Claudia Gundacker

Perinatal lead and mercury exposure in Austria

OBJECTIVE The heavy metals lead (Pb) and mercury (Hg) are ubiquitous environmental pollutants with high neurotoxic potential. We aimed to compare perinatal Pb and Hg concentrations and to explore the potential association between Pb and Hg exposure and newborn anthropometry. STUDY DESIGN Pregnant women were recruited in 2005 at the General Hospital Vienna for participation in this longitudinal study. Pb and Hg concentrations were measured in maternal blood and hair, placenta, cord blood, meconium, and breast milk of 53 mother-child pairs by CV-AAS, GF-AAS, and HPLC-CV-ICPMS. We conducted bivariate analyses and categorical regression analysis (CATREG) to evaluate the determinants of Pb and Hg exposure, and of infant anthropometry. RESULTS Median Pb and total Hg contents were low, i.e., 25 μg/L (maternal blood-Pb), 13 μg/L (cord blood-Pb), 0.7 μg/L (maternal blood-Hg), and 1.1 μg/L (cord blood-Hg). Hg levels in maternal and fetal tissues were frequently correlated (r>0.3, P<0.05, respectively). Regarding Pb, only maternal blood and cord blood concentrations correlated (P=0.043). Cord blood levels indicated higher Hg exposure but lower Pb exposure relative to maternal blood contents. Adjusted CATREG models indicated the significant predictors of birth length (placenta-Pb, gestational length, meconium-Pb), birth weight (placenta-Pb, gestational length, maternal blood-Pb), and head circumference (maternal education, maternal height). Besides one significant correlation between maternal hair Hg and birth length, the mercury levels were not associated with newborn anthropometry. CONCLUSIONS Our data implicate that different modes of action may exist for placentar transfer of Pb and Hg as well as that low Pb exposure levels can result in lower birth weight. The findings related to newborn anthropometry need to be confirmed by the examination of larger study groups. Further research is needed to clarify the mechanisms of Pb and Hg transfer via the placenta, and to explore how prenatal Pb exposure is related to intrauterine growth.

The relevance of the individual genetic background for the toxicokinetics of two significant neurodevelopmental toxicants: Mercury and lead

The heavy metals mercury and lead are well-known and significant developmental neurotoxicants. This review summarizes the genetic factors that modify their toxicokinetics. Understanding toxicokinetics (uptake, biotransformation, distribution, and elimination processes) is a key precondition to understanding the individual health risks associated with exposure. We selected candidate susceptibility genes when evidence was available for (1) genes/proteins playing a significant role in mercury and lead toxicokinetics, (2) gene expression/protein activity being induced by these metals, and (3) mercury and lead toxicokinetics being affected by gene knockout/knockdown or (4) by functional gene polymorphisms. The genetic background is far better known for mercury than for lead toxicokinetics. Involved are genes encoding L-type amino acid transporters, organic anion transporters, glutathione (GSH)-related enzymes, metallothioneins, and transporters of the ABC family. Certain gene variants can influence mercury toxicokinetics, potentially explaining part of the variable susceptibility to mercury toxicity. Delta-aminolevulinic acid dehydratase (ALAD), vitamin D receptor (VDR) and hemochromatosis (HFE) gene variants are the only well-established susceptibility markers of lead toxicity in humans. Many gaps remain in our knowledge about the functional genomics of this issue. This calls for studies to detect functional gene polymorphisms related to mercury- and lead-associated disease phenotypes, to demonstrate the impact of functional polymorphisms and gene knockout/knockdown in relation to toxicity, to confirm the in vivo relevance of genetic variation, and to examine gene-gene interactions on the respective toxicokinetics. Another crucial aspect is knowledge on the maternal-fetal genetic background, which modulates fetal exposure to these neurotoxicants. To completely define the genetically susceptible risk groups, research is also needed on the genes/proteins involved in the toxicodynamics, i.e., in the mechanisms causing adverse effects in the brain. Studies relating the toxicogenetics to neurodevelopmental disorders are lacking (mercury) or very scarce (lead). Thus, the extent of variability in susceptibility to heavy metal-associated neurological outcomes is poorly characterized.

The role of the placenta in fetal exposure to heavy metals.

ZusammenfassungSeit langem ist bekannt, dass die Schwermetalle Quecksilber, Blei und Cadmium plazentagängig sind und in fetalen Geweben akkumulieren. Pränatale Quecksilber- und Blei-Belastungen können die neurologische Entwicklung beeinträchtigen. Fetale Blei- und Cadmium-Belastungen korrelieren mit verringertem Geburtsgewicht und verringerter Geburtslänge. Während Quecksilber und Blei die Plazenta ungehindert passieren, gelangt nur wenig Cadmium zum Fetus. Dies dürfte daran liegen, dass Cadmium in höherem Ausmaß an Metallothionein bindet als Quecksilber und Blei. Die Plazenta stellt für Cadmium also zumindest eine partielle Barriere dar. Unklar ist, welche Proteine am plazentaren Metalltransport beteiligt sind und wo solche Transporter in der Plazentaschranke lokalisiert sind. Bislang sind also nur wenige Aspekte der Metall-Toxikokinetik in Plazenta bekannt. Quecksilber, Blei und Cadmium schädigen nachweislich die Plazentazellen. Beides, der metallspezifische Transfer über die Plazenta aber auch die metall-induzierte Schädigung der Plazenta können den Zusammenhang zwischen pränataler Metall-Belastung und den beobachteten Schadwirkungen auf die kindliche Entwicklung erklären.SummaryThe heavy metals mercury, lead, and cadmium are toxicants, which are well-known to cross the placenta and to accumulate in fetal tissues. Prenatal exposure to mercury and lead poses a health threat particularly to the developing brain. Fetal exposures to lead and cadmium correlate with reduced birth weight and birth size. The placental passage of cadmium is limited suggesting a partial barrier for this metal. It is very likely that metallothionein is responsible for placental storage of the metals especially of cadmium. It is unclear, however, which proteins are involved in placental uptake and efflux of the metals and where the transporters are located at the placental barrier. Hence, only certain aspects of placental metal toxicokinetics are known so far. The metals have also been shown to adversely affect placental functions. Both metal-specific placental transfer and impairment of placental function can explain the relationships between prenatal metal exposures and adverse effects on intrauterine growth and (neuro)development.

Genetic background of lead and mercury metabolism in a group of medical students in Austria

BACKGROUND Information on the impact of genetic predisposition on metal toxicokinetics in the human body is limited. There is increasing evidence that certain genetic polymorphisms modify lead and mercury toxicokinetics. This called for analysis of further candidate genes. OBJECTIVES Medical students (N=324) were examined in order to detect potential associations between lead exposure and polymorphisms in HFE, VDR, ALAD, and MT genes, as well as between mercury exposure and GSTT1, GSTM1, GSTA1, GSTP1, GCLC, and MT polymorphisms. METHODS The levels of lead and mercury exposure of students were determined by blood, urine, and hair analyses (ICP-MS, CV-AAS). Genotyping of common polymorphisms was examined by MALDI-TOF MS and the TaqMan methodology. Associations between lead and mercury exposures and genetic background were examined by bivariate analysis, and by categorical regression analysis (CATREG) controlled by metal- and matrix-specific variables. RESULTS Lead and mercury levels in urine, blood, and hair indicated low exposures. VDR polymorphism and joint presence of VDR/ALAD polymorphisms were significantly and independently associated with urine lead concentrations (CATREG P<0.05). Polymorphisms in GSTP1-114 and MT4 genes as well as dual gene combinations including GSTP1, GCLC, GSTT1, and GSTM1 polymorphisms were independent variables related to mercury body burdens (CATREG P<0.05). GSTP1-114/GSTT1 and GSTP1-105/GCLC combinations showed synergistic effects on hair mercury levels compared to single-gene variants. CONCLUSIONS We found evidence that certain genetic backgrounds were associated with lead and mercury metabolism, suggesting gene-environment and gene-gene-environment interactions. The modes of interaction remain to be evaluated.

Geophagy and potential health implications: geohelminths, microbes and heavy metals

The practice of geophagy (soil-eating) is widespread among pregnant and breast-feeding women in sub-Saharan Africa. To assess some of the potential risks accompanying the consumption of geophagic material, we analysed contamination with bacteria, fungi, and geohelminths as well as heavy metals (lead, mercury and cadmium) in 88 African geophagic soil samples, which were purchased in Central, West and East Africa, Europe and the United States. Median microbial viable counts of positive samples were 440 cfu/g (maximum 120,000 cfu/g). The median metal concentrations were 40 mg/kg lead (up to 148 mg/kg), 0.05 mg/kg mercury (up to 0.64 mg/kg), and 0.055 mg/kg cadmium (maximum 0.57 mg/kg). No geohelminth eggs were found in these samples. Our results suggest that geophagic soil samples can be highly contaminated with microbes and may contain high levels of lead. Geophagy, however, is not a cause of adult helminth infection. The periodic consumption of geophagic materials at high dosages might be problematic particularly during pregnancy.

Characterization of intrinsic and extrinsic risk factors for celery allergy in immunosenescence

Recent studies indicated an underestimation of allergies in elderly. In our experimental food allergy model of protein feeding under acid-suppression we aimed to assess whether food allergy can be induced in immunosenescent mice. Furthermore, the impact of gastric digestion on celery allergenicity was evaluated in aged patients. Measurements of serum zinc and iron levels in senescent and adult BALB/c mice for definition of the nutritional status indicated a possible alteration of the immune response in the aged animals due to reduced zinc and iron levels. Feedings of mice with digestion-sensitive celery proteins under physiological gastric conditions induced IgG1 and IgG2a in the aged and preferentially IgG1 in the adult animals. In contrast, incomplete digestion due to acid-suppression rendered celery-specific IgE, positive skin tests and elevated IL-5 levels in both age groups. Also in aged celery allergic patients (mean age 72 years) properly digested celery showed decreased capacity to bind and crosslink IgE as evaluated by skin tests and IgE immunoblot. Thus, in the geriatric murine model, celery allergy was induced only if gastric digestion was hindered. Accordingly, gastric proteolysis decreased in vitro and in vivo IgE-reactivity against celery proteins in aged allergic patients.

Smoking, cereal consumption, and supplementation affect cadmium content in breast milk

Breast milk might be a source of potentially toxic metals such as cadmium (Cd). The purpose of the present study is to provide data pertaining to the influence of maternal lifestyles on Cd concentrations in breast milk in the Austrian setting. Breast milk was obtained from 124 Austrian women. Each participant provided 10 ml of milk. A second group of eight mothers were recruited to investigate changes in their milk cadmium levels at 1, 3, 5, 7 and 9 weeks post partum. The study participants filled a questionnaire concerning nutrition, supplementation, and smoking habits. The samples were analyzed using GF-Atomic Absorption Spectrophotometer (AAS). The mean Cd content in breast milk was among the lowest in Europe (0.086±0.085 μg/l, 95% CI: 0.07–0.10; n=124). Increased Cd levels in breast milk were found to be significantly associated with frequent cereal consumption and smoking. Smokers had a two-fold higher concentration than did non-smokers (0.15 versus 0.07 μg/l; P=0.000). In contrast, low Cd levels in breast milk were associated with the intake of supplements containing trace elements or vitamins and trace elements (P<0.05). This protective effect of supplements on Cd levels was only observed in non-smokers. The Cd levels registered in the present investigation were far below critical levels. We conclude that the current maternal Cd levels in Austria signify no risk for the breastfed infant of a healthy mother. Further research will have to focus on the specific effects of supplementation and smoking on Cd concentrations.

Renal differentiation of amniotic fluid stem cells: perspectives for clinical application and for studies on specific human genetic diseases

Eur J Clin Invest 2012; 42 (6): 677–684

Mercury toxicokinetics of the healthy human term placenta involve amino acid transporters and ABC transporters.

BACKGROUND The capacity of the human placenta to handle exogenous stressors is poorly understood. The heavy metal mercury is well-known to pass the placenta and to affect brain development. An active transport across the placenta has been assumed. The underlying mechanisms however are virtually unknown. OBJECTIVES Uptake and efflux transporters (17 candidate proteins) assumed to play a key role in placental mercury transfer were examined for expression, localization and function in human primary trophoblast cells and the trophoblast-derived choriocarcinoma cell line BeWo. METHODS To prove involvement of the transporters, we used small interfering RNA (siRNA) and exposed cells to methylmercury (MeHg). Total mercury contents of cells were analyzed by Cold vapor-atomic fluorescence spectrometry (CV-AFS). Localization of the proteins in human term placenta sections was determined via immunofluorescence microscopy. RESULTS We found the amino acid transporter subunits L-type amino acid transporter (LAT)1 and rBAT (related to b(0,+) type amino acid transporter) as well as the efflux transporter multidrug resistance associated protein (MRP)1 to be involved in mercury kinetics of trophoblast cells (t-test P<0.05). CONCLUSION The amino acid transporters located at the apical side of the syncytiotrophoblast (STB) manage uptake of MeHg. Mercury conjugated to glutathione (GSH) is effluxed via MRP1 localized to the basal side of the STB. The findings can well explain why mercury is transported primarily towards the fetal side.

Genetics of the human placenta: implications for toxicokinetics

Exposure to chemicals and environmental pollutants among them cadmium, lead, and mercury can harm reproduction. The metals cross the placenta, accumulate in placental tissue, and pass onto fetal blood and fetal organs to variable amounts. Still, the mechanisms underlying their transplacental passage are largely unknown and the human placenta is the most poorly understood organ in terms of reproduction toxicology. The genetic factors modulating placental toxicokinetics remain unclear just as well. From a genetic perspective, three aspects, which influence capacities of the human placenta to metabolize and transport toxicants, need to be considered. These are 1/presence and interplay of two genotypes, 2/chromosomal aberrations including aneuploidies and sequence variations, and 3/epigenetics and genetic imprinting. In this review, we summarize the current state of knowledge on how genetics and epigenetics affect placental (patho)physiology and thus fetal development and health.