Maria Kippler

Accumulation of cadmium in human placenta interacts with the transport of micronutrients to the fetus.

Cadmium (Cd) is a widespread, highly toxic environmental pollutant known to accumulate in human placenta. The aim of the present study was to elucidate to what extent the accumulation of Cd in human placenta interacts with the transport of micronutrients to the fetus. Cd and micronutrients were measured in placenta and umbilical cord blood from 44 non-smoking, rural Bangladeshi women, using ICPMS. Metallothionein (MT) protein expression was determined in placenta using Western blot. Cd in placenta (median 110 microg/kg dry weight, 20 microg/kg wet weight) was positively associated with maternal urinary Cd. It was also positively associated with Cd in umbilical cord blood (median 0.16 microg/kg), but negatively associated with zinc (Zn; median 3mg/kg) in umbilical cord blood. Umbilical cord blood Zn was positively associated with birth anthropometry measures, and the Cd-related impairment of Zn in umbilical cord blood seemed to decrease size at birth. In multivariate analysis, MT protein expression was associated with Cd (positively) in placenta, but not with Zn or copper (Cu) in placenta. In conclusion, the Cd concentrations in placenta were clearly elevated, which seemed to impair Zn transfer to the fetus. Induction of MT explained the placental accumulation of Cd, but not the impairment of Zn transport.

Maternal Cadmium Exposure during Pregnancy and Size at Birth: A Prospective Cohort Study

Background: Cadmium (Cd) is an embryotoxic and teratogenic metal in a variety of animal species, but data from humans are limited. Objectives: The aim of the present study was to assess the effects of maternal Cd exposure in pregnancy on size at birth. Methods: This prospective cohort study was nested in a population-based nutritional supplementation trial in pregnancy conducted in rural Bangladesh. We selected women recruited from February 2002 through January 2003 who had a singleton birth with measurements of size at birth and had donated a urine sample in early pregnancy for Cd analyses (n = 1,616). Urinary Cd was measured with inductively coupled plasma mass spectrometry and adjusted for specific gravity. Results: Multiple linear regression analyses adjusted for sex and other potential confounders showed that maternal urinary Cd (median, 0.63 μg/L) was significantly negatively associated with birth weight [unstandardized regression coefficient B = –31.0; 95% confidence interval (CI): –59, –2.8] and head circumference (B = –0.15; 95% CI: –0.27, –0.026). However, associations appeared to be limited to girls, with little evidence of effects in boys. A 1-μg/L increase in Cd in maternal urine was associated with a 0.26-cm (95% CI: –0.43, –0.088 cm) and 0.24-cm (95% CI: –0.44, –0.030 cm) decrease in girls’ head and chest circumferences, respectively, and a 45-g (95% CI: –82.5, 7.3 g) decrease in birth weight. Quantile regression analyses indicated that associations with maternal Cd were similar for girls of smaller (25th percentile) and larger (50th and 75th percentiles) sizes at birth. Conclusion: We found evidence of a sex difference in the association between maternal Cd exposure and birth size, which was apparent only in girls. Results add support for the need to reduce Cd pollution to improve public health.

Sex-specific effects of early life cadmium exposure on DNA methylation and implications for birth weight

Dietary cadmium exposure was recently found to alter DNA methylation in adults, but data on effects early in life are lacking. Our objective was to evaluate associations between prenatal cadmium exposure, DNA methylation and birth weight. In total 127 mother-child pairs from rural Bangladesh were studied. For comparison, we included 56 children at 4.5 y. Cadmium concentrations in mothers’ blood (gestational week 14) and children’s urine were measured by ICPMS. Global DNA methylation was analyzed by Infinium HumanMethylation450K BeadChip in cord blood and children’s blood. Maternal cadmium exposure was associated with cord blood DNA methylation (p-value < 10–16). The association was markedly sex-specific. In boys, 96% of the top 500 CpG sites showed positive correlations (rS-values > 0.50), whereas most associations in girls were inverse; only 29% were positive (rS > 0.45). In girls we found overrepresentation of methylation changes in genes associated with organ development, morphology and mineralization of bone, whereas changes in boys were found in cell death-related genes. Several individual CpG sites that were positively associated with cadmium were inversely correlated with birth weight, although none statistically significant after correction for multiple comparisons. The associations were, however, fairly robust in multivariable-adjusted linear regression models. We identified CpG sites that were significantly associated with cadmium exposure in both newborns and 4.5-y-old children. In conclusion, cadmium exposure in early life appears to alter DNA methylation differently in girls and boys. This is consistent with previous findings of sex-specific cadmium toxicity. Cadmium-related changes in methylation were also related to lower birth weight.

Early-life cadmium exposure and child development in 5-year-old girls and boys: a cohort study in rural Bangladesh.

Background: Cadmium is a commonly occurring toxic food contaminant, but health consequences of early-life exposure are poorly understood. Objectives: We evaluated the associations between cadmium exposure and neurobehavioral development in preschool children. Methods: In our population-based mother–child cohort study in rural Bangladesh, we assessed cadmium exposure in 1,305 women in early pregnancy and their children at 5 years of age by measuring concentrations in urine (U-Cd), using inductively coupled plasma mass spectrometry. Children’s IQ at 5 years of age, including Verbal (VIQ), Performance (PIQ), and Full-Scale IQ (FSIQ), were measured by Wechsler Preschool and Primary Scale of Intelligence. Behavior was assessed by the Strengths and Difficulties Questionnaire (SDQ). Results: In multiple linear regression models, adjusted for sex, home stimulation, socioeconomic status (SES), and maternal and child characteristics, a doubling of maternal U-Cd was inversely associated with VIQ (–0.84 points; 95% confidence interval: –1.3, –0.40), PIQ (–0.64 points; –1.1, –0.18), and FSIQ (–0.80 points; –1.2, –0.39). Concurrent child U-Cd showed somewhat weaker association with VIQ and FSIQ, but not PIQ. Stratification by sex and SES indicated slightly stronger associations with PIQ and FSIQ in girls than in boys and in higher-income compared with lower-income families. Concurrent U-Cd was inversely associated with SDQ-prosocial behavior and positively associated with SDQ-difficult behavior, but associations were close to the null after adjustment. Quantile regression analysis showed similar associations across the whole range of each developmental outcome. Conclusion: Early-life low-level cadmium exposure was associated with lower child intelligence scores in our study cohort. Further research in this area is warranted.

Factors influencing intestinal cadmium uptake in pregnant Bangladeshi women—A prospective cohort study

Experimental studies indicate that zinc (Zn) and calcium (Ca) status, in addition to iron (Fe) status, affect gastrointestinal absorption of cadmium (Cd), an environmental pollutant that is toxic to kidneys, bone and endocrine systems. The aim of this study was to evaluate how various nutritional factors influence the uptake of Cd in women, particularly during pregnancy. The study was carried out in a rural area of Bangladesh, where malnutrition is prevalent and exposure to Cd via food appears elevated. The uptake of Cd was evaluated by associations between erythrocyte Cd concentrations (Ery-Cd), a marker of ongoing Cd exposure, and concentrations of nutritional markers. Blood samples, collected in early pregnancy and 6 months postpartum, were analyzed by inductively coupled plasma mass spectrometry (ICPMS). Ery-Cd varied considerably (range: 0.31-5.4microg/kg) with a median of 1.1microg/kg (approximately 0.5microg/L in whole blood) in early pregnancy. Ery-Cd was associated with erythrocyte manganese (Ery-Mn; positively), plasma ferritin (p-Ft; negatively), and erythrocyte Ca (Ery-Ca; negatively) in decreasing order, indicating common transporters for Cd, Fe and Mn. There was no evidence of Cd uptake via Zn transporters, but the association between Ery-Cd and p-Ft seemed to be dependent on adequate Zn status. On average, Ery-Cd increased significantly by 0.2microg/kg from early pregnancy to 6 months postpartum, apparently due to up-regulated divalent metal transporter 1 (DMT1). In conclusion, intestinal uptake of Cd appears to be influenced either directly or indirectly by several micronutrients, in particular Fe, Mn and Zn. The negative association with Ca may suggest that Cd inhibits the transport of Ca to blood.

Arsenic methylation efficiency increases during the first trimester of pregnancy independent of folate status.

Exposure to inorganic arsenic during pregnancy may negatively influence the offspring, though efficient metabolism of arsenic to dimethylarsinic acid (DMA) likely reduces the health risks. This study aimed to evaluate methylation of arsenic over the entire pregnancy and the influence of nutritional status. We studied longitudinally the arsenic metabolite pattern in the urine of 324 pregnant women exposed to arsenic via drinking water and food in rural Bangladesh. Metabolism of arsenic to DMA increased markedly over the course of pregnancy, with the greatest improvement occurring in the first trimester, along with a marked decrease in the most risk-associated monomethylated metabolite. This improvement in methylation was not associated with nutritional status, including vitamin B(12) and folate. Efficient methylation to DMA was associated with improved urinary excretion of arsenic, relative to blood arsenic concentrations, indicating that micronutrient-independent up-regulation of arsenic metabolism already in early pregnancy may provide protection for the fetus.

Cadmium interacts with the transport of essential micronutrients in the mammary gland-A study in rural Bangladeshi women

Although the concentrations of the toxic metal cadmium in breast milk are generally low (< 1 microg/L), experimental studies indicated neurobehavioral and endocrine effects in the suckling offspring. The aim of the present study was to elucidate how cadmium is transported to breast milk by assessing interactions with essential micronutrients. The study is nested into a food and micronutrient supplementation trial conducted among pregnant women in Matlab, a rural area in Bangladesh, where malnutrition is prevalent and the cadmium exposure is relatively high. We measured cadmium in breast milk (BM-Cd; median 0.14 microg/kg; range <0.050-1.0 microg/kg), in erythrocytes (Ery-Cd; median 1.5 microg/kg; range 0.46-4.8 microg/kg) and in urine (U-Cd; median 0.63 microg/L; range 0.050-4.5 microg/L), using inductively coupled plasma mass spectrometry (ICPMS). We found a significant positive association between Ery-Cd and BM-Cd and a breast milk-plasma ratio of approximately 3-4, indicating no barrier against cadmium transport from plasma to breast milk. BM-Cd was positively associated with manganese (r(s)=0.56; p<0.01) and iron (r(s)=0.55; p<0.01) in breast milk, but not with plasma ferritin. On the other hand, BM-Cd was negatively associated with BM-Ca (r(s)=-0.17; p=0.05), indicating that cadmium inhibits the transport of calcium to breast milk. In conclusion, the present study may indicate that cadmium shares common transporters with iron and manganese for transfer to breast milk, but inhibits secretion of calcium to breast milk.

Environmental exposure to arsenic and cadmium during pregnancy and fetal size: a longitudinal study in rural Bangladesh.

Prenatal exposures to arsenic (As) and cadmium (Cd) have been associated with decreased size at birth. We here studied associations of prenatal As and Cd exposures with multiple fetal size parameters measured by ultrasound in gestational week (GW) 14 and 30 in a population-based mother-child cohort in rural Bangladesh. We measured As (n=1929) and Cd (n=1616) in urine during pregnancy. In the longitudinal evaluation of combined exposure, urinary Cd (UCd) showed an inverted U-shaped association (turning-point 1.5 μg Cd/L) with all fetal size parameters, while UAs showed no significant association. Cross-sectional analyses indicated that associations with UCd were somewhat stronger in early gestation. Stratification indicated stronger associations between UCd and fetal size in girls than in boys, and in poorer than in richer families, while UAs was weakly associated with fetal size in boys. In conclusion, particularly Cd, but also As, appeared to influence fetal development in a sex-dependent manner.

Environmental Exposure to Metals and Children's Growth to Age 5 Years: A Prospective Cohort Study

In this prospective cohort study, based on 1,505 mother-infant pairs in rural Bangladesh, we evaluated the associations between early-life exposure to arsenic, cadmium, and lead, assessed via concentrations in maternal and child urine, and childrens weights and heights up to age 5 years, during the period 2001–2009. Concurrent and prenatal exposures were evaluated using linear regression analysis, while longitudinal exposure was assessed using mixed-effects linear regression. An inverse association was found between childrens weight and height, age-adjusted z scores, and growth velocity at age 5 years and concurrent exposure to cadmium and arsenic. In the longitudinal analysis, multivariable-adjusted attributable differences in childrens weight at age 5 years were −0.33 kg (95% confidence interval (CI): −0.60, −0.06) for high (≥95th percentile) arsenic exposure and −0.57 kg (95% CI: −0.88, −0.26) for high cadmium exposure, in comparison with children with the lowest exposure (≤5th percentile). Multivariable-adjusted attributable differences in height were −0.50 cm (95% CI: −1.20, 0.21) for high arsenic exposure and −1.6 cm (95% CI: −2.4, −0.77) for high cadmium exposure. The associations were apparent primarily among girls. The negative effects on childrens growth at age 5 years attributable to arsenic and cadmium were of similar magnitude to the difference between girls and boys in terms of weight (−0.67 kg, 95% CI: −0.82, −0.53) and height (−1.3 cm, 95% CI: −1.7, −0.89).

Burden of cadmium in early childhood: Longitudinal assessment of urinary cadmium in rural Bangladesh

Chronic cadmium exposure is associated with many adverse health effects in adults, but little is known about the scenario early in life. This study assessed cadmium exposure and body burden in young children, born to women with known cadmium exposure via rice. As part of our ongoing population-based, longitudinal study of health effects of early-life toxicants exposure in rural Bangladesh, we measured cadmium in urine of about 350 children at 1.5 and 5 years of age, and in 92 children at 3 months of age. Median cadmium concentrations in urine were 0.30, 0.16 and 0.30 microg/L at 3 months, 1.5 and 5 years of age, respectively (0.6 microg/L in mothers). Cadmium concentrations in infants urine correlated with concentrations in maternal breast milk, saliva, and urine. As expected, concentrations in urine increased from 1.5 to 5 years of age. Rice (median 47 microgCd/kg) is most likely the main source of exposure. In conclusion, we found unexpectedly high cadmium exposure among children in rural Bangladesh. Urinary cadmium concentrations were particularly elevated at 3 months of age, indicating limited reabsorption and accumulation of cadmium in the kidneys, known to be the main site of cadmium burden in older children and adults.