Biomarkers of maternal lead exposure during pregnancy using micro-spatial child deciduous dentine measurements.

BACKGROUND: Lead is a toxic chemical of public health concern, however limited biomarkers are able to reconstruct prior lead exposures in early-life when biospecimens are not collected and stored. Although child tooth dentine measurements accurately assess past child perinatal lead exposure, it has not been established if they reflect maternal exposure in pregnancy. AIM: To assess the prenatal relationship between child tooth dentine and maternal blood lead measurements and to estimate maternal lead exposure during the 2nd and 3rd trimesters of pregnancy from weekly child dentine profiles. METHODS: We measured early-life lead exposure in child tooth dentine and maternal blood from 419 child-mother dyads enrolled in the Programming Research in Obesity, Growth, Environment and Social Stress (PROGRESS) cohort. We employed the Super-Learner algorithm to determine the relationship of dentine lead data with maternal blood lead concentrations and to predict maternal lead from child dentine lead data in blinded analyses. We validated and quantified the bias of our results internally. RESULTS: Mothers had moderate blood lead levels (trimesters: 2nd = 29.45 ug/L, 3rd = 31.78 ug/L). Trimester-averaged and weekly child dentine lead measurements were highly correlated with maternal blood levels in the corresponding trimesters. The predicted trimester-specific maternal lead levels were significantly correlated with actual measured blood values (trimesters: 2nd = 0.83; 3rd = 0.88). Biomarkers of maternal lead exposure discriminated women highly exposed to lead (>mean) with 85 % and 96 % specificity in the 2nd and 3rd trimesters, respectively, with 80 % sensitivity. DISCUSSION: Weekly child dentine lead levels can serve as biomarkers of past child and maternal lead exposures during pregnancy.

Hair mercury levels, intake of omega-3 fatty acids and ovarian reserve among women attending a fertility center.

OBJECTIVE: To investigate the association of hair mercury (Hg) levels with antral follicle count (AFC), as a marker of ovarian reserve, and evaluate whether this relationship differed among women with high vs. low total intake of long chain omega-3 polyunsaturated fatty acids (n3PUFA) from foods and supplements. DESIGN: We included 353 women attending an academic fertility center (2007-2019) who had data on hair Hg levels, total n3PUFA intake, and AFC. METHODS: Hair Hg levels were assessed using a Direct Mercury Analyser, total n3PUFA intake was estimated using an extensively validated food frequency questionnaire, and AFC was assessed by transvaginal ultrasonography. Poisson regression models adjusted for potential confounders were used to evaluate the association of hair Hg levels (divided into tertiles, and as above vs below EPA reference (1 ppm)) with AFC. Associations were also evaluated after stratification by median n3PUFA intake (≤0.124% vs. >0.125% calories/week). RESULTS: Women's median hair Hg level was 0.60 ppm (range = 0.001-8.60 ppm), with more than 30% > 1 ppm (EPA reference level). Hair Hg was positively related to AFC after adjusting for age, BMI, smoking status, infertility diagnosis, and alcohol intake. However, associations became attenuated after adjustment for intake of total n3PUFA. The positive associations of hair Hg and AFC were observed only among women above the median total n3PUFA intake. Specifically, women who consumed >0.125% calories/week of total n3PUFA had mean AFCs of 11.9, 13.2 and 14.1, respectively, across increasing tertiles of hair Hg (p,trend = 0.004). Similar results were found when hair Hg was divided above vs below EPA reference (mean AFC = 12.7 vs. 14.1, p = 0.008). CONCLUSIONS: In these women, positive associations of hair Hg with AFC may be reflective of beneficial effects of n3PUFA on ovarian reserve rather than a beneficial effect of Hg per se. Our findings highlight the importance of considering diet when exploring Hg effects on women's reproductive health in urban settings.

Altered cord blood mitochondrial DNA content and pregnancy lead exposure in the PROGRESS cohort.

INTRODUCTION: Lead (Pb) crosses the placenta and can cause oxidative stress, reduced fetal growth and neurological problems. The principal source of oxidative stress in human cells is mitochondria. Therefore, disruption of normal mitochondrial function during pregnancy may represent a primary mechanism behind the adverse effects of lead. We sought to assess the association of Pb exposure during pregnancy with mitochondrial DNA (mtDNA) content, a sensitive marker of mitochondrial function, in cord blood. MATERIALS AND METHODS: This study comprised mother-infant pairs from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a prospective birth-cohort that enrolled 1050 pregnant women from Mexico City who were receiving prenatal care between December 2007 and July 2011. Quantitative PCR was used to calculate relative MtDNA content (mitochondrial-to-nuclear DNA ratio (mtDNA/nDNA)) in cord blood. Lead concentrations in both maternal blood (2nd and 3rd trimester and at delivery day) and in cord blood were measured by ICP-MS. Multivariable regression models adjusting for multiple confounders were fitted with 410 mother-infant pairs for whom complete data for mtDNA content, lead levels, and covariates were available. RESULTS: Maternal blood Pb measured in the second (mean 3.79 µg/dL, SD 2.63; ß = 0.059, 95% CI 0.008, 0.111) and third trimester (mean 3.90 µg/dL; SD 2.84; ß = 0.054, 95% CI 0.002, 0.107) during pregnancy and PB in cord blood (mean 3.50 µg/dL, SD 2.59; ß = 0.050, 95% CI 0.004; 0.096) were associated with increased cord blood mtDNA content (mean 1.46, SD 0.44). In two-way interaction analyses, cord blood Pb marginally interacted with gestational age leading to an increase in mtDNA content for pre-term births (Benjamini-Hochberg False Discovery Rate correction; BH-FDR = 0.08). CONCLUSION: This study shows that lead exposure in pregnancy alters mtDNA content in cord blood; therefore, alteration of mtDNA content might be a mechanism underlying the toxicity of lead.

Hair mercury (Hg) levels, fish consumption and semen parameters among men attending a fertility center.

General population exposure to methylmercury (MeHg), the most common organic mercury compound found in the environment, occurs primarily through the consumption of contaminated fish and shellfish. Due to limited studies and lack of consideration of effect modification by fish consumption, it remains uncertain if exposure to mercury affects semen parameters. Thus, we investigated whether hair Hg levels, a biomarker of mercury exposure, were associated with semen parameters among men attending an academic fertility center, and whether this relationship was modified by intake of fish. This analysis included 129 men contributing 243 semen samples who were enrolled in the Environment and Reproductive Health (EARTH) Study between 2005 and 2013, and had data of hair Hg, intake of fish and semen parameters available. Hair Hg levels were assessed using a direct mercury analyzer. Intake of fish was collected using a validated food frequency questionnaire. Semen parameters were analyzed following WHO 2010 evaluation criteria. Generalized linear mixed models with random intercepts accounting for within-man correlations across semen samples were used to evaluate the association of hair Hg levels and semen parameters adjusting for age, BMI, smoking status, abstinence time and alcohol intake. Effect modification by total fish intake (≤1.68 vs. >1.68 servings/week) was tested. The median hair Hg levels of the men was 0.72ppm and ranged from 0.03 to 8.01ppm; almost 30% of the men had hair Hg levels >1ppm. Hair Hg levels were positively related with sperm concentration, total sperm count, and progressive motility, after adjusting for potential confounders and became attenuated after further adjustment for fish intake. Specifically, men in the highest quartile of hair mercury levels had 50%, 46% and 31% higher sperm concentration, total sperm count and progressive motility, respectively, compared to men in the lowest quartile. These associations were stronger among men whose fish intake was above the study population median. Semen volume and normal morphology were unrelated to hair Hg levels. These results confirmed exposure to MeHg through fish intake and showed the important role of diet when exploring the associations between heavy metals and semen parameters among men of couples seeking fertility care. Further research is needed to clarify the complex relationship between fish intake and Hg, and potential effects on male reproductive health, specifically, semen parameters.

Prenatal Exposure to Mercury: Associations with Global DNA Methylation and Hydroxymethylation in Cord Blood and in Childhood.

BACKGROUND: Mercury is a global pollutant, and prenatal exposure is associated with adverse health effects. To date, no studies have evaluated the association between prenatal mercury exposure and DNA hydroxymethylation, an epigenetic modification important for tissue differentiation and embryonic development. OBJECTIVES: We sought to evaluate the association between prenatal mercury exposure and offspring global DNA methylation and hydroxymethylation at birth and test for persistence of the association in childhood. METHODS: Within Project Viva, a U.S. prebirth cohort, we examined associations of maternal second trimester red blood cell mercury (RBC-Hg) concentrations with global 5-hydroxymethylcytosine (%-5hmC) and 5-methylcytosine (%-5mC) DNA content in blood collected at birth (n=306), early childhood (n=68; 2.9 to 4.9 y), and midchildhood (n=260; 6.7 to 10.5 y). RESULTS: Median prenatal RBC-Hg concentration was 3.23µg/g [interquartile range (IQR)=3.29]. At birth, median cord blood %-5mC, %-5hmC, and their ratio were 4.95%, 0.22%, and 24.37, respectively. The mean adjusted difference [95% confidence interval (CI)] of blood %-5hmC for a doubling in prenatal RBC-Hg concentration was -0.013% (-0.029, 0.002), -0.031% (-0.056, -0.006), and 0.005% (-0.007, 0.018) at birth, early, and midchildhood, respectively. The corresponding relative adjusted change in the genomic ratio of %-5mC to %-5hmC for a doubling in prenatal RBC-Hg concentration was 4.70% (0.04, 9.58), 22.42% (7.73, 39.11), and 0.73% (-4.18, 5.88) at birth, early, and midchildhood, respectively. No associations were present between prenatal maternal RBC-Hg and %-5mC at any time point. CONCLUSIONS: Prenatal mercury exposure was associated with lower %-5hmC genomic content and a corresponding increase in the ratio of %-5mC to %-5hmC in cord blood. This association was persistent in early but not midchildhood blood. Our results demonstrate the potential malleability of epigenetic modifications associated with mercury exposure in utero. https://doi.org/10.1289/EHP1467.

Persistent DNA methylation changes associated with prenatal mercury exposure and cognitive performance during childhood.

Prenatal exposure to mercury, a known neurotoxic metal, is associated with lower cognitive performance during childhood. Disruption of fetal epigenetic programming could explain mercury's neurodevelopmental effects. We screened for epigenome-wide methylation differences associated with maternal prenatal blood mercury levels in 321 cord blood DNA samples and examined the persistence of these alterations during early (n = 75; 2.9-4.9 years) and mid-childhood (n = 291; 6.7-10.5 years). Among males, prenatal mercury levels were associated with lower regional cord blood DNA methylation at the Paraoxonase 1 gene (PON1) that persisted in early childhood and was attenuated in mid-childhood blood. Cord blood methylation at the PON1 locus predicted lower cognitive test scores measured during early childhood. Methylation at the PON1 locus was associated with PON1 expression in an independent set of cord blood samples. The observed persistent epigenetic disruption of the PON1 gene may modulate mercury toxicity in humans and might serve as a biomarker of exposure and disease susceptibility.

Prenatal lead exposure and fetal growth: Smaller infants have heightened susceptibility.

BACKGROUND: As population lead levels decrease, the toxic effects of lead may be distributed to more sensitive populations, such as infants with poor fetal growth. OBJECTIVES: To determine the association of prenatal lead exposure and fetal growth; and to evaluate whether infants with poor fetal growth are more susceptible to lead toxicity than those with normal fetal growth. METHODS: We examined the association of second trimester maternal blood lead levels (BLL) with birthweight-for-gestational age (BWGA) z-score in 944 mother-infant participants of the PROGRESS cohort. We determined the association between maternal BLL and BWGA z-score by using both linear and quantile regression. We estimated odds ratios for small-for-gestational age (SGA) infants between maternal BLL quartiles using logistic regression. Maternal age, body mass index, socioeconomic status, parity, household smoking exposure, hemoglobin levels, and infant sex were included as confounders. RESULTS: While linear regression showed a negative association between maternal BLL and BWGA z-score (ß=-0.06 z-score units per log2 BLL increase; 95% CI: -0.13, 0.003; P=0.06), quantile regression revealed larger magnitudes of this association in the <30th percentiles of BWGA z-score (ß range [-0.08, -0.13] z-score units per log2 BLL increase; all P values<0.05). Mothers in the highest BLL quartile had an odds ratio of 1.62 (95% CI: 0.99-2.65) for having a SGA infant compared to the lowest BLL quartile. CONCLUSIONS: While both linear and quantile regression showed a negative association between prenatal lead exposure and birthweight, quantile regression revealed that smaller infants may represent a more susceptible subpopulation.

Associations between metals in residential environmental media and exposure biomarkers over time in infants living near a mining-impacted site.

Infant exposures to metals are a concern for mining-impacted communities, although limited information is available to assess residential exposures over the first year of life. We measured lead (Pb), manganese, arsenic, and cadmium in indoor air, house dust, yard soil, and tap water from 53 infants' homes near the Tar Creek Superfund Site (Oklahoma, USA) at two time points representing developmental stages before and during initial ambulation (age 0-6 and 6-12 months). We measured infant metal biomarkers in: umbilical cord blood (n=53); 12- (n=43) and 24- (n=22) month blood; and hair at age 12 months (n=39). We evaluated cross-sectional and longitudinal associations between infant residential and biomarker concentrations. A doubling of mean dust Pb concentration was consistently associated with 36-49% higher 12-month blood Pb adjusting for cord blood Pb (P⩽0.05). Adjusted dust concentration explained 29-35% of blood Pb variance, and consistent associations with other media were not observed. Although concentrations in dust and blood were generally low, strong and consistent associations between dust and body burden suggest that house dust in mining-impacted communities may impact children's health. These relationships were observed at a young age, typically before blood Pb levels peak and when children's development may be particularly vulnerable to toxic insult.

Very low maternal lead level in pregnancy and birth outcomes in an eastern Massachusetts population.

PURPOSE: Maternal lead exposure is associated with poor birth outcomes in populations with moderate to high blood levels. However, no studies have looked at exposure levels commonly experienced by US women. METHODS: We evaluated the relationship between maternal red blood cell (RBC) lead levels in midpregnancy and birth outcomes in 949 mother-child pairs in a prebirth cohort. We used multiple linear regression and logistic regression, adjusted for potential confounders including maternal age, race, prepregnancy body mass index, and smoking to relate maternal lead to infant birth size and risk for preterm birth (<37 weeks). RESULTS: Mean RBC lead level was 1.2 µg/dL (range, 0.0-5.0). Mean (standard deviation) birthweight was 3505 (520) g, birthweight for gestational age z-score 0.22 (0.93), and length of gestation 39.5 (1.7) weeks. Mothers in the highest versus lowest lead quartile did not have higher odds (OR, 1.85; 95% confidence interval [CI], 0.79-4.34) of preterm delivery; after stratifying by child sex, there was an association among males (OR, 5.51; 95% CI, 1.21-25.15) but not females (OR, 0.82; 95% CI, 0.24-2.85). Maternal RBC lead was not associated with any continuous outcomes in combined or sex-stratified analyses. CONCLUSIONS: Maternal lead exposure, even at very low levels, may adversely affect some childbirth outcomes, particularly preterm birth among males.

Prenatal organochlorine and methylmercury exposure and memory and learning in school-age children in communities near the New Bedford Harbor Superfund site, Massachusetts.

BACKGROUND: Polychlorinated biphenyls (PCBs), organochlorine pesticides, and methylmercury (MeHg) are environmentally persistent with adverse effects on neurodevelopment. However, especially among populations with commonly experienced low levels of exposure, research on neurodevelopmental effects of these toxicants has produced conflicting results. OBJECTIVES: We assessed the association of low-level prenatal exposure to these contaminants with memory and learning. METHODS: We studied 393 children, born between 1993 and 1998 to mothers residing near a PCB-contaminated harbor in New Bedford, Massachusetts. Cord serum PCB, DDE (dichlorodiphenyldichloroethylene), and maternal peripartum hair mercury (Hg) levels were measured to estimate prenatal exposure. Memory and learning were assessed at 8 years of age (range, 7-11 years) using the Wide Range Assessment of Memory and Learning (WRAML), age-standardized to a mean ± SD of 100 ± 15. Associations with each WRAML index-Visual Memory, Verbal Memory, and Learning-were examined with multivariable linear regression, controlling for potential confounders. RESULTS: Although cord serum PCB levels were low (sum of four PCBs: mean, 0.3 ng/g serum; range, 0.01-4.4), hair Hg levels were typical of the U.S. fish-eating population (mean, 0.6 µg/g; range, 0.3-5.1). In multivariable models, each microgram per gram increase in hair Hg was associated with, on average, decrements of -2.8 on Visual Memory (95% CI: -5.0, -0.6, p = 0.01), -2.2 on Learning (95% CI: -4.6, 0.2, p = 0.08), and -1.7 on Verbal Memory (95% CI: -3.9, 0.6, p = 0.14). There were no significant adverse associations of PCBs or DDE with WRAML indices. CONCLUSIONS: These results support an adverse relationship between low-level prenatal MeHg exposure and childhood memory and learning, particularly visual memory.

Associations of prenatal maternal blood mercury concentrations with early and mid-childhood blood pressure: a prospective study.

BACKGROUND: Childhood blood pressure (BP) is an important determinant of adult cardiovascular disease. Prenatal exposure to methylmercury through maternal fish consumption has been reported to increase the BP of children years later. METHODS: Mother-child pairs were enrolled from Project Viva, a prospective cohort study in Massachusetts. From second trimester maternal blood samples, we measured erythrocyte mercury concentration. Systolic BP in children, measured up to 5 times per visit in early and mid-childhood (median ages 3.2 and 7.7 years), was the primary outcome. We used mixed-effect regression models to account for variation in the number of BP measurements and to average effects over both time points. RESULTS: Among 1103 mother-child pairs, mean (SD) second trimester total erythrocyte mercury concentration was 4.0 (3.9)ng/g among mothers whose children were assessed in early childhood and 4.0 (4.0)ng/g for children assessed in mid-childhood. Mean (SD) offspring systolic BP was 92.1 (10.4)mm Hg in early childhood and 94.3 (8.4)mm Hg in mid-childhood. After adjusting for mother and infant characteristics, mean second trimester blood mercury concentration was not associated with child systolic BP (regression coefficient, 0.1mm Hg; 95% CI, -1.3 to 1.5 for quartile 4 vs. quartile 1) at either time period. Further adjusting for second trimester maternal fish consumption, as well as docosahexaenoic acid and eicosapentaenoic acid consumption, did not substantially change the estimates. CONCLUSIONS: The results of this study demonstrate an absence of association between childhood blood pressure and low-level mercury exposure typical of the general US population.

Maternal blood, plasma, and breast milk lead: lactational transfer and contribution to infant exposure.

BACKGROUND: Human milk is a potential source of lead exposure. Yet lactational transfer of lead from maternal blood into breast milk and its contribution to infant lead burden remains poorly understood. OBJECTIVES: We explored the dose-response relationships between maternal blood, plasma, and breast milk to better understand lactational transfer of lead from blood and plasma into milk and, ultimately, to the breastfeeding infant. METHODS: We measured lead in 81 maternal blood, plasma, and breast milk samples at 1 month postpartum and in 60 infant blood samples at 3 months of age. Milk-to-plasma (M/P) lead ratios were calculated. Multivariate linear, piecewise, and generalized additive models were used to examine dose-response relationships between blood, plasma, and milk lead levels. RESULTS: Maternal lead levels (mean±SD) were as follows: blood: 7.7±4.0 µg/dL; plasma: 0.1±0.1 µg/L; milk: 0.8±0.7 µg/L. The average M/P lead ratio was 7.7 (range, 0.6-39.8) with 97% of the ratios being >1. The dose-response relationship between plasma lead and M/P ratio was nonlinear (empirical distribution function=6.5, p=0.0006) with the M/P ratio decreasing by 16.6 and 0.6 per 0.1 µg/L of plasma lead, respectively, below and above 0.1 µg/L plasma lead. Infant blood lead level (3.4±2.2 µg/dL) increased by 1.8 µg/dL per 1 µg/L milk lead (p<0.0001, R2=0.3). CONCLUSIONS: The M/P ratio for lead in humans is substantially higher than previously reported, and transfer of lead from plasma to milk may be higher at lower levels of plasma lead. Breast milk is an important determinant of lead burden among breastfeeding infants.

Assessment of dietary fish consumption in pregnancy: comparing one-, four- and thirty-six-item questionnaires.

OBJECTIVE: Fish consumption influences a number of health outcomes. Few studies have directly compared dietary assessment methods to determine the best approach to estimating intakes of fish and its component nutrients, including DHA, and toxicants, including methylmercury. Our objective was to compare three methods of assessing fish intake. DESIGN: We assessed 30 d fish intake using three approaches: (i) a single question on total fish consumption; (ii) a brief comprehensive FFQ that included four questions about fish; and (iii) a focused FFQ with thirty-six questions about different finfish and shellfish. SETTING: Obstetrics practices in Boston, MA, USA. SUBJECTS: Fifty-nine pregnant women who consumed ≤2 monthly fish servings. RESULTS: Estimated intakes of fish, DHA and Hg were lowest with the one-question screener and highest with the thirty-six-item fish questionnaire. Estimated intake of DHA with the thirty-six-item questionnaire was 4·4-fold higher (97 v. 22 mg/d), and intake of Hg was 3·8-fold higher (1·6 v. 0·42 µg/d), compared with the one-question screener. Plasma DHA concentration was correlated with fish intake assessed with the one-question screener (Spearman r = 0·27, P = 0·04), but not with the four-item FFQ (r = 0·08, P = 0·54) or the thirty-six-item fish questionnaire (r = 0·01, P = 0·93). In contrast, blood and hair Hg concentrations were similarly correlated with fish and Hg intakes regardless of the assessment method (r = 0·35 to 0·52). CONCLUSIONS: A longer questionnaire provides no advantage over shorter questionnaires in ranking intakes of fish, DHA and Hg compared with biomarkers, but estimates of absolute intakes can vary by as much as fourfold across methods.

Comparison of digestion procedures and methods for quantification of trace lead in breast milk by isotope dilution inductively coupled plasma mass spectrometry.

Measurement of lead in breast milk is an important public health consideration and can be technically quite challenging. The reliable and accurate determination of trace lead in human breast milk is difficult for several reasons including: potential for contamination during sample collection, storage, and analysis; complexities related to the high fat content of human milk; and poor analytic sensitivity at low concentrations. Breast milk lead levels from previous published studies should therefore be reviewed with caution. Due to the difficulty in identifying a method that would successfully digest samples with 100% efficiency, we evaluated three different digestion procedures including: (1) dry ashing in a muffle furnace, (2) microwave oven digestion, and (3) digestion in high pressure asher. High temperature, high pressure asher digestion was selected as the procedure of choice for the breast milk samples. Trace lead analysis was performed using isotope dilution (ID) inductively coupled plasma mass spectrometry (ICP-MS). Measured lead concentrations in breast milk samples (n = 200) from Mexico ranged from 0.2 to 6.7 ng ml-1. The precision for these measurements ranged from 0.27-7.8% RSD. Use of strict contamination control techniques and of a very powerful digestion procedure, along with an ID-ICP-MS method for lead determination, enables us to measure trace lead levels as low as 0.2 ng ml-1 in milk (instrument detection limit = 0.01 ng ml-1).

Characterization of a nucleotide kinase encoded by bacteriophage T7.

Gene 1.7 protein is the only known nucleotide kinase encoded by bacteriophage T7. The enzyme phosphorylates dTMP and dGMP to dTDP and dGDP, respectively, in the presence of a phosphate donor. The phosphate donors are dTTP, dGTP, and ribo-GTP as well as the thymidine and guanosine triphosphate analogs ddTTP, ddGTP, and dITP. The nucleotide kinase is found in solution as a 256-kDa complex consisting of ~12 monomers of the gene 1.7 protein. The two molecular weight forms co-purify as a complex, but each form has nearly identical kinase activity. Although gene 1.7 protein does not require a metal ion for its kinase activity, the presence of Mg(2+) in the reaction mixture results in either inhibition or stimulation of the rate of kinase reactions depending on the substrates used. Both the dTMP and dGMP kinase reactions are reversible. Neither dTDP nor dGDP is a phosphate acceptor of nucleoside triphosphate donors. Gene 1.7 protein exhibits two different equilibrium patterns toward deoxyguanosine and thymidine substrates. The K(m) of 4.4 × 10(-4) M obtained with dTTP for dTMP kinase is ~3-fold higher than that obtained with dGTP for dGMP kinase (1.3 × 10(-4) M), indicating that a higher concentration of dTTP is required to saturate the enzyme. Inhibition studies indicate a competitive relationship between dGDP and both dGTP, dGMP, whereas dTDP appears to have a mixed type of inhibition of dTMP kinase. Studies suggest two functions of dTTP, as a phosphate donor and a positive effector of the dTMP kinase reaction.

Rationally engineered polymeric cisplatin nanoparticles for improved antitumor efficacy.

The use of cisplatin, a first line chemotherapy for most cancers, is dose-limited due to nephrotoxicity. While this toxicity can be addressed through nanotechnology, previous attempts at engineering cisplatin nanoparticles have been limited by the impact on the potency of cisplatin. Here we report the rational engineering of a novel cisplatin nanoparticle by harnessing a novel polyethylene glycol-functionalized poly-isobutylene-maleic acid (PEG-PIMA) copolymer, which can complex with cis-platinum (II) through a monocarboxylato and a coordinate bond. We show that this complex self-assembles into a nanoparticle, and exhibits an IC(50) = 0.77 ± 0.11 µM comparable to that of free cisplatin (IC(50) = 0.44 ± 0.09 µM). The nanoparticles are internalized into the endolysosomal compartment of cancer cells, and release cisplatin in a pH-dependent manner. Furthermore, the nanoparticles exhibit significantly improved antitumor efficacy in a 4T1 breast cancer model in vivo, with limited nephrotoxicity, which can be explained by preferential biodistribution in the tumor with reduced kidney concentrations. Our results suggest that the PEG-PIMA-cisplatin nanoparticle can emerge as an attractive solution to the challenges in cisplatin chemotherapy.

Three cases of lead toxicity associated with consumption of ayurvedic medicines.

Ayurveda is a traditional form of medicine used by majority of the Indians. Here we report three cases of lead toxicity, following intake of Ayurvedic medicines. Three patients presented with blood lead levels (BLLs) of 122.4, 115 and 42.8 µg/dl respectively at the time of hospitalization. The first case was chelated with D- penicillamine, the second with calcium disodium ethylene diamino tetra acetate (EDTA) and the third with environmental intervention and education. Associated Ayurvedic products were collected from patients and analyzed for metallic concentration. Cessation of Ayurvedic medication along with chelation, nutritional intervention and education, reduced the BLL to 27.4 µg/dl in the first case after 1 year, 21.1 µg/dl after 9 months in the second and 18.2 µg/dl after 6 months in the third case.

Maternal arsenic exposure and impaired glucose tolerance during pregnancy.

BACKGROUND: Accumulating evidence has shown an increased risk of type 2 diabetes in general populations exposed to arsenic, but little is known about exposures during pregnancy and the association with gestational diabetes (GD). OBJECTIVES: We studied 532 women living proximate to the Tar Creek Superfund Site to investigate whether arsenic exposure is associated with impaired glucose tolerance during pregnancy. METHODS: Blood glucose was measured between 24 and 28 weeks gestation after a 1-hr oral glucose tolerance test (GTT) as part of routine prenatal care. Blood and hair were collected at delivery and analyzed for arsenic using inductively coupled plasma mass spectrometry with dynamic reaction cell. RESULTS: Arsenic concentrations ranged from 0.2 to 24.1 microg/L (ppb) (mean +/- SD, 1.7 +/-1.5) and 1.1 to 724.4 ng/g (ppb) (mean +/- SD, 27.4 +/- 61.6) in blood and hair, respectively. One-hour glucose levels ranged from 40 to 284 mg/dL (mean +/- SD, 108.7 +/- 29.5); impaired glucose tolerance was observed in 11.9% of women when using standard screening criterion (> 140 mg/dL). Adjusting for age, Native-American race, prepregnancy body mass index, Medicaid use, and marital status, women in the highest quartile of blood arsenic exposure had 2.8 higher odds of impaired GTT than women in the lowest quartile of exposure (95% confidence interval, 1.1-6.9) (p-trend = 0.008). CONCLUSIONS: Among this population of pregnant women, arsenic exposure was associated with increased risk of impaired GTT at 24-28 weeks gestation and therefore may be associated with increased risk of GD.

Maternal blood manganese levels and infant birth weight.

BACKGROUND: Manganese is both an essential element and a known neurotoxicant to children. High manganese exposures have been associated with negative reproductive outcomes in animals, but few epidemiologic studies have examined the effects of human fetal manganese exposure. METHODS: We studied the association between maternal and umbilical cord blood manganese levels and birth weight in a cohort of 470 mother-infant pairs born at term (>or=37 weeks gestation) in Ottawa County, Oklahoma. Nonlinear spline and quadratic regression models were used to test the hypothesis of an inverted U-shaped relationship between manganese levels and birth weight. RESULTS: Mean (standard deviation) concentration of manganese was 2.4 (0.95) microg/dL in the maternal blood and 4.2 (1.6) microg/dL in the cord blood. Umbilical cord manganese was not associated with birth weight. A nonlinear relationship was observed between maternal manganese and birth weight after adjusting for potential confounders. Birth weight increased with manganese levels up to 3.1 microg/L, and then a slight reduction in weight was observed at higher levels. Compared with the 3.1-microg/L point of inflection, birth weight estimates at the 5th (1.3 microg/L) and 95th (4.0 microg/L) percentiles of exposure were -160 g (95% confidence interval = -286 to -33) and -46 g (-38 to 131), respectively. CONCLUSIONS: Maternal blood manganese levels during pregnancy are associated with birth weight in a nonlinear pattern in full-term infants. These findings suggest that manganese may affect fetal growth. Possible detrimental effects of elevated manganese levels on the fetus should be further examined in more highly exposed populations.

Maternal fish intake during pregnancy, blood mercury levels, and child cognition at age 3 years in a US cohort.

The balance of contaminant risk and nutritional benefit from maternal prenatal fish consumption for child cognitive development is not known. Using data from a prospective cohort study of 341 mother-child pairs in Massachusetts enrolled in 1999-2002, the authors studied associations of maternal second-trimester fish intake and erythrocyte mercury levels with children's scores on the Peabody Picture Vocabulary Test (PPVT) and Wide Range Assessment of Visual Motor Abilities (WRAVMA) at age 3 years. Mean maternal total fish intake was 1.5 (standard deviation, 1.4) servings/week, and 40 (12%) mothers consumed >2 servings/week. Mean maternal mercury level was 3.8 (standard deviation, 3.8) ng/g. After adjustment using multivariable linear regression, higher fish intake was associated with better child cognitive test performance, and higher mercury levels with poorer test scores. Associations strengthened with inclusion of both fish and mercury: effect estimates for fish intake of >2 servings/week versus never were 2.2 (95% confidence interval (CI): -2.6, 7.0) for the PPVT and 6.4 (95% CI: 2.0, 10.8) for the WRAVMA; for mercury in the top decile, they were -4.5 (95% CI: -8.5, -0.4) for the PPVT and -4.6 (95% CI: -8.3, -0.9) for the WRAVMA. Fish consumption of < or =2 servings/week was not associated with a benefit. Dietary recommendations for pregnant women should incorporate the nutritional benefits as well as the risks of fish intake.