Transthyretin is not necessary for thyroid hormone metabolism in conditions of increased hormone demand

Thyroid hormones circulate in blood mainly bound to plasma proteins. Transthyretin is the major thyroxine plasma carrier in mice. Studies in transthyretin-null mice revealed that the absence of transthyretin results in euthyroid hypothyroxinemia and normal thyroid hormone tissue distribution, with the exception of the choroid plexus in the brain. Therefore, transthyretin does not influence normal thyroid hormone homeostasis under standard laboratory conditions. To investigate if transthyretin has a buffer/storage role we challenged transthyretin-null and wild-type mice with conditions of increased hormone demand: (i) exposure to cold, which elicits thermogenesis, a process that requires thyroid hormones; and (ii) thyroidectomy, which abolishes thyroid hormone synthesis and secretion and induces severe hypothyroidism. Transthyretin-null mice responded as the wild-type both to changes induced by stressful events, namely in body weight, food intake and thyroid hormone tissue content, and in the mRNA levels of genes whose expression is altered in such conditions. These results clearly exclude a role for transthyretin in thyroid hormone homeostasis even under conditions of increased hormone demand.POCTI/NSE/37315/2001, from Fundação para a Ciência e Tecnologia (Portugal) and FEDER; J C S is a recipient of a PhD fellowship from Fundação para a Ciência e Tecnologia (Portugal

Evaluation of the U.S. EPA/OSWER Preliminary Remediation Goal for Perchlorate in Groundwater: Focus on Exposure to Nursing Infants

BACKGROUND: Perchlorate is a common contaminant of drinking water and food. It competes with iodide for uptake into the thyroid, thus interfering with thyroid hormone production. The U.S. Environmental Protection Agency’s Office of Solid Waste and Emergency Response (OSWER) set a groundwater preliminary remediation goal (PRG) of 24.5 μg/L to prevent exposure of pregnant women that would affect the fetus. This does not account for the greater exposure that is possible in nursing infants or for the relative source contribution (RSC), a factor normally used to lower the PRG due to nonwater exposures. OBJECTIVES: Our goal was to assess whether the OSWER PRG protects infants against exposures from breast-feeding, and to evaluate the perchlorate RSC. METHODS: We used Monte Carlo analysis to simulate nursing infant exposures associated with the OSWER PRG when combined with background perchlorate. RESULTS: The PRG can lead to a 7-fold increase in breast milk concentration, causing 90% of nursing infants to exceed the reference dose (RfD) (average exceedance, 2.8-fold). Drinking-water perchlorate must be < 6.9 μg/L to keep the median, and < 1.3 μg/L to keep the 90th-percentile nursing infant exposure below the RfD. This is 3.6- to 19-fold below the PRG. Analysis of biomonitoring data suggests an RSC of 0.7 for pregnant women and of 0.2 for nursing infants. Recent data from the Centers for Disease Control and Prevention (CDC) suggest that the RfD itself needs to be reevaluated because of hormonal effects in the general population. CONCLUSIONS: The OSWER PRG for perchlorate can be improved by considering infant exposures, by incorporating an RSC, and by being responsive to any changes in the RfD resulting from the new CDC data

Role of Haptoglobin in Polycystic Ovary Syndrome (PCOS), Obesity and Disorders of Glucose Tolerance in Premenopausal Women

alleles of the haptoglobin α–chain polymorphism reduce the anti-oxidant properties and increase the pro-inflammatory actions of this acute-phase protein in a gene-dosage fashion. We hypothesized that the haptoglobin polymorphism might contribute to the increased oxidative stress and low-grade chronic inflammation frequently associated with polycystic ovary syndrome, obesity, and abnormalities of glucose tolerance.<0.001), yet no association was found between obesity and haptoglobin genotypes. No differences were observed in haptoglobin levels or genotype frequencies depending on glucose tolerance. Fifty percent of the variation in serum haptoglobin concentrations was explained by the variability in serum C-reactive protein concentrations, BMI, insulin sensitivity and haptoglobin genotypes. alleles suggests that the anti-oxidant and anti-inflammatory properties of haptoglobin may be reduced in these patients

Development of a Health-Protective Drinking Water Level for Perchlorate

We evaluated animal and human toxicity data for perchlorate and identified reduction of thyroidal iodide uptake as the critical end point in the development of a health-protective drinking water level [also known as the public health goal (PHG)] for the chemical. This work was performed under the drinking water program of the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. For dose–response characterization, we applied benchmark-dose modeling to human data and determined a point of departure (the 95% lower confidence limit for 5% inhibition of iodide uptake) of 0.0037 mg/kg/day. A PHG of 6 ppb was calculated by using an uncertainty factor of 10, a relative source contribution of 60%, and exposure assumptions specific to pregnant women. The California Department of Health Services will use the PHG, together with other considerations such as economic impact and engineering feasibility, to develop a California maximum contaminant level for perchlorate. We consider the PHG to be adequately protective of sensitive subpopulations, including pregnant women, their fetuses, infants, and people with hypothyroidism

Thyroid-Disrupting Chemicals: Interpreting Upstream Biomarkers of Adverse Outcomes

Background There is increasing evidence in humans and in experimental animals for a relationship between exposure to specific environmental chemicals and perturbations in levels of critically important thyroid hormones (THs). Identification and proper interpretation of these relationships are required for accurate assessment of risk to public health. Objectives We review the role of TH in nervous system development and specific outcomes in adults, the impact of xenobiotics on thyroid signaling, the relationship between adverse outcomes of thyroid disruption and upstream causal biomarkers, and the societal implications of perturbations in thyroid signaling by xenobiotic chemicals. Data sources We drew on an extensive body of epidemiologic, toxicologic, and mechanistic studies. Data synthesis THs are critical for normal nervous system development, and decreased maternal TH levels are associated with adverse neuropsychological development in children. In adult humans, increased thyroid-stimulating hormone is associated with increased blood pressure and poorer blood lipid profiles, both risk factors for cardiovascular disease and death. These effects of thyroid suppression are observed even within the “normal” range for the population. Environmental chemicals may affect thyroid homeostasis by a number of mechanisms, and multiple chemicals have been identified that interfere with thyroid function by each of the identified mechanisms. Conclusions Individuals are potentially vulnerable to adverse effects as a consequence of exposure to thyroid-disrupting chemicals. Any degree of thyroid disruption that affects TH levels on a population basis should be considered a biomarker of adverse outcomes, which may have important societal outcomes

Temporal Patterns in Perchlorate, Thiocyanate, and Iodide Excretion in Human Milk

BACKGROUND: Perchlorate and thiocyanate interfere with iodide uptake at the sodium–iodide symporter and are potential disruptors of thyroid hormone synthesis. Perchlorate is a common contaminant of water, food, and human milk. Although it is known that iodide undergoes significant diurnal variations in serum and urinary excretion, less is known about diurnal variations of milk iodide levels. OBJECTIVES: Variability in perchlorate and thiocyanate excretion in human milk has not been examined. Our objective was to determine variability of perchlorate, thiocyanate, and iodide in serially collected samples of human milk. METHODS: Ten lactating women were asked to collect six milk samples on each of 3 days. As an alternative, subjects were asked to collect as many milk samples as comfortably possible over 3 days. Samples were analyzed for perchlorate, iodide, and thiocyanate by ion chromatography coupled with mass spectrometry. RESULTS: Individual perchlorate, iodide, and thiocyanate levels varied significantly over time; there was also considerable variation among individuals. The iodide range, mean ± SD, and median for all samples (n = 108) were 3.1–334 μg/L, 87.9 ± 80.9 μg/L, and 55.2 μg/L, respectively. The range, mean ± SD, and median of perchlorate in all samples (n = 147) were 0.5–39.5 μg/L, 5.8 ± 6.2 μg/L, and 4.0 μg/L. The range, mean ± SD, and median of thiocyanate in all samples (n = 117) were 0.4 –228.3 μg/L, 35.6 ± 57.9 μg/L, and 5.6 μg/L. The data are not symmetrically distributed; the mean is higher than the median in all cases. CONCLUSIONS: Iodine intake may be inadequate in a significant fraction of this study population. Perchlorate and thiocyanate appear to be common in human milk. The role of these chemicals in reducing breast milk iodide is in need of further investigation

Neurobehavioral Deficits and Increased Blood Pressure in School-Age Children Prenatally Exposed to Pesticides

Background: The long-term neurotoxicity risks caused by prenatal exposures to pesticides are unclear, but a previous pilot study of Ecuadorian school children suggested that blood pressure and visuospatial processing may be vulnerable. Objectives: In northern Ecuador, where floriculture is intensive and relies on female employment, we carried out an intensive cross-sectional study to assess children’s neurobehavioral functions at 6–8 years of age. Methods: We examined all 87 children attending two grades in the local public school with an expanded battery of neurobehavioral tests. Information on pesticide exposure during the index pregnancy was obtained from maternal interview. The children’s current pesticide exposure was assessed from the urinary excretion of organophosphate metabolites and erythrocyte acetylcholine esterase activity. Results: Of 84 eligible participants, 35 were exposed to pesticides during pregnancy via maternal occupational exposure, and 23 had indirect exposure from paternal work. Twenty-two children had detectable current exposure irrespective of their prenatal exposure status. Only children with prenatal exposure from maternal greenhouse work showed consistent deficits after covariate adjustment, which included stunting and socioeconomic variables. Exposure-related deficits were the strongest for motor speed (Finger Tapping Task), motor coordination (Santa Ana Form Board), visuospatial performance (Stanford-Binet Copying Test), and visual memory (Stanford-Binet Copying Recall Test). These associations corresponded to a developmental delay of 1.5–2 years. Prenatal pesticide exposure was also significantly associated with an average increase of 3.6 mmHg in systolic blood pressure and a slight decrease in body mass index of 1.1 kg/m2. Inclusion of the pilot data strengthened these results. Conclusions: These findings support the notion that prenatal exposure to pesticides—at levels not producing adverse health outcomes in the mother—can cause lasting adverse effects on brain development in children. Pesticide exposure therefore may contribute to a “silent pandemic” of developmental neurotoxicity

Thyroid-Hormone–Disrupting Chemicals: Evidence for Dose-Dependent Additivity or Synergism

Endocrine disruption from environmental contaminants has been linked to a broad spectrum of adverse outcomes. One concern about endocrine-disrupting xenobiotics is the potential for additive or synergistic (i.e., greater-than-additive) effects of mixtures. A short-term dosing model to examine the effects of environmental mixtures on thyroid homeostasis has been developed. Prototypic thyroid-disrupting chemicals (TDCs) such as dioxins, polychlorinated biphenyls (PCBs), and poly-brominated diphenyl ethers have been shown to alter thyroid hormone homeostasis in this model primarily by up-regulating hepatic catabolism of thyroid hormones via at least two mechanisms. Our present effort tested the hypothesis that a mixture of TDCs will affect serum total thyroxine (T(4)) concentrations in a dose-additive manner. Young female Long-Evans rats were dosed via gavage with 18 different polyyhalogenated aromatic hydrocarbons [2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin-like PCBs] for 4 consecutive days. Serum total T(4) was measured via radioimmunoassay in samples collected 24 hr after the last dose. Extensive dose–response functions (based on seven to nine doses per chemical) were determined for individual chemicals. A mixture was custom synthesized with the ratio of chemicals based on environmental concentrations. Serial dilutions of this mixture ranged from approximately background levels to 100-fold greater than background human daily intakes. Six serial dilutions of the mixture were tested in the same 4-day assay. Doses of individual chemicals that were associated with a 30% TH decrease from control (ED(30)), as well as predicted mixture outcomes were calculated using a flexible single-chemical-required method applicable to chemicals with differing dose thresholds and maximum-effect asymptotes. The single-chemical data were modeled without and with the mixture data to determine, respectively, the expected mixture response (the additivity model) and the experimentally observed mixture response (the empirical model). A likelihood-ratio test revealed statistically significant departure from dose additivity. There was no deviation from additivity at the lowest doses of the mixture, but there was a greater-than-additive effect at the three highest mixtures doses. At high doses the additivity model underpredicted the empirical effects by 2- to 3-fold. These are the first results to suggest dose-dependent additivity and synergism in TDCs that may act via different mechanisms in a complex mixture. The results imply that cumulative risk approaches be considered when assessing the risk of exposure to chemical mixtures that contain TDCs

Nutritional status of iodine in pregnant women in Catalonia (Spain): study on hygiene-dietetic habits and iodine in urine

<p>Abstract</p> <p>Background</p> <p>It is a priority to achieve an adequate nutritional status of iodine during pregnancy since iodine deficiency in this population may have repercussions on the mother during both gestation and post partum as well as on the foetus, the neonate and the child at different ages. According to the WHO, iodine deficiency is the most frequent cause of mental retardation and irrreversible cerebral lesions around the world. However, few studies have been published on the nutritional status of iodine in the pregnant population within the Primary Care setting, a health care level which plays an essential role in the education and control of pregnant women. Therefore, <b>the aim of the present study </b>is: 1.- To know the hygiene-dietetic habits related to the intake of foods rich in iodine and smoking during pregnancy. 2.- To determine the prevalence of iodine deficiency and the factors associated with its appearance during pregnancy.</p> <p>Methods/design</p> <p>We will perform a cluster randomised, controlled, multicentre trial. Randomisation unit: Primary Care Team. Study population: 898 pregnant women over the age of 17 years attending consultation to a midwife during the first trimester of pregnancy in the participating primary care centres. Outcome measures: consumption of iodine-rich foods and iodine deficiency. Points of assessment: each trimester of the gestation. Intervention: group education during the first trimester of gestation on healthy hygiene-dietetic habits and the importance of an adequate iodine nutritional status. Statistical analysis: descriptive analysis of all variables will be performed as well as multilevel logistic regression. All analyses will be done carried out on an intention to treat basis and will be fitted for potential confounding factors and variables of clinical importance.</p> <p>Discussion</p> <p>Evidence of generalised iodine deficiency during pregnancy could lead to the promotion of interventions of prevention such as how to improve and intensify health care educational programmes for pregnant women.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01301768">NCT01301768</a></p