Further Comparisons of Empirical and Epidemiological Data with Predictions of the Integrated Exposure Uptake Biokinetic Model for Lead in Children

Observed blood lead levels for young children from several communities are compared with blood lead levels predicted for those communities using the USEPA's Integrated Exposure Uptake Biokinetic (IEUBK) Model. In contrast to the compari sons described elsewhere, the blood lead levels observed in the communities con sidered here are not well represented by the model's predictions. The model's predictions for Midvale, UT; Sandy, UT; Cincinnati, OH; and a recent data set for Palmerton, PA, show considerable deviation from observation both for the geometric mean blood lead level and the percent of blood lead levels above 10?µg/dL. Various adjustments in the model to consider play area soils, site specific geometric standard deviations and the time children spend away from their homes do not substantially improve the comparisons to observation. It is difficult to predict a priori the data sets for which the model will yield adequate predictions. This reduces the value of the model for use in communities where blood lead measurements have not been made, and suggests that caution should be exercised when using the model to set soil lead cleanup levels or to predict the result of remediation.     

Lead Crystal: An Important Potential Source of Lead Exposure

Abstract

We have examined the potential of alcoholic beverages to elute Pb from crystal wine decanters and glasses. Port wine containing 89 Pb L^?1 was aliquoted into three lead crystal wine decanters. The wine Pb content rose steadily to a mean of 3,518 μg L^?1 after 4 months. We then analyzed wines and liquors which had been stored in crystal decanters in the homes of our colleagues for periods of six months or longer. In the first four homes, eight decanters contained beverages with a mean Pb concentration of 7,781μg L^?1 In a short-term experiment, white wine was found to elute small quantities of Pb from lead crystal glasses within minutes; the mean wine Pb concentration rose from 33 μg L^?1 at time zero to a mean of 99 μg L^?1 after four hours. We conclude that, in particular, lead crystal wine decanters are potentially an important source of Pb exposure for a segment of the population. In addition, lead crystal baby bottles, although not as widely available, were found to elute Pb into apple juice and infant formula; their sale should be banned.     

Determining Prenatal,Early Childhood and Cumulative Long-Term Lead Exposure Using Micro-Spatial Deciduous Dentine Levels

The aim of this study was to assess the validity of micro-spatial dentine lead (Pb) levels as a biomarker for accurately estimating exposure timing over the prenatal and early childhood periods and long-term cumulative exposure to Pb. In a prospective pregnancy cohort sub-sample of 85 subjects, we compared dentine Pb levels measured using laser ablation-inductively coupled plasma mass spectrometry with Pb concentrations in maternal blood collected in the second and third trimesters, maternal bone, umbilical cord blood, and childhood serial blood samples collected from the ages of 3 months to ≥6 years. We found that Pb levels (as ²⁰⁸Pb:⁴³Ca) in dentine formed at birth were significantly associated with cord blood Pb (Spearman ρ = 0.69; n = 27; p<0.0001). The association of prenatal dentine Pb with maternal patella Pb (Spearman ρ = 0.48; n = 59; p<0.0001) was stronger than that observed for tibia Pb levels (Spearman ρ = 0.35; n = 41; p<0.03). When assessing postnatal exposure, we found that Pb levels in dentine formed at 3 months were significantly associated with Pb concentrations in children’s blood collected concurrently (Spearman ρ = 0.64; n = 55; p<0.0001). We also found that mean Pb concentrations in secondary dentine (that is formed from root completion to tooth shedding) correlated positively with cumulative blood lead index (Spearman ρ = 0.38; n = 75; p<0.0007). Overall, our results support that micro-spatial measurements of Pb in dentine can be reliably used to reconstruct Pb exposure timing over the prenatal and early childhood periods, and secondary dentine holds the potential to estimate long-term exposure up to the time the tooth is shed.     

Determination of Human Exposure to Lead and Cadmium: A WHO/UNEP Pilot Study

Abstract

In Stockholm, methods for measuring exposure to lead and cadmium from air, food and beverages were studied in 1988 in a group of 15 non-smoking women, as part of the WHO/UNEP HEAL programme. Airborne particles in the breathing zone air (24-hour samples), duplicate diets (24-hour samples), and faeces (all the stools produced) were collected during 7 consecutive days. Blood was sampled before and immediately after the study period. The results confirmed the need for personal monitoring in the assessment of human exposure to lead and cadmium via air and food. There is need for suitable equipment for 24-hour personal air monitoring. On average, dietary lead (26 μg day^?1, SD 7.9) contributed more than 80% of the total lead uptake, while dietary cadmium (8.5 μg day^?1 SD 2.1) contributed about 99% of the total cadmium uptake. Occasionally consumed foodstuffs with high levels of lead or cadmium seemed to be responsible for a large part of the total weekly intake of lead and cadmium. Fecal lead and cadmium were found to be useful indicators of the total amounts of these metals ingested. Due to the large day-to-day variation observed in the dietary intake of lead and cadmium, the sampling period for duplicate diets and faeces should be at least 5–6 days.     

Global Expanded Nutrient Supply (GENuS) Model: A New Method for Estimating the Global Dietary Supply of Nutrients

Insufficient data exist for accurate estimation of global nutrient supplies. Commonly used global datasets contain key weaknesses: 1) data with global coverage, such as the FAO food balance sheets, lack specific information about many individual foods and no information on micronutrient supplies nor heterogeneity among subnational populations, while 2) household surveys provide a closer approximation of consumption, but are often not nationally representative, do not commonly capture many foods consumed outside of the home, and only provide adequate information for a few select populations. Here, we attempt to improve upon these datasets by constructing a new model—the Global Expanded Nutrient Supply (GENuS) model—to estimate nutrient availabilities for 23 individual nutrients across 225 food categories for thirty-four age-sex groups in nearly all countries. Furthermore, the model provides historical trends in dietary nutritional supplies at the national level using data from 1961–2011. We determine supplies of edible food by expanding the food balance sheet data using FAO production and trade data to increase food supply estimates from 98 to 221 food groups, and then estimate the proportion of major cereals being processed to flours to increase to 225. Next, we estimate intake among twenty-six demographic groups (ages 20+, both sexes) in each country by using data taken from the Global Dietary Database, which uses nationally representative surveys to relate national averages of food consumption to individual age and sex-groups; for children and adolescents where GDD data does not yet exist, average calorie-adjusted amounts are assumed. Finally, we match food supplies with nutrient densities from regional food composition tables to estimate nutrient supplies, running Monte Carlo simulations to find the range of potential nutrient supplies provided by the diet. To validate our new method, we compare the GENuS estimates of nutrient supplies against independent estimates by the USDA for historical US nutrition and find very good agreement for 21 of 23 nutrients, though sodium and dietary fiber will require further improvement.     

Environmental Lead Exposure among Preschool Children in Shanghai,China: Blood Lead Levels and Risk Factors

Objective

To determine blood lead levels and to identify related risk factors among children in Shanghai; to explore the lead change trend of children after industrial transformation and to provide data for policy development to control environmental lead pollution in Shanghai.

Methods

A stratified-clustered-random sampling method was used. A tungsten atomizer absorption spectrophotometer was employed to determine blood lead levels.

Results

The arithmetic mean, geometric mean and median of blood lead levels of 0- to 6-year-old children from Shanghai were 22.49 µg/L, 19.65 µg/L and 19.5 µg/L, including 0.26% (6/2291) with concentrations ≥100 µg/L and 2.7% (61/2291) with concentrations ≥50 µg/L. Boys'' levels (23.57 µg/L) were greater than those of girls (21.2 µg/L). The blood lead levels increased with age. This survey showed that the Chongming district was the highest and Yangpu district was the lowest, this result is completely opposite with the earlier survey in Shanghai. Risk factors for lead contamination included housing environment, parents'' education levels, social status, hobbies, and children''s nutritional status.

Conclusions

The blood lead levels of children in Shanghai were lower than the earlier data of Shanghai and those of published studies in China, but higher than the blood lead levels of developed countries. The blood lead levels of urban districts are higher than the central districts with the industrial transformation. Society and the government should take an active interest in childhood lead poisoning of urban areas.     

Multi-Wall Carbon Nanotubes Effects on Plant Seedlings Growth and Cadmium/Lead Uptake In Vitro

The effects of multi-wall carbon nanotubes (MWCNTs) on plant growth and Cd/Pb accumulation was investigated on seedlings of three plant species including Brassica napus L., Helianthus annus L. and Cannabis sativa L. The experiment consisted of MWCNTs on three concentration levels (0, 10, 50 mg/L) and 200 μM CdCl₂ or 500 μM Pb(NO₃)₂. MWCNTs application effectively improved root and shoot growth inhibited by Cd and Pb salts. In B. napus, total chlorophyll (Chl) content increased by both MWCNTs 10 and 50 mg/L exposure under cadmium or lead stress. MWCNT 10 mg/L mitigated the deleterious effects of Cd ions on total chlorophyll content of H. annus and C. sativa. Wherease higher concentration of MWCNTs decreased Chl content under either Cd or Pb treatments on sunflower seedlings. MWCNT10 effectivly raised cadmium accumulation in seedlings of all three species. MWCNT10 and 50 mg/L also caused higher Pb accumulation in canola and cannabis seedlings, respectively. Based on the results, it seems that the effects of MWCNTs on growth parameters and heavy metal accumulation in plant seedlings is strongly depends on heavy metal type, MWCNTs concentration and plant species.     

Child Mortality Estimation: Estimating Sex Differences in Childhood Mortality since the 1970s

Introduction

Producing estimates of infant (under age 1 y), child (age 1–4 y), and under-five (under age 5 y) mortality rates disaggregated by sex is complicated by problems with data quality and availability. Interpretation of sex differences requires nuanced analysis: girls have a biological advantage against many causes of death that may be eroded if they are disadvantaged in access to resources. Earlier studies found that girls in some regions were not experiencing the survival advantage expected at given levels of mortality. In this paper I generate new estimates of sex differences for the 1970s to the 2000s.

Methods and Findings

Simple fitting methods were applied to male-to-female ratios of infant and under-five mortality rates from vital registration, surveys, and censuses. The sex ratio estimates were used to disaggregate published series of both-sexes mortality rates that were based on a larger number of sources. In many developing countries, I found that sex ratios of mortality have changed in the same direction as historically occurred in developed countries, but typically had a lower degree of female advantage for a given level of mortality. Regional average sex ratios weighted by numbers of births were found to be highly influenced by China and India, the only countries where both infant mortality and overall under-five mortality were estimated to be higher for girls than for boys in the 2000s. For the less developed regions (comprising Africa, Asia excluding Japan, Latin America/Caribbean, and Oceania excluding Australia and New Zealand), on average, boys'' under-five mortality in the 2000s was about 2% higher than girls''. A number of countries were found to still experience higher mortality for girls than boys in the 1–4-y age group, with concentrations in southern Asia, northern Africa/western Asia, and western Africa. In the more developed regions (comprising Europe, northern America, Japan, Australia, and New Zealand), I found that the sex ratio of infant mortality peaked in the 1970s or 1980s and declined thereafter.

Conclusions

The methods developed here pinpoint regions and countries where sex differences in mortality merit closer examination to ensure that both sexes are sharing equally in access to health resources. Further study of the distribution of causes of death in different settings will aid the interpretation of differences in survival for boys and girls. Please see later in the article for the Editors'' Summary.     

Nutrient Uptake by Protocells: A Liposome Model System

Over the past decade, several liposome-basedmodels for protocells have been developed. Forexample, liposome systems composed of polymeraseenzymes encapsulated with their substrates havedemonstrated that complex compartmentalized reactionscan be carried out under conditions in which polymericproducts are protected from degradation by hydrolyticenzymes present in the external medium. However, suchsystems do not have nutrient uptake mechanisms, whichwould be essential for primitive cells lacking thehighly evolved nutrient transport processes present inall contemporary cells. In this report, we explorepassive diffusion of solutes across lipid bilayers asone possible uptake mechanism. We have establishedconditions under which ionic substrates as large asATP can permeate bilayers at rates capable ofsupplying an encapsulated template-dependent RNApolymerase. Furthermore, while allowing the permeationof monomer substrates such as ATP, bilayer vesiclesselectively retained polymerization products as smallas dimers and as large as a transfer RNA. Theseobservations demonstrate that passive diffusion couldbe used by the earliest forms of cellular life fortransport of important nutrients such as amino acids,phosphate, and phosphorylated organic solutes.     

Lead Bullet Fragments in Venison from Rifle-Killed Deer: Potential for Human Dietary Exposure

Human consumers of wildlife killed with lead ammunition may be exposed to health risks associated with lead ingestion. This hypothesis is based on published studies showing elevated blood lead concentrations in subsistence hunter populations, retention of ammunition residues in the tissues of hunter-killed animals, and systemic, cognitive, and behavioral disorders associated with human lead body burdens once considered safe. Our objective was to determine the incidence and bioavailability of lead bullet fragments in hunter-killed venison, a widely-eaten food among hunters and their families. We radiographed 30 eviscerated carcasses of White-tailed Deer (Odocoileus virginianus) shot by hunters with standard lead-core, copper-jacketed bullets under normal hunting conditions. All carcasses showed metal fragments (geometric mean = 136 fragments, range = 15–409) and widespread fragment dispersion. We took each carcass to a separate meat processor and fluoroscopically scanned the resulting meat packages; fluoroscopy revealed metal fragments in the ground meat packages of 24 (80%) of the 30 deer; 32% of 234 ground meat packages contained at least one fragment. Fragments were identified as lead by ICP in 93% of 27 samples. Isotope ratios of lead in meat matched the ratios of bullets, and differed from background lead in bone. We fed fragment-containing venison to four pigs to test bioavailability; four controls received venison without fragments from the same deer. Mean blood lead concentrations in pigs peaked at 2.29 µg/dL (maximum 3.8 µg/dL) 2 days following ingestion of fragment-containing venison, significantly higher than the 0.63 µg/dL averaged by controls. We conclude that people risk exposure to bioavailable lead from bullet fragments when they eat venison from deer killed with standard lead-based rifle bullets and processed under normal procedures. At risk in the U.S. are some ten million hunters, their families, and low-income beneficiaries of venison donations.     

Exposure of Dunaliella tertiolecta to Lead and Aluminum: Toxicity and Effects on Ultrastructure

The growth response of the marine alga Dunaliella tertiolecta to different concentrations of lead and aluminum was investigated. Both metals had a stimulatory effect at low concentration and an inhibitory effect at high concentration (hormesis). The IC₂₅ values of lead are 8.43, 7.29, and 6.74 mg L⁻¹ for 24, 48, and 72 h, respectively. The corresponding values for aluminum are 30.54, 22.42, and 18.16 mg L⁻¹. Although it seems that the two metals are not directly toxic to the alga at the concentrations found in the environment, as implied by the IC₂₅ values and the environmental concentrations of the metals, low concentrations of both metals, alone and in combination, affected the ultrastructure. The growth of batch-grown cells exposed to 0.5 mg L⁻¹ lead and aluminum, alone and combined, during the 24-h exponential phase was investigated. The same cells were also examined under an electron microscope to determine the biological effects of the two metals on the ultrastructure. The most obvious effects of lead were disrupted thylakoidal membranes, accumulated polyphosphate bodies and vacuoles, and lead precipitates on the cell surface. These ultrastructural alterations were partially present in aluminum-treated and lead–aluminum-treated cells. In joint exposure, the most important change was the lysis of the cell membrane. Aluminum and lead seem to act synergistically on the cell membrane leading to cell membrane lysis.     

Lead Exposure: A Contributing Cause of the Current Breast Cancer Epidemic in Nigerian Women

The paper discusses various approaches used to investigate biocompatibility by the analysis of metals release by the materials of which orthodontic appliances are made. Analysis of various biomarkers of exposure: saliva, serum, mucosa cells, or urine is used in in vivo tests. In this work, the techniques, results, and conclusions of original papers were compared by the implementation of the concept of a systematic review. The aim of the present work was to report the state-of-the-art in the research on methods used to assess exposure to trace metals from orthodontic appliances. The PubMed search identified 35 studies, among which nine met the selection criteria. The general conclusion in the studies was that metal ions were released mostly in the initial stage of the treatment. However, the majority of studies included 1–2 months long period and did not reflect long-term changes nor the impact of the complete treatment, the duration of which is several years, on the whole organism and the overall accumulation of metals from orthodontic appliances. In studies which evaluated nickel concentrations in blood and urine, long-term metal release was detected and significant differences were found. It leads to the conclusion that nickel ions are released from orthodontic appliances in measurable amounts to human organism.     

An Arsenic Exposure Model: Probabilistic Validation Using Empirical Data

This paper describes development of a multi-pathway arsenic exposure model. The model uses information on arsenic concentrations in food, water, soil, and dust, combined with estimates of intake and medium-specific absorption. Urinary arsenic is predicted assuming that 60% of absorbed arsenic is excreted in urine under steady state conditions. Fecal arsenic is predicted assuming all unabsorbed arsenic is excreted in feces. We applied this model at a former copper smelter site. Site specific distributions were available for the following parameters: soil and dust arsenic concentration (geometric mean approximately 100 to 200?ppm and 50 to 100?ppm, respectively); the combined childhood soil and dust ingestion rate (geometric mean of 20?mg/d); soil and dust arsenic relative bioavailability (geometric mean 0.20 and 0.28, respectively); exposure duration; water arsenic concentration; air arsenic concentration; and total arsenic in food. Monte Carlo simulation was used to predict daily arsenic uptake and excretion in urine and feces for children. Predicted urine arsenic levels were less than measured levels (73% to 88% of measured values, depending on region of site). On the other hand, predicted fecal arsenic levels exceeded measured levels by a factor of 1.7 to 4.6. We were able to improve the correspondence between predicted and measured arsenic excretion rates by decreasing the assumed value of the combined soil and dust ingestion rate, and increasing the assumed bioavailability of arsenic in soil and dust.     

ADHD-Type Behavior and Harmful Dysfunction in Childhood: A Cross-Cultural Model

Cross-cultural studies of psychiatric phenomena allow testing of assumptions of biological consistency and improved understanding of how disorders are culturally formulated. We used a comparative approach to test for population variation in degrees of harmful academic and social dysfunction associated with children's display of behaviors considered symptomatic of Attention Deficit Hyperactivity Disorder (ADHD). Teacher ratings on psychometric scales described behavior and functioning in population-representative samples of Colombian and United States schoolchildren. Mean levels of the behaviors were similar across populations, including a constant gender difference. A multiple regression model showed remarkably consistent relationships of hyperactivity and inattention to harmful dysfunction across populations and genders. Increasing inattention was associated with increasing harmful dysfunction. Increased hyperactivity was associated with improved functioning to a uniform threshold, beyond which more hyperactivity was associated with greater harmful dysfunction. Patterns of relationships between ADHD-associated behaviors and their consequences may prove useful as a basis for cross-cultural investigation of ADHD. The idea of ADHD as psychiatric disease concept or construct with some cross-cultural (external) validity is supported by these data, [cross-cultural psychology, ADHD (Attention deficit hyperactivity disorder), child behavioral disorders, Colombia]     

Chronic Lead Exposure Decreases the Vascular Reactivity of Rat Aortas: The Role of Hydrogen Peroxide

We investigated whether exposure to small concentrations of lead alters blood pressure and vascular reactivity. Male Wistar rats were sorted randomly into the following two groups: control (Ct) and treatment with 100 ppm of lead (Pb), which was added to drinking water, for 30 days. Systolic blood pressure (BP) was measured weekly. Following treatment, aortic ring vascular reactivity was assessed. Tissue samples were properly stored for further biochemical investigation. The lead concentration in the blood reached approximately 8 μg/dL. Treatment increased blood pressure and decreased the contractile responses of the aortic rings to phenylephrine (1 nM–100 mM). Following N-nitro-L arginine methyl ester (L-NAME) administration, contractile responses increased in both groups but did not differ significantly between them. Lead effects on R_max were decreased compared to control subjects following superoxide dismutase (SOD) administration. Catalase, diethyldithiocarbamic acid (DETCA), and apocynin increased the vasoconstrictor response induced by phenylephrine in the aortas of lead-treated rats but did not increase the vasoconstrictor response in the aortas of untreated rats. Tetraethylammonium (TEA) potentiated the vasoconstrictor response induced by phenylephrine in aortic segments in both groups, but these effects were greater in lead-treated rats. The co-incubation of TEA and catalase abolished the vasodilatory effect noted in the lead group. The present study is the first to demonstrate that blood lead concentrations well below the values established by international legislation increased blood pressure and decreased phenylephrine-induced vascular reactivity. The latter effect was associated with oxidative stress, specifically oxidative stress induced via increases in hydrogen peroxide levels and the subsequent effects of hydrogen peroxide on potassium channels.     

Erratum to: Lead Exposure: A Contributing Cause of the Current Breast Cancer Epidemic in Nigerian Women

Breast cancer incidence in Nigerian women has significantly increased during the past three decades in parallel with the rapid industrialization of that country. This suggested that the associated widespread contamination of the soil and of the water supplies by lead (Pb) and other industrial metals was a major contributing cause. Because of its many domestic, industrial, and automotive uses, Pb is of particular concern as it has been shown to promote the development of mammary tumors in murine mammary tumor virus-infected female C3H mice at levels as low of 0.5 ppm Pb in the drinking water. Lead belongs to the group of selenium-antagonistic elements that interact with selenium (Se), abolishing its anti-carcinogenic effect. Lead on chronic, low-level exposure in addition also accelerates tumor growth rates. Higher levels of Pb were found in blood and head hair samples of newly diagnosed patients with breast cancer, all with infiltrating ductal carcinoma, the most common form of breast cancer in Nigeria, seen at Obafemi Awolowo University, than in cancer-free controls from the same area. Evidence for interactions between Pb and Se was obtained from blood, hair, and tumor biopsy tissue analyses. Furthermore, the Pb levels in hair samples of the patients were directly correlated with the volumes of their tumors, in accord with the tumor growth-promoting effects of Pb. Conversely, Se levels in hair and blood were inversely correlated with the tumor volumes, consistent with the anti-proliferative effects of Se. Several other elements, e.g., Cd, Hg, Cr, Sn, and As, were detected in the scalp hair of the patients and the controls, although at significantly lower levels than those of Pb. However, correlation calculations revealed them also to interact with Se, suggesting that only a fraction of the Se in organs and tissues is actually present in bioactive forms. In metal-exposed subjects, a state of latent Se deficiency may exist, resulting in depressed immune functions and increased cancer susceptibility. Evidence is presented to show that Pb and other metals also interact with iodine, another vitally important essential trace element believed to protect against breast cancer development. Public health programs aiming at lowering the breast cancer risk of Nigerian women thus will have to include effective measures to protect the population from exposures to Pb and other industrial metals that are presently contaminating the environment and the water supplies.     

An Acute Glutamate Exposure Induces Long-Term Down Regulation of GLAST/EAAT1 Uptake Activity in Cultured Bergmann Glia Cells

Glutamate, the major excitatory neurotransmitter in the vertebrate brain, is a potent neurotoxin therefore its extracellular levels have to be tightly regulated by means of sodium-dependent glutamate uptake systems of the slc1A family. The glial glutamate/aspartate transporter (GLAST/EAAT1) and the glutamate transporter 1 carry most of the uptake activity in cerebellum and in the forebrain, respectively. In the cerebellar cortex, GLAST is profusely expressed in Bergmann glia cells, which completely enwrap the parallel fiber-Purkinje cells synapses. Glutamate exposure in these cells, down regulates the activity as well as the expression levels of this transporter. In order to characterize the persistence of a single glutamate exposure, we followed the [³H]-d-aspartate uptake activity as a function of time after the removal of the glutamatergic stimulus. We were able to demonstrate that a single 30 min exposure to glutamate reduces the uptake activity for up to 3 h. This effect is dose-dependent and it is not reproduced neither by ionotropic nor metabotropic glutamate receptors agonists. In contrast, transporter specific ligands such as d-aspartate or l-(?)-threo-3-Hydroxyaspartic acid fully reproduce the glutamate effect. Equilibrium binding experiments revealed a decrease in [³H]-d-aspartate Bmax without a significant change in affinity, clearly suggesting that a reduction in the availability of plasma membrane glutamate transporters is the molecular basis of this effect. Interestingly, neither Glast mRNA nor its protein levels were significantly reduced upon the single glutamate exposure. Taken together, these results favor the notion of a transporter-mediated tight control of the uptake process.     

Effect of Different Photoperiod Exposure on [3H]Imipramine Binding and Serotonin Uptake in the Rat Brain

Seasonal rhythmicity in the occurrence of acute depressive episodes and the therapeutic efficacy of light exposure suggest the possible involvement of the pineal gland or other biological oscillators in the pathophysiology of depressive illness. We have performed studies to clarify whether different light/dark (LD) cycle schedules may induce changes in the biochemical targets of antidepressants in the rat CNS. In particular, we have investigated the effect of short- (LD 8:16) or long-day (LD 14:10) photoperiods on different biochemical parameters of serotonergic neurons. A significant increase in the density of [3H]imipramine ([3H]IMI) binding and in the Vmax of 5-[3H]hydroxytryptamine (5-[3H]HT) uptake was found in the hypothalamus of LD 8:16-with respect to LD 14:10-exposed rats, whereas no difference was found in the kinetic properties of postsynaptic 5-HT receptors and in 5-HT metabolism in the hypothalami and cerebral cortices of rats exposed to the two different photoperiods. A seasonal rhythm of [3H]IMI binding sites and 5-HT uptake seems to exist only in certain brain areas, such as the hypothalamus, because no differences were found in the cerebral cortex of LD 14:10- and LD 8:16-accustomed rats. [3H]IMI binding and 5-HT uptake were significantly increased in the hypothalamus of rats accustomed to a light/dark-inverted cycle (DL 10:14) and killed 6 h after the stopping of lighting in comparison to rats exposed to normal LD 14:10 cycles and killed 6 h after the beginning of lighting. Therefore, a circadian modification of the serotonergic presynaptic sites seems to be present and related to light/dark exposure. Because the existence of endogenous compounds able to modulate [3H]IMI binding and 5-HT uptake, other than 5-HT, has been postulated in the mammalian brain, the involvement of these substances in the periodic changes observed could be suggested.     

Endoplasmic Reticulum Stress and Apoptosis Triggered by Sub-Chronic Lead Exposure in Mice Spleen: a Histopathological Study

Lead (Pb) is an environmental oncogenic metal that induces immunotoxicity and anaemia. Emerging evidence has linked Pb toxicity with endoplasmic reticulum-driven apoptosis and autophagy. Glucose-regulated protein of 78 kDa (Grp78 or binding immunoglobulin protein (BiP)), a master endoplasmic reticulum chaperone, drives macrophage activation and regulates protein folding and calcium flux in response to heavy metals. The spleen may be involved in Pb poisoning due to its crucial role in erythrocatheresis and immune response, although there are no data to support this theory. Here, we found haematic and histopathological changes in the spleen of mice exposed to medium doses of Pb acetate (200 ppm–1 mM) in drinking water for 45 days. Pb deposition was also detected in organs such as the liver, kidney, brain, bone, blood and faeces, indicating an accumulation of this metal despite relatively short exposure time. Blood Pb content (BBL) reached 21.6 μg/dL; echinocytes and poikilocytes were found in Pb smears of treated group. Inside the spleen, higher Fe(II) and Fe(III) deposits inside macrophages were observed. Grp78 immunostaining, weakly expressed in spleen cells of control mice, after Pb exposure was specifically restricted to macrophages and megakaryocytes of the marginal zone of red pulp. Furthermore, Pb exposure induced superoxide dismutase 1 (SOD1) expression, cleaved caspase-3 and p62/SQSTM1, consistent with oxidative stress, apoptosis and dysregulated autophagy in spleen compartments. We suggest that even at a middle dose, oral Pb intake induces oxidant iron deposition in the spleen and that this may trigger sustained Grp78 redistribution to cells, thus leading to oxidative and autophagy dysfunction as early local reactions to this dangerous metal.