Nicolas Van Larebeke

Endocrine-Disrupting Chemicals: Associated Disorders and Mechanisms of Action

The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.

Endocrine disruptors and abnormalities of pubertal development.

Onset and development of puberty is regulated by the neuroendocrine system. Population-based studies worldwide have observed secular trends towards earlier puberty development. These changes are apparently caused by environmental factors such as improved socio-economic status, improved health care and nutrition. However, they may also partly result from endocrine-disrupting chemicals in the environment. Epidemiological studies have investigated the relationship between pubertal development and exposure to endocrine-disrupting chemicals (polychlorinated biphenyls, polybrominated biphenyls, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, phthalate esters, furans and the pesticide endosulfan). Associations with both perinatal and postnatal exposure have been reported. Studies in experimental animals support some of these findings and point to differential endocrine regulatory mechanisms linked to pubertal development acting in the perinatal and the pre-pubertal period. Pubertal development is naturally associated with growth and body composition. There is increasing evidence for a link between prenatal development and pubertal onset. In girls born small for gestational age (SGA), pubertal onset and age at menarche often are advanced, especially if there has been an extensive catch-up growth during the first months of life. In utero growth retardation may have multiple causes including exposure to xenobiotic substances as was suggested for some endocrine-disrupting chemicals. An abnormal perinatal environment of children born SGA may alter the endocrine status and the sensitivity of the receptors for endocrine and metabolic signalling that may have effects on maturation of brain and gonads. However, the causal pathways and the molecular mechanisms that may link the pubertal growth pattern of children born SGA, pubertal development and endocrine-disrupting chemicals need further study.

Concept of the Flemish human biomonitoring programme

Since 2002 a human biomonitoring network has been established in Flanders (Belgium) as part of a programme on environmental health surveillance. The human biomonitoring network should support environmental health policy by identifying priorities for further action. The first cycle of the programme (2002-2006) confirmed the hypotheses that living in areas with different environmental pressure is reflected in different loads of environmental chemicals in the residents. In the second cycle of the programme (2007-2011) the number of environmental chemicals for which human biomonitoring data were obtained was expanded substantially. The goal of the Flemish programme is to use and translate the scientific results into policy actions. Its further orientation in the second cycle to human biomonitoring in hot spots and sensitive age groups or susceptible persons with underlying complications (e.g. persons with diabetes) are linked to these goals. Interaction with stakeholders is embedded in the programme emphasizing transparency of the choices that are made and direct communication. The Flemish human biomonitoring programme is organized centrally with major involvement of research partners from different disciplines which allows engrafting environmental health research on the programme. One of the major focuses is the question whether combinations of pollutants in the general population are associated with biological effects. The objective of this paper is to review and discuss the options that were taken in the human biomonitoring programme in order to achieve its goals.

Neurobehavioral function and low-level exposure to brominated flame retardants in adolescents: a cross-sectional study

BackgroundAnimal and in vitro studies demonstrated a neurotoxic potential of brominated flame retardants, a group of chemicals used in many household and commercial products to prevent fire. Although the first reports of detrimental neurobehavioral effects in rodents appeared more than ten years ago, human data are sparse.MethodsAs a part of a biomonitoring program for environmental health surveillance in Flanders, Belgium, we assessed the neurobehavioral function with the Neurobehavioral Evaluation System (NES-3), and collected blood samples in a group of high school students. Cross-sectional data on 515 adolescents (13.6-17 years of age) was available for the analysis. Multiple regression models accounting for potential confounders were used to investigate the associations between biomarkers of internal exposure to brominated flame retardants [serum levels of polybrominated diphenyl ether (PBDE) congeners 47, 99, 100, 153, 209, hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA)] and cognitive performance. In addition, we investigated the association between brominated flame retardants and serum levels of FT3, FT4, and TSH.ResultsA two-fold increase of the sum of serum PBDE’s was associated with a decrease of the number of taps with the preferred-hand in the Finger Tapping test by 5.31 (95% CI: 0.56 to 10.05, p = 0.029). The effects of the individual PBDE congeners on the motor speed were consistent. Serum levels above the level of quantification were associated with an average decrease of FT3 level by 0.18 pg/mL (95% CI: 0.03 to 0.34, p = 0.020) for PBDE-99 and by 0.15 pg/mL (95% CI: 0.004 to 0.29, p = 0.045) for PBDE-100, compared with concentrations below the level of quantification. PBDE-47 level above the level of quantification was associated with an average increase of TSH levels by 10.1% (95% CI: 0.8% to 20.2%, p = 0.033), compared with concentrations below the level of quantification. We did not observe effects of PBDE’s on neurobehavioral domains other than the motor function. HBCD and TBBPA did not show consistent associations with performance in the neurobehavioral tests.ConclusionsThis study is one of few studies and so far the largest one investigating the neurobehavioral effects of brominated flame retardants in humans. Consistently with experimental animal data, PBDE exposure was associated with changes in the motor function and the serum levels of the thyroid hormones.

Internal exposure to pollutants and sexual maturation in Flemish adolescents.

Flanders is densely populated with much industry and intensive farming. Sexual maturation of adolescents (aged 14–15 years) was studied in relation to internal exposure to pollutants. Serum levels of pollutants and sex hormones were measured in 1679 participants selected as a random sample of the adolescents residing in the study areas. Data on sexual development were obtained from the medical school examination files. Self-assessment questionnaires provided information on health, use of medication and lifestyle factors. In boys, serum levels of hexachlorobenzene (HCB), p,p′-DDE and polychlorinated biphenyls (sum of marker PCB138, 153 and 180) were significantly and positively associated with pubertal staging (pubic hair and genital development). Higher levels of serum HCB and blood lead were associated with, respectively, a lower and a higher risk of gynecomastia. In girls, significant and negative associations were detected between blood lead and pubic hair development; higher exposure to PCBs was significantly associated with a delay in timing of menarche. Environmental exposures to pollutants at levels actually present in the Flemish population are associated with measurable effects on pubertal development. However, further understanding of toxic mode of action and sensitive windows of exposure is needed to explain the current findings.

Serum dioxin-like activity is associated with reproductive parameters in young men from the general flemish population

Background 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and some related environmental contaminants are aryl hydrocarbon receptor (AhR) ligands that exert reproductive and developmental toxicity in laboratory animals. In humans, fertility-related effects are less documented. Objective The aim of this study was to investigate the relationship between dioxin-like biological activity in serum and parameters of reproductive status in men from the general population 5 months after a polychlorinated biphenyl and dioxin food-contamination episode in Belgium. Design In the framework of the cross-sectional Flemish Environment and Health Study (FLEHS), we recruited 101 men 20–40 years of age and evaluated sperm parameters, measured sex hormones, and gathered information on a number of lifestyle factors. In addition, we determined the AhR-mediated enzymatic response elicited by individual serum samples and expressed it as TCDD equivalent concentrations (CALUX-TEQs) using an established transactivation assay. Results Age (p = 0.04) and the frequency of fish (p = 0.02) and egg (p = 0.001) consumption were independent positive determinants of serum dioxin-like activity. After correcting for possible confounders, we found that a 2-fold increase in CALUX-TEQ > 16 pg/L was associated with a 7.1% and 6.8% (both p = 0.04) decrease in total and free testosterone, respectively. We also observed a more pronounced drop in semen volume of 16.0% (p = 0.03), whereas sperm concentration rose by 25.2% (p = 0.07). No relationship was found with total sperm count or sperm morphology. Conclusions These data suggest an interaction of dioxin-like compounds with the secretory function of the seminal vesicles or prostate, possibly indirectly through an effect on testosterone secretion, at levels not affecting spermatogenesis as such.

Biomarkers of human exposure to personal care products: Results from the Flemish Environment and Health Study (FLEHS 2007–2011)

Personal care products (PCPs), such as soaps, perfumes, cosmetics, lotions, etc., contain a variety of chemicals that have been described as potentially hormone disrupting chemicals. Therefore, it is important to assess the internal exposure of these chemicals in humans. Within the 2nd Flemish Environment and Health Study (FLEHS II, 2007-2011), the human exposure to three classes of pollutants that are present in a wide variety of PCPs--i.e. polycyclic musks (galaxolide, HHCB and tonalide, AHTN in blood), parabens (urinary para-hydroxybenzoic acid, HBA) and triclosan (urinary TCS)--was assessed in 210 Flemish adolescents (14-15 years) and in 204 adults (20-40 years) randomly selected from the general population according to a stratified two stage clustered study design. The aim of this study was to define average levels of exposure in the general Flemish population and to identify determinants of exposure. Average levels (GM (95% CI)) in the Flemish adolescents were 0.717 (0.682-0.753) μg/L for blood HHCB; 0.118 (0.108-0.128) μg/L for blood AHTN; 1022 (723-1436) μg/L for urinary HBA and 2.19 (1.64-2.92) μg/L for urinary TCS. In the adults, levels of HBA were on average 634 (471-970) μg/L. Inter-individual variability was small for HHCB and AHTN, intermediate for HBA, and large for TCS. All biomarkers were positively associated with the use of PCPs. Additionally, levels of HHCB and AHTN increased with higher educational level of the adolescents. Both in adults and adolescents, urinary HBA levels were negatively correlated with BMI. We define here Flemish exposure values for biomarkers of PCPs, which can serve as baseline exposure levels to identify exposure trends in future biomonitoring campaigns.

Persistent organochlorine pollutants in human serum of 50-65 years old women in the Flanders Environmental and Health Study (FLEHS): part 2: correlations among PCBs, PCDD/PCDFs and the use of predictive markers

In 1999, the FLEHS was set by the Flemish Ministry of Health, Belgium to assess pollutant concentrations and related health effect biomarkers in humans living in Flanders. Concentrations of selected organochlorine pesticides, polychlorinated biphenyls (PCB) and polychlorinated dibenzo-p-dioxins (PCDD) and furans (PCDF) were measured by gas chromatography-mass spectrometry and Chemical-Activated LUciferase gene eXpression (CALUX) bioassay in 47 serum pools of 200 women between 50 and 65 years living in two areas of Flanders. Correlation between TEQ values of different groups of compounds were computed in these pool results and it was found that total toxic equivalencies (TEQs) correlated well with the values of the groups of contributing compounds: mono-ortho PCBs (r = 0.77), non-ortho PCBs (r = 0.65) and PCDD/Fs (r = 0.88). The total TEQ was lower correlated to the CALUX-TEQ (r = 0.57). When calculating associations between those classes of compounds in the two studied regions separately, they were all higher correlated in the urban area compared to the more rural region. High correlation coefficients (r > 0.80) were also calculated between individual compounds and groups of compounds. It was suggested that in this studied background-exposed population, some compounds could be good predictors for a group: e.g. PCB 153 for indicator and total PCBs, PCB 118 for total PCB TEQ, PCB 156 for mono-ortho PCB-TEQs and total TEQ, 2,3,4,7,8-P5CDF for PCDD/F TEQs and total TEQs. This means that in pooled serum samples correlations between persistent organochlorine compounds are as strong as for individual POP measurements observed in earlier studies.

Human exposure to endocrine, disrupting chemicals and fertility: a case-control study in male subfertility patients

BACKGROUND Dioxins, PCBs, chlorinated pesticides, brominated flame retardants, bisphenol A, triclosan, perfluorinated compounds and phthalates are known as endocrine disrupting chemicals (EDCs). OBJECTIVES The aim of our study was to investigate whether higher exposure to EDCs is associated with increased subfertility in men. METHODS We measured biomarkers of exposure in 163 men, recruited through four fertility clinics. According to WHO guidelines, we used a total motility count (TMC) of 20 million as cut-off value. We assigned patients to the case group when two semen samples - collected at least one week apart - had a TMC<20 and to the control group when both samples had a TMC≥20. To estimate the risk of subfertility and alteration in sex hormone concentrations we used multivariable-adjusted analysis, using logistic and linear regressions, respectively. RESULTS For an IQR increase in serum oxychlordane, the odds ratio for subfertility was 1.98 (95% CI: 1.07; 3.69). Furthermore, men with serum levels of BDE209 above the quantification limit had an odds of 7.22 (1.03; 50.6) for subfertility compared with those having values below the LOQ. Urinary levels of phthalates and triclosan were negatively associated with inhibin B and positively with LH. Urinary bisphenol A correlated negatively with testosterone levels. CONCLUSIONS Our study in men showed that internal body concentrations of endocrine disrupting chemicals are associated with an increased risk of subfertility together with alterations in hormone levels. The results emphasize the importance to reduce chemicals in the environment in order to safeguard male fertility.

Dietary exposure to total and toxic arsenic in Belgium: Importance of arsenic speciation in North Sea fish

Total and toxic (sum of As(III), As(V), monomethylarsenic (MMA), and dimethylarsenic (DMA)) As concentrations were assessed in 19 respectively 4 different fish and shellfish species from the North Sea. Following results were obtained: (i) for fish an average total As concentration of 12.8 microg/g ww and a P90 value of 30.6 microg/g ww; (ii) for shellfish an average total As concentration of 21.6 microg/g ww and a P90 value of 40.0 microg/g ww; (iii) for fish an average toxic As concentration of 0.132 microg/g ww and a P90 value of 0.232 microg/g ww; (iv) for shellfish an average toxic As concentration of 0.198 microg/g ww and a P90 value of 0.263 microg/g ww. For the Belgian consumer the average daily intake of total arsenic from fish, shellfish, fruit, and soft drinks (the main food carriers of As in Belgium) amounts to 285 microg/day with more than 95% coming from fish and shellfish, while for a high level consumer it amounts to 649 microg/day, more than twice the average value. Using the same daily consumption pattern for the selected food products as for total As, we find that the average daily intake of toxic As amounts to 5.8 microg/day, with a 50% contribution of fish and shellfish and the high level intake to 9.5 microg/day. When considering the FOA/WHO Expert Committees recommendation for inorganic As intake of 2 microg/kg bw/day or 140 microg/day for a 70 kg person, the toxic dose in Belgium is thus an order of magnitude lower.