT). We performed multivariable linear regression analyses adjusting for maternal and child characteristics including home environment and maternal intelligence. RESULTS: Among 1068 pairs (872 with blood), mean (SD) exposures were: maternal fish intake 1.7 (1.5)servings/week, mercury 4.0 (3.6)ng/g, DHA+EPA 98.4 (41.8)mcg/ml, selenium 205.6 (34.6)ng/ml. Child KBIT verbal scores (mean 112.2, SD 15.0) were not related to any exposures: maternal fish intake (0.15; 95% CI: -0.50, 0.79), mercury (0.08; -0.18, 0.35), DHA+EPA (0.01; -0.22, 0.24), and selenium (0.20; -0.09, 0.50). Associations with KBIT nonverbal scores and tests of memory and visual motor abilities were similarly null. Mutual adjustment for each of the exposure measures did not substantially change estimates. CONCLUSIONS: In this population with an average fish consumption of about 1 1/2 weekly servings, we did not see any evidence for an association of maternal prenatal fish intake, or of mercury, DHA+EPA, or selenium status, with verbal or non-verbal intelligence, visual motor function, or visual memory at median 7.7years of age.

Racial/ethnic and sociodemographic factors associated with micronutrient intakes and inadequacies among pregnant women in an urban US population.

OBJECTIVE: To assess sociodemographic correlates of micronutrient intakes from food and dietary supplements in an urban, ethnically diverse sample of pregnant women in the USA. DESIGN: Cross-sectional analyses of data collected using a validated semi-quantitative FFQ. Associations between racial, ethnic and sociodemographic factors and micronutrient intakes were examined using logistic regression controlling for pre-pregnancy BMI, maternal age and smoking status. SETTING: Prenatal clinics, Boston, MA, USA. SUBJECTS: Analyses included pregnant women (n 274) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) study, an urban longitudinal cohort designed to examine how stress influences respiratory health in children when controlling for other environmental exposures (chemical stressors, nutrition). RESULTS: High frequencies of vitamin E (52 %), Mg (38 %), Fe (57 %) and vitamin D (77 %) inadequacies as well as suboptimal intakes of choline (95 %) and K (99 %) were observed. Factors associated with multiple antioxidant inadequacies included being Hispanic or African American, lower education and self-reported economic-related food insecurity. Hispanics had a higher prevalence of multiple methyl-nutrient inadequacies compared with African Americans; both had suboptimal betaine intakes and higher odds for vitamin B6 and Fe inadequacies compared with Caucasians. Nearly all women (98 %) reported Na intakes above the tolerable upper limit; excessive intakes of Mg (35 %), folate (37 %) and niacin (38 %) were also observed. Women reporting excessive intakes of these nutrients were more likely Caucasian or Hispanic, more highly educated, US-born and did not report food insecurity. CONCLUSIONS: Racial/ethnic and other sociodemographic factors should be considered when tailoring periconceptional dietary interventions for urban ethnic women in the USA.

Maternal MTHFR genotype and haplotype predict deficits in early cognitive development in a lead-exposed birth cohort in Mexico City.

BACKGROUND: Maternal folate nutritional status and prenatal lead exposure can influence fetal development and subsequent health. The methylenetetrahydrofolate reductase (MTHFR) gene is important for folate metabolism, and 2 common polymorphisms, C677T and A1298C, reduce enzymatic activity; C677T is present at high penetrance in Mexican populations. OBJECTIVE: The objective of this study was to examine potential links between maternal and child MTHFR polymorphisms and child neurodevelopment in a lead-exposed population. DESIGN: Data regarding MTHFR polymorphisms C677T and A1298C, peri- and postnatal lead measures, and Bayley Mental Development Index at 24 mo of age (MDI-24) scores were available for 255 mother-child pairs who participated in the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) study during 1994-1995. RESULTS: In covariate-adjusted regression models, maternal MTHFR 677 genotype predicted MDI-24 scores, in which each copy of the maternal MTHFR 677T variant allele was associated with lower MDI-24 scores (beta = -3.52; 95% CI: -6.12, -0.93; P = 0.004). Maternal MTHFR haplotype also predicted MDI-24 scores (mean +/- SE: 93.3 +/- 1.2 for 677C-1298A compared with 89.9 +/- 0.8 for 677T-1298A; P < 0.05). MDI-24 scores were not associated with maternal MTHFR 1298 genotype or child MTHFR genotypes. We did not observe significant MTHFR genotype x lead interactions with respect to any of the subject biomarkers of lead exposure. CONCLUSIONS: The maternal MTHFR 677T allele is an independent predictor of poorer child neurodevelopment at 24 mo. These results suggest that maternal genetic variations in folate metabolism during pregnancy may program offspring neurodevelopment trajectories. Further research is warranted to determine the generalizability of these results across other populations.

Determination of in vitro bioaccessibility of Pb, As, Cd and Hg in selected traditional Indian medicines.

In vitro bioaccessibility of Pb, As, Cd and Hg in five traditional Indian medicine samples was measured as a determinant of bioavailability. The method is based on simulation of human digestion in the passage of material from the gastric to intestinal portions of the gastrointestinal tract. Total concentration and concentration in extracts from gastric and intestinal phases were analyzed for Pb, As and Cd by dynamic reaction cell inductively coupled plasma mass spectrometry (DRC-ICP-MS) and for Hg by direct mercury analyzer (DMA). Total lead ranged from 1.9 to 36000 µg g(-1). In each of the samples bioaccessibility of lead was significantly higher (range 28-88%) in the gastric phase than in the intestinal phase (range 1.4-75.4%). Only Ekangvir Ras had measurable arsenic (304 µg g(-1)). Its bioaccessibility in the gastric phase and intestinal phase was 82.6% and 78.1%, respectively. Only Ayu-Nephro-Tone had measurable cadmium (14.4 µg g(-1)). Its bioaccessibility in the gastric phase and intestinal phase was 80.5% and 2.2%, respectively. Three samples had measurable mercury (range 37 µg g(-1)-10000 µg g(-1)). Mercury in these samples was not bioaccessible. For the samples with measurable amount of metal, the estimated daily amount of bioaccessible (EDAB) metal was calculated. When compared with the most liberal published safety guideline, EDAB-Pb in Mahayograj Guggulu and Ekangvir Ras were 37 and 45 fold greater. When compared with the most conservative published safety guideline, all samples had higher EDAB-Pb or EDAB-As than the suggested limits. The EDAB-Cd and EDAB-Hg were acceptably below published safety limits.

Maternal dietary intake of polyunsaturated fatty acids modifies the relationship between lead levels in bone and breast milk.

Whereas dietary fats are known to influence bone mineral density, little is known about their effect on the skeletal stores of lead that are a pervasive source of fetal and infant lead exposure from heightened mobilization during pregnancy and lactation. This cross-sectional study examined the potential influence of maternal dietary intake of saturated and unsaturated fats on the relationship of lead levels in bone and breast milk during lactation. Lead was measured in blood, breast milk, and bone (patella and tibia) at 1 mo postpartum in 310 women in Mexico City. Dietary nutrient intake was assessed using a validated FFQ. Multivariate linear regression analyses were used to study the influence of dietary saturated and unsaturated fats on the association between bone and breast milk lead. In multivariate models that included both the dietary intake of SFA and PUFA, an interquartile range increase in patella lead [approximately 20 microg/g (0.097 micromol/g)] was associated with a 24% (95% CI = 5-43) higher increase in breast milk lead in women in the lowest tertile of PUFA intake compared with those in the highest tertile of PUFA intake. Monounsaturated fatty acids did not modify the relationship between lead levels in patella and breast milk. In conclusion, higher maternal dietary intake of PUFA may limit the transfer of lead from bone to breast milk.