Chronic Low-dose Exposure Research Articles

EFFECT OF SUB-CHRONIC EXPOSURE TO CHROMIUM ON HAEMATOLOGICAL AND BIOCHEMICAL PARAMETERS OF MALE ALBINO RAT

Objectives : Exposure to chromium, the transition element found in many compounds of earth’s crust, leads to various health hazards including cancer, dermatitis, damage of liver and kidneys and reproductive toxicity in both male and female. Toxic effect of chronic exposure to chromium at low environmentally relevant dose is recently recognized and less studied. In the present study, we evaluated the effect of sub-chronic exposure to low doses of chromium VI (K2Cr2O7) on various haematological and biochemical parameters in male albino rats.Methods : Male albino rats (160±10 gm) received 1/25, 1/50 and 1/100 of reported oral LD50 dose of chromium VI (K2Cr2O7) for 90 consecutive days. After treatment, the blood was collected for analysis of various haematological and biochemical parameters.Results : Exposure to chromium VI at 1/25 LD50 dose caused decrease in body weight gain and reduction in the weight of the reproductive organs along with increase in the weight of liver and kidney. Numbers of red blood cells, white blood cells, platelets and haemoglobin concentration reduced with increase in clotting time. The total sperm count and motility was also reduced in exposed rats. There was decrease in plasma protein and albumin concentration, with increase in plasma glucose and cholesterol level. The activity of enzyme alanine aminotransferase and enzyme aspertate aminotransferase was stimulated in treated rats.Conclusion : The results of the present study revealed that chronic low dose exposure to chromium VI resulted in a toxic effect in experimental male albino rats. Keywords: Chromium VI (K2Cr2O7), Haematological parameters, Biochemical parameters.

Red Bone Marrow and Male Breast Doses for a Cohort of Atomic Veterans.

Both red bone marrow and male breast doses with associated uncertainty have been reconstructed for a 1,982-person subset of a cohort of 114, 270 military personnel (referred to as "atomic veterans") who participated in U.S. atmospheric nuclear weapons testing from 1945 to 1962. The methods used to calculate these doses and corresponding uncertainty have been reported in detail by Till et al. in an earlier publication. In this current article we report the final results of those calculations. These doses are being used in a case-cohort design epidemiological investigation of leukemia and male breast cancer. This cohort of atomic veterans is one component in a broader-scope study of approximately one million U.S. persons designed to investigate risk from chronic low-dose radiation exposure. Doses to the atomic veterans in this sub-cohort were relatively low, with approximately two-thirds receiving red bone marrow doses <5 mGy and only four individuals receiving a red bone marrow dose >50 mGy. The average red bone marrow dose for members of the sub-cohort was 5.9 mGy. Doses to male breast were approximately 20% higher than red bone marrow doses. The uncertainty in the estimated doses was relatively low, considering relevant personnel dosimetry was available for only about 25% of the subjects, and most of the doses were reconstructed from film badges worn by co-workers or from the individual's military record and military unit activities. The average coefficient of variation for the individual dose estimates was approximately 0.5, comparable to the uncertainty in doses estimated for the Japanese A-bomb survivors. Although the reconstructed red bone marrow doses were about 36% lower on average than the conservative doses previously estimated by the military for compensation, the overall correlation was quite good, suggesting that the estimates of doses from external exposure by the military for all ∼115,000 cohort members could be adjusted appropriately and used in further epidemiological analyses.

Toxic mechanisms of microcystins in mammals.

Microcystins, such as microcystin-leucine arginine (MC-LR), are some of the most toxic and prevalent cyanotoxins produced by cyanobacteria in freshwater and saltwater algal blooms worldwide. Acute and chronic exposures to microcystins are primarily known to cause hepatotoxicity; cellular damage and genotoxicity within mammalian livers. However, in vivo studies indicate that similar damage may occur in other mammalian organs and tissues, such as the kidney, heart, reproductive systems, and lungs - particularly following chronic low-dose exposures. Mechanisms of toxicity of mycrocystins are reviewed herein; including cellular uptake, interaction with protein phosphatases PP1 and PP2A, cytoskeletal effects, formation of oxidative stress and induction of apoptosis. In general, the mode of action of toxicity by MCs in mammalian organs are similar to those that have been observed in liver tissues. A comprehensive understanding of the toxic mechanisms of microcystins in mammalian tissues and organs will assist in the development of risk assessment approaches to public health protection strategies and the development of robust drinking water policies.

Biomarkers for Uranium Risk Assessment for the Development of the CURE (Concerted Uranium Research in Europe) Molecular Epidemiological Protocol.

Despite substantial experimental and epidemiological research, there is limited knowledge of the uranium-induce health effects after chronic low-dose exposures in humans. Biological markers can objectively characterize pathological processes or environmental responses to uranium and confounding agents. The integration of such biological markers into a molecular epidemiological study would be a useful approach to improve and refine estimations of uranium-induced health risks. To initiate such a study, Concerted Uranium Research in Europe (CURE) was established, and involves biologists, epidemiologists and dosimetrists. The aims of the biological work package of CURE were: 1. To identify biomarkers and biological specimens relevant to uranium exposure; 2. To define standard operating procedures (SOPs); and 3. To set up a common protocol (logistic, questionnaire, ethical aspects) to perform a large-scale molecular epidemiologic study in uranium-exposed cohorts. An intensive literature review was performed and led to the identification of biomarkers related to: 1. retention organs (lungs, kidneys and bone); 2. other systems/organs with suspected effects (cardiovascular system, central nervous system and lympho-hematopoietic system); 3. target molecules (DNA damage, genomic instability); and 4. high-throughput methods for the identification of new biomarkers. To obtain high-quality biological materials, SOPs were established for the sampling and storage of different biospecimens. A questionnaire was developed to assess potential confounding factors. The proposed strategy can be adapted to other internal exposures and should improve the characterization of the biological and health effects that are relevant for risk assessment.

Regulation of cyclin D1 by arsenic and microRNA inhibits adipogenesis

Low-dose chronic exposure to arsenic in drinking water represents a global public health concern with established risks for metabolic and cardiovascular disease, as well as cancer. While the linkage between arsenic and disease is strong, further understanding of the molecular mechanisms of its pathogenicity is required. Previous reports demonstrated the ability of arsenic to interfere with adipogenesis, which may mediate its effects in promoting metabolic disease. We hypothesized that microRNA are important regulators of most if not all mesenchymal stem cell processes that are dysregulated by arsenic exposure to impair lipogenesis. Arsenic increased the expression of miR-29b in white adipose tissue, as well as human mesenchymal stem cells (hMSCs) isolated from adipose tissue. Exposing hMSCs to arsenic increased abundance of miR-29b and cyclin D1 to promote proliferation over differentiation. Paradoxically, inhibition of miR-29b enhanced the inhibitory effect of arsenic on differentiation. This paradox was attributed to a requirement for miR-29 in regulating cyclin D1 expression as stable inhibition of miR-29b eliminated the cyclic pattern of cyclin D1 expression. Temporal regulation of cyclin D1 is critical for adipogenic differentiation, and the data suggest a paradigm where arsenic disruption of miR-29b regulatory pathways impairs adipogenic differentiation and ultimately adipose metabolic homeostasis.

Radio-adaptive response in peripheral blood lymphocytes of individuals residing in high-level natural radiation areas of Kerala in the southwest coast of India.

The present study investigates whether the chronic low-dose radiation exposure induces an in vivo radio-adaptive response in individuals from high-level natural radiation areas (HLNRA) of the Kerala coast. Peripheral blood samples from 54 adult male individuals aged between 26 and 65 years were collected for the study with written informed consent. Each of the whole blood sample was divided into three, one was sham irradiated, second and third was exposed to challenging doses of 1.0 and 2.0 Gy gamma radiation, respectively. Cytokinesis-block micronucleus (CBMN) assay was employed to study the radio-adaptive response. Seventeen individuals were from normal-level natural radiation area (NLNRA ≤1.5 mGy/year) and 37 from HLNRA (> 1.5 mGy/year). Based on the annual dose received, individuals from HLNRA were further classified into low-dose group (LDG, 1.51-5.0 mGy/year, N = 19) and high-dose group (HDG >5.0 mGy/year, N = 18). Basal frequency of micronucleus (MN) was comparable across the three dose groups (NLNRA, LDG and HDG, P = 0.64). Age of the individuals showed a significant effect on the frequency of MN after challenging dose exposures. The mean frequency of MN was significantly lower in elder (>40 years) individuals from HDG of HLNRA as compared to the young (≤40 years) individuals after 1.0 Gy (P < 0.001) and 2.0 Gy (P = 0.002) of challenging doses. However, young and elder individuals within NLNRA and LDG of HLNRA showed similar frequency of MN after the challenging dose exposures. Thus, increased level of chronic low-dose radiation (>5.0 mGy/year) seems to act as a priming dose resulting in the induction of an in vivo radio-adaptive response in elder individuals of the Kerala coast.

Metabolomics reveals dose effects of low-dose chronic exposure to uranium in rats: identification of candidate biomarkers in urine samples.

IntroductionData are sparse about the potential health risks of chronic low-dose contamination of humans by uranium (natural or anthropogenic) in drinking water. Previous studies report some molecular imbalances but no clinical signs due to uranium intake.ObjectivesIn a proof-of-principle study, we reported that metabolomics is an appropriate method for addressing this chronic low-dose exposure in a rat model (uranium dose: 40 mg L−1; duration: 9 months, n = 10). In the present study, our aim was to investigate the dose–effect pattern and identify additional potential biomarkers in urine samples.MethodsCompared to our previous protocol, we doubled the number of rats per group (n = 20), added additional sampling time points (3 and 6 months) and included several lower doses of natural uranium (doses used: 40, 1.5, 0.15 and 0.015 mg L−1). LC–MS metabolomics was performed on urine samples and statistical analyses were made with SIMCA-P+ and R packages.ResultsThe data confirmed our previous results and showed that discrimination was both dose and time related. Uranium exposure was revealed in rats contaminated for 9 months at a dose as low as 0.15 mg L−1. Eleven features, including the confidently identified N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide and 4-hydroxyphenylacetylglycine, discriminated control from contaminated rats with a specificity and a sensitivity ranging from 83 to 96 %, when combined into a composite score.ConclusionThese findings show promise for the elucidation of underlying radiotoxicologic mechanisms and the design of a diagnostic test to assess exposure in urine, in a dose range experimentally estimated to be above a threshold between 0.015 and 0.15 mg L−1.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-016-1092-8) contains supplementary material, which is available to authorized users.

Chronic Acrylamide Exposure in Male Mice Results in Elevated DNA Damage in the Germline and Heritable Induction of CYP2E1 in the Testes.

Acute acrylamide exposure in male rodents results in reduced reproductive performance and dominant lethality. However, the reproductive effects of low dose chronic exposure, which better reflects the nature of human exposure, remain far less certain. Human dietary consumption of acrylamide has been estimated at an average of 1-4 µg/kg bw/day. In order to simulate this exposure, male mice were provided with acrylamide (1 µg/ml) via their drinking water continuously for six months, which was equivalent to a human dose of 10.5 µg/ kg bw/day. This exposure regime increased DNA damage in the spermatozoa, without affecting a concomitant reduction in overall fertility. The offspring of acrylamide treated mice did not have an increased incidence of skin papilloma formation following the two-stage tumor induction protocol. However, the male offspring of acrylamide treated fathers had significantly increased levels of DNA damage in their spermatozoa, despite having had no direct toxicant exposure. It was also found that the F0, and most crucially, F1 mice had increased levels of CYP2E1 protein in their germ cells. This is significant as CYP2E1 is the sole enzyme responsible for conversion of acrylamide to its harmful metabolite glycidamide. This altered expression may be due to epigenetic alterations. Additionally, the F0 and F1 mice had increased oxidative adducts in the DNA of their germ cells, which was hypothesized to arise as a byproduct of increased CYP2E1 activity. Therefore, chronic paternal acrylamide exposure in mice has consequences for their offspring, and raises concerns for the effects of acrylamide exposure in the human population and the accumulated effects with multiple generations of exposure.

Human Peripheral Blood Mononuclear Cell Function and Dendritic Cell Differentiation Are Affected by Bisphenol-A Exposure.

Environmental pollutants, including endocrine disruptor chemicals (EDCs), interfere on human health, leading to hormonal, immune and metabolic perturbations. Bisphenol-A (BPA), a main component of polycarbonate plastics, has been receiving increased attention due to its worldwide distribution with a large exposure. In humans, BPA, for its estrogenic activity, may have a role in autoimmunity, inflammatory and allergic diseases. To this aim, we assessed the effect of low BPA doses on functionality of human peripheral blood mononuclear cells (PBMCs), and on in vitro differentiation of dendritic cells from monocytes (mDCs). Fresh peripheral blood samples were obtained from 12 healthy adult volunteers. PBMCs were left unstimulated or were activated with the mitogen phytohemagglutinin (PHA) or the anti-CD3 and anti-CD28 antibodies and incubated in presence or absence of BPA at 0.1 and 1nM concentrations. The immune-modulatory effect of BPA was assessed by evaluating the cell proliferation and the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-10 (IL-10) and interleukin-13 (IL-13) secreted by PBMCs. mDCs were differentiated with IL-4 and GC-CSF with or without BPA and the expression of differentiation/maturation markers (CD11c, CD1a, CD86, HLA-DR) was evaluated by flow cytometry; furthermore, a panel of 27 different cytokines, growth factors and chemokines were assayed in the mDC culture supernatants. PBMCs proliferation significantly increased upon BPA exposure compared to BPA untreated cells. In addition, a significant decrease in IL-10 secretion was observed in PBMCs incubated with BPA, either in unstimulated or mitogen-stimulated cells, and at both 0.1 and 1nM BPA concentrations. Similarly, IL-13 was reduced, mainly in cells activated by antiCD3/CD28. By contrast, no significant changes in IFN-γ and IL-4 production were found in any condition assayed. Finally, BPA at 1nM increased the density of dendritic cells expressing CD1a and concomitantly decreased the expression of HLA-DR and CD86 activation markers. In conclusion, in humans the exposure to BPA causes on PBMCs a significant modulation of proliferative capacity and cytokine production, and on mDCs alteration in differentiation and phenotype. These immune cell alterations suggest that low dose chronic exposure to BPA could be involved in immune deregulation and possibly in the increased susceptibility to develop inflammatory and autoimmune diseases.

Simulating Space Radiation-Induced Breast Tumor Incidence Using Automata.

Estimating cancer risk from space radiation has been an ongoing challenge for decades primarily because most of the reported epidemiological data on radiation-induced risks are derived from studies of atomic bomb survivors who were exposed to an acute dose of gamma rays instead of chronic high-LET cosmic radiation. In this study, we introduce a formalism using cellular automata to model the long-term effects of ionizing radiation in human breast for different radiation qualities. We first validated and tuned parameters for an automata-based two-stage clonal expansion model simulating the age dependence of spontaneous breast cancer incidence in an unexposed U.S. We then tested the impact of radiation perturbation in the model by modifying parameters to reflect both targeted and nontargeted radiation effects. Targeted effects (TE) reflect the immediate impact of radiation on a cell's DNA with classic end points being gene mutations and cell death. They are well known and are directly derived from experimental data. In contrast, nontargeted effects (NTE) are persistent and affect both damaged and undamaged cells, are nonlinear with dose and are not well characterized in the literature. In this study, we introduced TE in our model and compared predictions against epidemiologic data of the atomic bomb survivor cohort. TE alone are not sufficient for inducing enough cancer. NTE independent of dose and lasting ∼100 days postirradiation need to be added to accurately predict dose dependence of breast cancer induced by gamma rays. Finally, by integrating experimental relative biological effectiveness (RBE) for TE and keeping NTE (i.e., radiation-induced genomic instability) constant with dose and LET, the model predicts that RBE for breast cancer induced by cosmic radiation would be maximum at 220 keV/μm. This approach lays the groundwork for further investigation into the impact of chronic low-dose exposure, inter-individual variation and more complex space radiation scenarios.

Low-level Chronic Lead Exposure Impairs Neural Control of Blood Pressure and Heart Rate in Rats.

Lead (Pb) induces adverse effects when it chronically accumulates in the body, including effects on the nervous and cardiovascular systems. Wistar rats were exposed to lead acetate for 30days (first dose 4µg/100g followed by 0.05µg/100g/day, i.m.) to investigate the cardiovascular system impact on the autonomic control. The femoral artery and vein were catheterised to perform hemodynamic evaluations in awake rats: heart rate variability (HRV), baroreflex sensitivity, cardiopulmonary reflex and hemodynamic responses to vagal and sympathetic pharmacological blockade. Rats exposed to Pb exhibited a higher blood pressure and reduced HRV in the time domain when compared to the saline-injected group. Spectral analysis of the HRV in the frequency-domain showed an augmented low-frequency component of the spectrum. Methylatropine and atenolol administration suggest increased sympathetic tone and reduced vagal tone on the control of heart rate. Chronic Pb exposure decreased the sensitivity of the baroreflex without significantly changing the cardiopulmonary reflex. This study demonstrated for the first time in an animal model of a controlled, low-dose chronic lead exposure that cardiovascular changes, such as arterial hypertension, are accompanied by impaired autonomic control of the cardiovascular system, as characterised by reduced baroreflex sensitivity and a sympathovagal imbalance.

Neurobehavioral deficits and brain oxidative stress induced by chronic low dose exposure of persistent organic pollutants mixture in adult female rat.

Persistent organic pollutants (POPs) are long-lived organic compounds that are considered one of the major risks to ecosystem and human health. Recently, great concerns are raised about POPs mixtures and its potential toxicity even in low doses of daily human exposure. The brain is mostly targeted by these lipophilic compounds because of its important contain in lipids. So, it would be quite interesting to study the effects of exposure to these mixtures and evaluate their combined toxicity on brain cells. The present study was designed to characterize the cognitive and locomotors deficits and brain areas redox status in rat model. An orally chronic exposure to a representative mixture of POPs composed of endosulfan (2.6μg/kg), chlorpyrifos (5.2μg/kg), naphthalene (0.023μg/kg) and benzopyrane (0.002μg/kg); the same mixture with concentration multiplied by 10 and 100 was also tested. Exposed rats have shown a disturbance of memory and a decrease in learning ability concluded by Morris water maze and the open field tests results and anxiolytic behaviour in the test of light/dark box compared to control. Concerning brain redox homeostasis, exposed rats have shown an increased malondialdehyde (MDA) amount and an alteration in glutathione (GSH) levels in both the brain mitochondria and cytosolic fractions of the cerebellum, striatum and hippocampus. These effects were accompanied by a decrease in levels of cytosolic glutathione S-transferase (GST) and a highly significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in both cytosolic and mitochondrial fractions. The current study suggests that environmental exposure to daily even low doses of POPs mixtures through diet induces oxidative stress status in the brain and especially in the mitochondria with important cognitive and locomotor behaviour variations in the rats.

Metallothionein MT2A A-5G Polymorphism as a Risk Factor for Chronic Kidney Disease and Diabetes: Cross-Sectional and Cohort Studies.

Metallothioneins (MTs) are proteins that protect cells from toxic agents such as heavy metal ions or reactive oxygen species. MT2A A-5G is a single nucleotide polymorphism in the promoter region of the MT2A gene, and the minor G allele results in lower transcription efficiency. We aimed to elucidate associations between MT2A A-5G and risks of 2 diseases potentially related to lowered MT expression, chronic kidney disease (CKD), and diabetes mellitus (DM), in a community-dwelling population. Study subjects were Nagoya city residents participating in the Japan Multi-Institutional Collaborative Cohort Study (J-MICC) Daiko Study, comprised 749 men and 2,025 women, aged 39–75 years. CKD (>stage 3) and DM were defined by standard guidelines. Associations were evaluated using logistic regression models with adjustments for age, sex and potential confounders in a cross-sectional study, and verified in a 5-year longitudinal study. Odds ratios (OR [95% confidence interval]) were calculated relative to the AA genotype. Serum MT (I + II), Cd and zinc levels were also determined by genotype. The OR of the GG genotype for CKD risk was 3.98 (1.50, 10.58) in the cross-sectional study and 5.17 (1.39, 19.28) in the longitudinal study. The OR of the GA genotype for DM was 1.86 (1.26, 2.75) in the cross-sectional study and 2.03 (1.19, 3.46) in the longitudinal study. MT2A A-5G may be associated with CKD and DM risks. This polymorphism is a promising target for evaluations of CKD and DM risks with possible involvement of low-dose chronic exposure to environmental pollutants.

Lack of increased DNA double-strand breaks in peripheral blood mononuclear cells of individuals from high level natural radiation areas of Kerala coast in India

The high level natural radiation area (HLNRA) of Kerala is a 55km long and 0.5km wide strip in south west coast of India. The level of background radiation in this area varies from <1.0mGy/year to 45.0mGy/year. It offers unique opportunity to study the effect of chronic low dose/low dose-rate radiation directly on human population. Spontaneous level of DNA double strand breaks (DSBs) was quantified in peripheral blood mononuclear cells of 91 random individuals from HLNRA (N=61, mean age: 36.1±7.43years) and normal level natural radiation area (NLNRA) (N=30, mean age: 35.5±6.35years) using gamma-H2AX as a marker. The mean annual dose received by NLNRA and HLNRA individuals was 1.28±0.086mGy/year and 8.28±4.96mGy/year, respectively. The spontaneous frequency of DSBs in terms of gamma-H2AX foci among NLNRA and HLNRA individuals were 0.095±0.009 and 0.084±0.004 per cell (P=0.22). The individuals from HLNRA were further classified as low dose group (LDG, 1.51–5.0mGy/year, mean dose: 2.63±0.76mGy/year) and high dose group (HDG, >5.0mGy/year, mean dose: 11.04±3.57mGy/year). The spontaneous frequency of gamma-H2AX foci per cell in NLNRA, LDG and HDG was observed to be 0.095±0.009, 0.096±0.008 and 0.078±0.004 respectively. Individuals belonging to HDG of HLNRA showed marginally lower frequency of DSBs as compared to NLNRA and LDG of HLNRA. This could be suggestive of either lower induction or better repair of DSBs in individuals from HDG of HLNRA. The present study indicated that 5.0mGy/year could be a possible threshold dose for DSB induction at chronic low-dose radiation exposure in vivo. However, further studies on DNA damage induction and repair kinetics are required to draw firm conclusions.

N-Acetyl cysteine does not prevent liver toxicity from chronic low-dose plus subacute high-dose paracetamol exposure in young or old mice.

Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute overexposures. The risk of hepatotoxicity from nonacute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for nonacute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and subacute paracetamol overexposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33 g/kg food) or control diet for 6 weeks. Mice were then dosed orally eight times over 3 days with additional paracetamol (250 mg/kg) or saline, followed by either one or two doses of oral NAC (1200 mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Subacute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from subacute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for subacute paracetamol toxicity.

The effect of pesticide exposure on cardiovascular system: a systematic review

Cardiovascular diseases (CVD) are the leading cause of death worldwide and along with traditional risk factors, environmental toxicants should be considered as important risk factors for CVD. However, the contribution of pesticide to CVD is still uncertain. In this systematic review we evaluated the evidence on the association between pesticide exposure and CVD in humans . We conducted a comprehensive methods search using Medline (PubMed), ProQuest, EBSCOhost Medical, Scopus and Google Scholar in October 2014. All studies included were epidemiology studies in humans focused on cardiovascular health effects that were published between 2004 and 2014. We had reviewed 26 papers on cardiovascular diseases with pesticide exposure which most studies documented mixed pesticide exposures but the majority of studies examined the health effects of organophosphate. Eight studies examined the long-term effects of chronic low dose exposure to pesticide while the rest were acute poisoning. Overall, there was little evidence of increased risk of myocardial infarction (MI) and MI mortality but individual pesticide evaluation revealed significantly associated with non-fatal MI. Organochlorine is significantly associated with peripheral arterial disease and stroke. In severe poisonings, general impression is that cardiac abnormalities are common. This systematic review suggests that pesticide exposure is associated with increased risk of CVD and CVD mortality. We hope our results will stimulate further evaluation of CVD incidence and mortality in pesticide-exposed cohorts.

Effects of chronic low-dose exposure to ionizing radiation on physician microvascular structure revealed by nail fold capillaroscopy.

The aim of this study was to assess the long-term asymptomatic effects of low-dose radiation on microvascular structure among interventional physicians, whose hands are exposed to ionizing radiation during daily practice. The study, approved by the national ethics committee, included 186 radiation-exposed (surgeons, cardiologists, radiologists) and 35 unexposed physicians, all of whom had provided written consent. The subjects completed a questionnaire describing their current and past daily practice, from which tentative estimates of current and cumulative radiation exposure estimates were computed. Subject dermal microcirculation state was assessed by capillaroscopy of the nail fold of eight fingers (thumbs excluded) based on photographs. Two quantitative scores characterizing extravasation and morphological abnormalities based on seven semiquantitative indices were obtained from post hoc coding of the photographs by five capillaroscopists. These evaluations were randomized and blind to the exposure. The effect of the radiation exposure on both abnormality scores was modelled using multilevel proportional odds regression adjusted for potential confounders. The proportion of physicians for which the most frequent act is close to the radiation source was highest among surgeons, but with fewer weekly acts. The median duration of exposure was highest among radiologists and cardiologists. No exposure effect could be detected on the extravasation score. The morphological anomaly score increased significantly with duration of exposure and estimated cumulative exposure among surgeons and interventional radiologists, unlike cardiologists among whom no effect could be detected. It is concluded that the shown effects of chronic low-dose exposure to ionizing radiation on physician microvascular structure reveal the importance of increased exposure monitoring and prevention.

Low dose exposure to Bisphenol A alters development of gonadotropin-releasing hormone 3 neurons and larval locomotor behavior in Japanese Medaka

Accumulating evidence indicates that chronic low dose exposure to Bisphenol A (BPA), an endocrine disruptor, may disrupt normal brain development and behavior mediated by the gonadotropin-releasing hormone (GnRH) pathways. While it is known that GnRH neurons in the hypothalamus regulate reproductive physiology and behavior, functional roles of extra-hypothalamic GnRH neurons remain unclear. Furthermore, little is known whether BPA interacts with extra-hypothalamic GnRH3 neural systems in vulnerable developing brains. Here we examined the impact of low dose BPA exposure on the developing GnRH3 neural system, eye and brain growth, and locomotor activity in transgenic medaka embryos and larvae with GnRH3 neurons tagged with GFP. Fertilized eggs were collected daily and embryos/larvae were chronically exposed to 200ng/ml of BPA, starting at 1 day post fertilization (dpf). BPA significantly increased fluorescence intensity of the GnRH3-GFP neural population in the terminal nerve (TN) of the forebrain at 3dpf, but decreased the intensity at 5dpf, compared with controls. BPA advanced eye pigmentation without affecting eye and brain size development, and accelerated times to hatch. Following chronic BPA exposure, 20dpf larvae showed suppression of locomotion, both in distance covered and speed of movement (47% and 43% reduction, respectively). BPA-induced hypoactivity was accompanied by decreased cell body sizes of individual TN-GnRH3 neurons (14% smaller than those of controls), but not of non-GnRH3 neurons. These novel data demonstrate complex neurobehavioral effects of BPA on the development of extra-hypothalamic GnRH3 neurons in teleost fish.

Abstract P056: MHC CLass II-associated Invariant Peptide (CLIP) Antagonism During Chronic Lipopolysaccharide Treatment Preserves Afferent Arteriolar Autoregulatory Behavior

Lipopolysaccharide (LPS) is a cell wall component of gram-negative bacteria that can activate toll-like receptor 4, which in turn, activates the innate immune system. Chronic immune system activation is linked to blunted afferent arteriolar autoregulatory behavior and kidney injury. MHC Class II-associated invariant peptide (CLIP) provides a critical step in antigen processing, presentation, and adaptive immune system activation. Accordingly, we postulated that treatment with a competitive CLIP antagonist (CAP) during chronic low-dose LPS exposure would preserve afferent arteriolar autoregulatory behavior. Rats were implanted with osmotic minipumps (day 0) for infusion of LPS (0.01mg/kg/day) or saline (0.9% NaCl; 0.5μl/hr) for 8 days and then the kidneys were harvested for juxtamedullary nephron studies. Four groups (n=6/group) were studied: Control, LPS, LPS + CAP and Sham + CAP. Both LPS + CAP and Sham + CAP groups were treated with CAP (3mg/kg/day; i.p.) on days 1-7. Autoregulatory behavior was assessed in these groups by increasing perfusion pressure in 15 mmHg increments from 65 to 170 mmHg. Starting baseline diameters were similar across the control (15.2 ± 1.2 μm), LPS (14.1 ± 1.0 μm), LPS + CAP (15.1 ± 1.0), and Sham + CAP (15.7 ± 0.6) groups. When perfusion pressure was increased from 65 to 170 mmHg, control and sham + CAP afferent arteriolar diameter decreased significantly by 26 ± 4% and 25 ± 2% (P&lt;0.05), respectively. In contrast, afferent diameters from LPS treated kidneys decreased by just 5 ± 2% over the same pressure range indicating impaired afferent arteriolar autoregulatory behavior. In LPS + CAP treated kidneys, afferent arteriolar diameter decreased by 17 ± 2% (P&lt;0.05) over the same pressure range signifying preservation of autoregulatory behavior. These data support the hypothesis that CLIP antagonism during chronic low dose LPS treatment preserves afferent arteriolar autoregulatory behavior. Inhibiting CLIP may open novel therapeutic targets for inflammatory kidney disease.

Use of Systematic Review and Meta-Analysis in Environmental Health Epidemiology: a Systematic Review and Comparison with Guidelines.

Systematic review (SR) and meta-analysis (MA) have potential to contribute substantially to environmental health (EH) risk assessment and policy-making, provided study questions are clear and methods sound. We undertook a systematic review of the published epidemiological literature for studies using both SR and MA examining associations between chronic low-dose chemical exposures and adverse health outcomes in general populations and compared actual methods and reporting with a checklist based on available published guidelines. We identified 48 EH SRMAs meeting these criteria. Associations were mainly positive and statistically significant, often involving large populations. A majority of studies followed most general SRMA guidance, although we identified weaknesses in problem formulation, study search, selection and data extraction, and integrating policy implications. Fewer studies followed EH-specific SRMA recommendations, particularly regarding exposure heterogeneity and other risks of bias. Development and adoption of EH-specific SRMA guidelines would contribute to strengthening these tools for public health decision-making.Electronic supplementary materialThe online version of this article (doi:10.1007/s40572-015-0062-z) contains supplementary material, which is available to authorized users.