Early Life Environmental Exposure to Cadmium, Lead, and Arsenic and Age at Menarche: A Longitudinal Mother-Child Cohort Study in Bangladesh

BACKGROUND: Several metals act as endocrine disruptors, but there are few large longitudinal studies about associations with puberty onset. OBJECTIVES: We evaluated whether early life cadmium, lead, and arsenic exposure was associated with timing of menarche. METHODS: In a mother-child cohort in rural Bangladesh (n=935), the exposure was assessed by concentrations in maternal erythrocytes in early pregnancy and in girls' urine at 5 and 10 years of age using inductively coupled plasma mass spectrometry. The girls were interviewed twice, at average ages 13.3 [standard deviation (SD)=0.43] and 13.8 (SD=0.43) y, and the date of menarche, if present, was recorded. Associations were assessed using Kaplan-Meier analysis and multivariable-adjusted Cox regression. RESULTS: In total, 77% of the girls (n=717) had reached menarche by the second follow-up. The median age of menarche among all girls was 13.0 y (25th-75th percentiles: 12.4-13.7 y). At 10 years of age, median urinary cadmium was 0.25μg/L (5th-95th percentiles: 0.087-0.72μg/L), lead 1.6μg/L (0.70-4.2μg/L), and arsenic 54μg/L (19-395μg/L). Given the same age, girls in the highest quartile of urinary cadmium at 5 and 10 years of age had a lower rate of menarche than girls in the lowest quartile, with an adjusted hazard ratio of (HR) 0.80 (95% CI: 0.62, 1.01) at 5 years of age, and 0.77 (95% CI: 0.60, 0.98) at 10 years of age. This implies that girls in the highest cadmium exposure quartile during childhood had a higher age at menarche. Comparing girls in the highest to the lowest quartile of urinary lead at 10 years of age, the former had a higher rate of menarche [adjusted HR = 1.23 (95% CI: 0.97, 1.56)], implying lower age at menarche, whereas there was no association with urinary lead at 5 years of age. Girls born to mothers in the highest quartile of erythrocyte arsenic during pregnancy were less likely to have attained menarche than girls born to mothers in the lowest quartile [adjusted HR= 0.79 (95% CI: 0.62, 0.99)]. No association was found with girls' urinary arsenic exposure. DISCUSSION: Long-term childhood cadmium exposure was associated with later menarche, whereas the associations with child lead exposure were inconclusive. Maternal exposure to arsenic, but not cadmium or lead, was associated with later menarche. https://doi.org/10.1289/EHP11121

Pneumocystis jirovecii pneumonia in tropical and low and middle income countries: a systematic review and meta-regression

Objective: Pneumocystis jirovecii pneumonia (PCP), the commonest opportunistic infection in HIV-infected patients in the developed world, is less commonly described in tropical and low and middle income countries (LMIC). We sought to investigate predictors of PCP in these settings. Design Systematic review and meta-regression. METHODS: Meta-regression of predictors of PCP diagnosis (33 studies). Qualitative and quantitative assessment of recorded CD4 counts, receipt of prophylaxis and antiretrovirals, sensitivity and specificity of clinical signs and symptoms for PCP, co-infection with other pathogens, and case fatality (117 studies). RESULTS: The most significant predictor of PCP was per capita Gross Domestic Product, which showed strong linear association with odds of PCP diagnosis (p30%; treatment was largely appropriate. Prophylaxis appeared to reduce the risk for development of PCP, however 24% of children with PCP were receiving prophylaxis. CD4 counts at presentation with PCP were usually <200×10 3/ ml. CONCLUSIONS: There is a positive relationship between GDP and risk of PCP diagnosis. Although failure to diagnose infection in poorer countries may contribute to this, we also hypothesise that poverty exposes at-risk patients to a wide range of infections and that the relatively non-pathogenic P. jirovecii is therefore under-represented. As LMIC develop economically they eliminate the conditions underlying transmission of virulent infection: P. jirovecii , ubiquitous in all settings, then becomes a greater relative threat

Early-life metal exposure and child growth and development

Cadmium, lead and arsenic are toxic metals, the exposure to which occurs primarily through food and drinking water. While many studies are available about their health effects in adults, studies in children and adolescents are more limited, especially for cadmium. The overall aim of this thesis was to assess if early-life metal exposure, especially cadmium, but also lead and arsenic, may affect children’s growth and pubertal development at schoolage. This research was conducted in a large mother-child cohort in a rural area called Matlab, in southern Bangladesh. The cohort was nested in a randomized food and micronutrient supplementation trial called MINIMat (Maternal and Infant Intervention, Matlab), which was established in 2001-2003. Women were recruited during early pregnancy and their children were followed up repeatedly from birth up to the age of 15 years. Urine and/or blood samples were collected from the mothers during pregnancy and from the children at several time points to assess their exposure to metals and to measure various health-related biomarkers. The children’s weight and height were measured during infancy, childhood and adolescence, and pubertal development in late childhood and adolescence. In Paper I, we investigated if early-life cadmium exposure was associated with changes in bone-related biomarkers at 9 years of age (n=504), as cadmium has been linked to bone toxicity in adults. Using adjusted linear regression analyses, we found that both children’s urinary cadmium (reflecting life-long exposure) and erythrocyte cadmium (reflecting the last few months) were associated with decreased levels of vitamin D3, a hormone involved in calcium homeostasis and with importance for bone mineralization. We also observed that childhood cadmium exposure was associated with changes in biomarkers of bone remodeling. Urinary cadmium was associated with an increase of both osteocalcin (biomarker of bone formation) and urinary deoxypyridinoline (DPD, biomarker of bone resorption). Interestingly, when stratifying the models by gender, we found that urinary cadmium was associated with an increase of osteocalcin in girls, but with a decrease of osteocalcin in boys, suggesting a dysregulation of the feedback mechanisms in bone remodeling in boys. We also observed a tendency of an inverse association between urinary cadmium and weightfor- age Z-score (WAZ) at 9 years, but the confidence intervals were wide. Therefore, in order to ascertain this association, we investigated this in a larger subset of children in the MINIMat cohort in Paper II (n=1530). We also explored associations with the children’s lead and arsenic exposure. In this larger sample, we found that concurrent urinary cadmium was inversely associated with WAZ and possibly also with height-for-age Z-score (HAZ) at 10 years, and that the associations were stronger in boys. We also found that short-term lead exposure, measured in urine, was associated with decreased WAZ and HAZ in boys, while neither maternal nor childhood arsenic exposure was associated with any measure of size, despite a very large variation in the arsenic exposure. In longitudinal analyses from birth to 10 years, we found that maternal erythrocyte cadmium in early pregnancy was associated with decreased WAZ in boys. As cadmium and lead are reported endocrine disruptors, we investigated if the exposure to these two metals was associated with changes of timing of menarche in girls in Paper III (n=935). Using survival analysis, we observed that an increased exposure to cadmium during childhood was associated with a delay in menarche. The potential impact of lead was less clear. To conclude, this research provides important evidence that early-life exposure to dietary cadmium can adversely affect child growth and pubertal development at exposure levels relevant for millions of children around the world. This emphasizes the need for further research in children and adolescents and that research on children should be considered in updates of the international health risk assessment of cadmium

Exploring telomere length in mother-newborn pairs in relation to exposure to multiple toxic metals and potential modifying effects by nutritional factors

Background: The uterine environment may influence telomere length at birth, which is essential for cellular function, aging, and disease susceptibility over the lifespan. However, little is known about the impact of toxic chemicals on early-life telomeres. Therefore, we assessed the potential impact of multiple toxic metals on relative telomere length (rTL) in the maternal blood, cord blood, and placenta, as well as the potential modifying effects of pro-oxidants. Method: In a mother-child cohort in northern Argentina (n = 169), we measured multiple toxic metals in the maternal blood or urine collected during late pregnancy, as well as the placenta and cord blood collected at delivery, using inductively coupled plasma mass spectrometry (ICP-MS). We assessed associations of log 2 -transformed metal concentrations with rTL, measured in maternal and cord blood leukocytes and the placenta by real-time PCR, using multivariable-adjusted linear regression. Additionally, we tested for modifications by antioxidants (zinc, selenium, folate, and vitamin D 3 ). Results: Exposure to boron and antimony during pregnancy was associated with shorter maternal rTL, and lithium with longer maternal rTL; a doubling of exposure was associated with changes corresponding to 0.2-0.4 standard deviations (SD) of the rTL. Arsenic concentrations in the placenta (n = 98), blood, and urine were positively associated with placental rTL, about 0.2 SD by doubled arsenic. In the cord blood (n = 88), only lead was associated with rTL (inversely), particularly in boys (p for interaction 0.09). Stratifying by newborn sex showed ten times stronger association in boys (about 0.6 SD) than in girls. The studied antioxidants did not modify the associations, except that with antimony. Conclusions: Elevated exposure to boron, lithium, arsenic, and antimony was associated with maternal or newborn rTL in a tissue-specific, for lead also sex-specific, manner. Nutritional antioxidants did not generally influence the associations

Environmental metal exposure and growth to 10 years of age in a longitudinal mother-child cohort in rural Bangladesh

Background: Early-life exposure to arsenic (As), cadmium (Cd), and lead (Pb) has been linked to smaller birth and early childhood anthropometry, but little is known beyond the first years in life. Objectives: To evaluate the impact of gestational and childhood exposures to As, Cd, and Pb on growth up to 10 years of age. Methods: We studied 1530 mother-child dyads from a nested sub-cohort of the MINIMat trial in rural Matlab, Bangladesh. Metal concentrations in maternal erythrocytes during pregnancy and in children's urine at 10y were measured by inductively coupled plasma mass spectroscopy. Child height and weight were measured at 19 occasions from birth until 10y and converted to height-for-age Z-scores (HAZ) and weight-for-age Z-scores (WAZ). Associations between log2-transformed metal concentrations and growth parameters were assessed with multivariable-adjusted regression models. Results: Children's concurrent urinary Cd (median 0.24 µg/L), reflecting long-term exposure, was inversely associated with WAZ (B: -0.072; 95% confidence interval (CI): -0.12, -0.020; p = 0.007), and possibly HAZ (B: -0.046; 95% CI: -0.096, 0.0014; p = 0.057), at 10y. The association with WAZ was stronger in boys than in girls. Maternal erythrocyte Cd (median 0.90 µg/kg) during pregnancy was inversely associated with WAZ during childhood only in boys (B: -0.071, 95% CI: -0.14, -0.0047, p = 0.036). Concurrent urinary Pb (median 1.6 µg/L) was inversely associated with WAZ (B: -0.084; 95% CI: -0.16, -0.0085; p = 0.029) and HAZ (B: -0.087; 95% CI: -0.15, -0.021; p = 0.010) in boys, but not in girls. Neither gestational nor childhood As exposure (median maternal erythrocyte As 4.3 µg/kg and children's urinary As 57 µg/L) was associated with growth up to 10y. Conclusions: While all effect estimates were small, environmental exposure to Cd and Pb is common and impaired growth is of public health concern, especially for children already at risk of reduced growth due to malnutrition. Gender differences in susceptibility need further investigation

Maternal exposure to cadmium during pregnancy is associated with changes in DNA methylation that are persistent at 9 years of age

Background: Cadmium (Cd) exposure during gestation has been associated with altered DNA methylation at birth, but it is not known if the changes in methylation persist into childhood. Objectives: To evaluate whether gestational Cd-related changes of DNA methylation persist from birth to 9 years of age. Methods: We studied mother–child dyads in a longitudinal cohort in rural Bangladesh. Cadmium concentrations in maternal blood (erythrocyte fraction; Ery-Cd) at gestational week 14 and in child urine (U-Cd, long-term exposure marker) at 9 years were measured using inductively coupled plasma mass spectrometry. The epigenome-wide DNA methylation was measured in mononuclear cells (PBMCs) prepared from cord blood and peripheral blood at 9 years in 71 children (hereafter referred to as the explorative group) by Infinium HumanMethylation450K BeadChip. Replication of one differentially methylated region (DMR; 9 CpG sites) was performed in PBMCs of 160 9-year-old children (validation group) by EpiTyper MALDI-TOF mass spectrometry. Results: The median maternal Ery-Cd concentration was 1.24 µg/kg (range 0.35, 4.55) in the explorative group and 0.83 µg/kg (0.08, 2.97) in the validation group. The median U-Cd concentration in the 9-year-old children was 0.26 µg/L (0.09, 1.06) in the explorative group and 0.32 µg/L (0.07, 1.33) in the validation group. In the explorative group, we identified ten DMRs, both in cord blood and in PBMCs at 9 years, that were associated with maternal Ery-Cd. Eight out of the ten DMRs were hypomethylated and three of the hypomethylated DMRs were located in the HLA region on chromosome 6. One of the DMRs (hypomethylated) in the HLA region (upstream of the zinc finger protein 57 homolog, ZFP57 gene) was replicated in the validation group, and we found that it was hypomethylated in relation to maternal Ery-Cd, but not child U-Cd. Conclusion: Gestational exposure to Cd appears to be associated with regional changes, especially hypomethylated, in DNA methylation that linger from birth up to prepubertal age

Polycyclic aromatic hydrocarbon (PAH) exposure during pregnancy and child anthropometry from birth to 10 years of age : Sex-specific evidence from a cohort study in rural Bangladesh

Polycyclic aromatic hydrocarbons (PAHs) have endocrine disrupting properties and they cross the placental barrier, but studies on gestational exposure and child anthropometry are inconclusive. We aimed to elucidate the impact of early gestational PAH exposure on anthropometry from birth to 10 years of age in 1295 mother-child pairs from a nested sub-cohort of the MINIMat trial in Bangladesh. Several PAH metabolites [1- hydroxyphenanthrene (1-OH-Phe), E2-,3-hydroxyphenanthrene (E2-,3-OH-Phe), 4-hydroxyphenanthrene (4- OH-Phe), 1-hydroxypyrene (1-OH-Pyr), E2-,3-hydroxyfluorene (E2-,3-OH-Flu)] were quantified in spot urine collected around gestational week 8 using LC-MS/MS. Child weight and height were measured at 19 occasions from birth to 10 years. Multivariable-adjusted regression models were used to assess associations of maternal PAH metabolites (log2-transformed) with child anthropometry. The median concentration of 1-OH-Phe, E2-,3- OH-Phe, 4-OH-Phe, 1-OH-Pyr and E2-,3-OH-Flu was 1.5, 1.9, 0.14, 2.5, and 2.0 ng/mL, respectively. All maternal urinary PAH metabolites were positively associated with newborn weight and length and all associations were more pronounced in boys than in girls (p interaction for all &lt;0.14). In boys, the strongest associations were observed with E2-,3-OH-Phe and E2-,3-OH-Flu for which each doubling increased mean birth weight by 41 g (95% CI: 13; 69 and 12; 70) and length by 0.23 cm (0.075; 0.39) and 0.21 cm (0.045; 0.37), respectively. Maternal urinary PAH metabolites were not associated with child anthropometry at 10 years. In longitudinal analysis, however, maternal urinary PAH metabolites were positively associated with boys' weight-for-age (WAZ) and height-for-age Z-scores (HAZ) from birth to 10 years, but only the association of 4-OH-Phe with HAZ was significant (B: 0.080 Z-scores; 95% CI 0.013, 0.15). No associations were observed with girls' WAZ or HAZ. In conclusion, gestational PAH exposure was positively associated with fetal and early childhood growth, especially in boys. Further studies are needed to confirm causality and to explore long-term health effects