Mercury (Hg) has long been recognized as a neurotoxicant; however, recent work in animal models has implicated Hg as an immunotoxicant. In particular, Hg has been shown to induce autoimmune disease ...in susceptible animals with effects including overproduction of specific autoantibodies and pathophysiologic signs of lupus-like disease. However, these effects are only observed at high doses of Hg that are above the levels to which humans would be exposed through contaminated fish consumption. While there is presently no evidence to suggest that Hg induces frank autoimmune disease in humans, a recent epidemiological study has demonstrated a link between occupational Hg exposure and lupus.
In our studies, we have tested the hypothesis that Hg does not cause autoimmune disease directly, but rather that it may interact with triggering events, such as genetic predisposition, exposure to antigens, or infection, to exacerbate disease. Treatment of mice that are not susceptible to Hg-induced autoimmune disease with very low doses and short term exposures of inorganic Hg (20–200 μg/kg) exacerbates disease and accelerates mortality in the graft versus host disease model of chronic lupus in C57Bl/6 × DBA/2 mice. Furthermore, low dose Hg exposure increases the severity and prevalence of experimental autoimmune myocarditis (induced by immunization with cardiac myosin peptide in adjuvant) in A/J mice. To test our hypothesis further, we examined sera from Amazonian populations exposed to Hg through small-scale gold mining, with and without current or past malaria infection. We found significantly increased prevalence of antinuclear and antinucleolar antibodies and a positive interaction between Hg and malaria. These results suggest a new model for Hg immunotoxicity, as a co-factor in autoimmune disease, increasing the risks and severity of clinical disease in the presence of other triggering events, either genetic or acquired.
Mass drug treatment with azithromycin (MDA) is part of the WHO-endorsed 'SAFE' strategy for trachoma control in endemic communities. MDA has been associated with reduced trachoma prevalence and ...short-term reductions in other bacterial infections, but can also lead to increased circulation of macrolide-resistant bacteria.
We prospectively monitored macrolide resistance in fecal E. coli collected from young children participating in the PRET+ Study in rural Tanzania. MDA was administered in four villages with >10% trachoma prevalence. Four nearby communities with lower trachoma prevalence served as controls. Rectal swabs were collected during cross-sectional surveys performed at baseline, 1, 3 and 6 months after MDA. Fecal E. coli isolates were screened for macrolide susceptibility using disc diffusion and minimum inhibitory concentration methods. Cross-sectional and longitudinal differences in resistance prevalence by MDA exposure were compared using t-tests and logistic regression.
There was no difference in the proportion of individuals carrying azithromycin-resistant E. coli at baseline (0.21 vs. 0.16, P > 0.05). Azithromycin resistance carriage prevalence remained stable over follow-up in non-MDA villages but increased sharply in MDA villages (0.61 at 1 month, 0.42 at 3 months and 0.31 at 6 months). MDA exposure was highly associated with azithromycin resistance carriage at 1 month post-MDA (OR 15.27, P < 0.001) and subsequent surveys. Younger age and recent diarrhoea were also associated with increased odds of resistance (P < 0.01).
MDA resulted in significantly increased prevalence of macrolide resistance in E. coli. Although MDA is effective for trachoma elimination, it has costs; it is essential to monitor antimicrobial resistance following MDA.
The use of antimicrobials in commercial broiler poultry production results in the presence of drug-resistant bacteria shed in the excreta of these birds. Because these wastes are largely ...land-disposed these pathogens can affect the surrounding environment and population. In this analysis, we characterized the survival of antimicrobial-resistant enterococci and staphylococci and resistance genes in poultry litter. Temperature, moisture, and pH were measured in the litter over a 120-day period from storage sheds at three conventional US broiler chicken farms, as well as colony-forming units of
Enterococcus spp. and
Staphylococcus spp. Selected isolates from each sampling event were tested for resistance to eight antimicrobials used in poultry feeds as well as the presence of resistance genes and mobile genetic elements. Temperatures greater than 60
°C were only intermittently observed in the core of the litter piles. Both antimicrobial-resistant enterococci and staphylococci, as well as resistance genes persisted throughout the 120-day study period. Resistance genes identified in the study include:
erm(A),
erm(B), erm (C),
msr(A/B),
msr(C), and
vat(E). This study indicates that typical storage practices of poultry litter are insufficient for eliminating drug-resistant enterococci and staphylococci, which may then be released into the environment through land disposal.
Abstract
This study evaluated the association of arsenic exposure, as measured in urine, with diabetes prevalence, glycated hemoglobin, and insulin resistance in American Indian adults from Arizona, ...Oklahoma, and North and South Dakota (1989–1991). We studied 3,925 men and women 45–74 years of age with available urine arsenic measures. Diabetes was defined as a fasting glucose level of 126 mg/dL or higher, a 2-hour glucose level of 200 mg/dL or higher, a hemoglobin A1c (HbA1c) of 6.5% or higher, or diabetes treatment. Median urine arsenic concentration was 14.1 µg/L (interquartile range, 7.9–24.2). Diabetes prevalence was 49.4%. After adjustment for sociodemographic factors, diabetes risk factors, and urine creatinine, the prevalence ratio of diabetes comparing the 75th versus 25th percentiles of total arsenic concentrations was 1.14 (95% confidence interval: 1.08, 1.21). The association between arsenic and diabetes was restricted to participants with poor diabetes control (HbA1c ≥8%). Arsenic was positively associated with HbA1c levels in participants with diabetes. Arsenic was not associated with HbA1c or with insulin resistance (assessed by homeostatic model assessment to quantify insulin resistance) in participants without diabetes. Urine arsenic was associated with diabetes control in a population from rural communities in the United States with a high burden of diabetes. Prospective studies that evaluate the direction of the relation between poor diabetes control and arsenic exposure are needed.
Background: Arsenic exposure in drinking water disproportionately affects small communities in some U. S. regions, including American Indian communities. In U. S. adults with no seafood intake, ...median total urine arsenic is 3.4 μg/L. Objective: We evaluated arsenic exposure and excretion patterns using urine samples collected over 10 years in a random sample of American Indians from Arizona, Oklahoma, and North and South Dakota who participated in a cohort study from 1989 to 1999. Methods: We measured total urine arsenic and arsenic species inorganic arsenic (arsenite and arsenate), methylarsonate (MA), dimethylarsinate (DMA), and arsenobetaine concentrations in 60 participants (three urine samples each, for a total of 180 urine samples) using inductively coupled plasma/mass spectrometry (ICPMS) and high-performance liquid chromatography/ICPMS, respectively. Results: Median (10th, 90th percentiles) urine concentration for the sum of inorganic arsenic, MA, and DMA at baseline was 7.2 (3.1, 16.9) μg/g creatinine; the median was higher in Arizona (12.5 μg/g), intermediate in the Dakotas (9.1 μg/g), and lower in Oklahoma (4.4 μg/g). The mean percentage distribution of arsenic species over the sum of inorganic and methylated species was 10.6% for inorganic arsenic, 18.4% for MA, and 70.9% for DMA. The intradass correlation coefficient for three repeated arsenic measurements over a 10-year period was 0.80 for the sum of inorganic and methylated species and 0.64, 0.80, and 0.77 for percent inorganic arsenic, percent MA, and percent DMA, respectively. Conclusions: This study found low to moderate inorganic arsenic exposure and confirmed longterm constancy in arsenic exposure and urine excretion patterns in American Indians from three U. S. regions over a 10-year period. Our findings support the feasibility of analyzing arsenic species in large population-based studies with stored urine samples.
Aneuploidy, defined as structural and numerical aberrations of chromosomes, continues to draw attention as an informative effect biomarker for carcinogens and male reproductive toxicants. It has been ...well documented that aneuploidy is a hallmark of cancer. Aneuploidies in oocytes and spermatozoa contribute to infertility, pregnancy loss and a number of congenital abnormalities, and sperm aneuploidy is associated with testicular cancer. It is striking that several carcinogens induce aneuploidy in somatic cells, and also adversely affect the chromosome compliment of germ cells. In this paper we review 1) the contributions of aneuploidy to cancer, infertility, and developmental abnormalities; 2) techniques for assessing aneuploidy in precancerous and malignant lesions and in sperm; and 3) the utility of aneuploidy as a biomarker for integrated chemical assessments of carcinogenicity, and reproductive and developmental toxicity.
Background: Models of between-farm transmission of pathogens have identified service vehicles and social groups as risk factors mediating the spread of infection. Because of high levels of economic ...organization in much of the poultry industry, we examined the importance of company affiliation, as distinct from social contacts, in a model of the potential spread of avian influenza among broiler poultry farms in a poultry-dense region in the United States. The contribution of company affiliation to risk of between-farm disease transmission has not been previously studied. Methodology/Principal Findings: We obtained data on the nature and frequency of business and social contacts through a national survey of broiler poultry growers in the United States. Daily rates of contact were estimated using Monte Carlo analysis. Stochastic modeling techniques were used to estimate the exposure risk posed by a single infectious farm to other farms in the region and relative risk of exposure for farms under different scenarios. The mean daily rate of vehicular contact was 0.82 vehicles/day. The magnitude of exposure risk ranged from <1% to 25% under varying parameters. Risk of between-farm transmission was largely driven by company affiliation, with farms in the same company group as the index farm facing as much as a 5-fold increase in risk compared to farms contracted with different companies. Employment of part-time workers contributed to significant increases in risk in most scenarios, notably for farms who hired day-laborers. Social visits were significantly less important in determining risk. Conclusions/Significance: Biosecurity interventions should be based on information on industry structure and company affiliation, and include part-time workers as potentially unrecognized sources of viral transmission. Modeling efforts to understand pathogen transmission in the context of industrial food animal production should consider company affiliation in addition to geospatial factors and pathogen characteristics. Restriction of social contacts among farmers may be less useful in reducing between-farm transmission.
Lead exposures have been shown to be associated with increased blood pressure and risk of hypertension in older men. In perimenopausal women, skeletal lead stores are an important source of ...endogenous lead exposure due to increased bone demineralization.
To examine the relationship of blood lead level with blood pressure and hypertension prevalence in a population-based sample of perimenopausal and postmenopausal women in the United States.
Cross-sectional sample of 2165 women aged 40 to 59 years, who participated in a household interview and physical examination, from the Third National Health and Nutrition Examination Survey conducted from 1988 to 1994.
Associations of blood lead with blood pressure and hypertension, with age, race and ethnicity, cigarette smoking status, body mass index, alcohol use, and kidney function as covariates.
A change in blood lead levels from the lowest (quartile 1: range, 0.5-1.6 micro g/dL) to the highest (quartile 4: range, 4.0-31.1 microg/dL) was associated with small statistically significant adjusted changes in systolic and diastolic blood pressures. Women in quartile 4 had increased risks of diastolic (>90 mm Hg) hypertension (adjusted odds ratio OR, 3.4; 95% confidence interval CI, 1.3-8.7), as well as moderately increased risks for general hypertension (adjusted OR, 1.4; 95% CI, 0.92-2.0) and systolic (>140 mm Hg) hypertension (adjusted OR, 1.5; 95% CI, 0.72-3.2). This association was strongest in postmenopausal women, in whom adjusted ORs for diastolic hypertension increased with increasing quartile of blood lead level compared with quartile 1 (adjusted OR, 4.6; 95% CI, 1.1-19.2 for quartile 2; adjusted OR, 5.9; 95% CI, 1.5-23.1 for quartile 3; adjusted OR, 8.1; 95% CI, 2.6-24.7 for quartile 4).
At levels well below the current US occupational exposure limit guidelines (40 microg/dL), blood lead level is positively associated with both systolic and diastolic blood pressure and risks of both systolic and diastolic hypertension among women aged 40 to 59 years. The relationship between blood lead level and systolic and diastolic hypertension is most pronounced in postmenopausal women. These results provide support for continued efforts to reduce lead levels in the general population, especially women.
For nearly five decades long-term studies in rodents have been the accepted benchmark for assessing chronic long-term toxic effects, particularly carcinogenicity, of chemicals. The European Food ...Safety Authority (EFSA) and the World Health Organization (WHO) have pointed out that the current set of internationally utilized test methods capture only some of the potential adverse effects associated with exposures to these agents over the lifetime.
In this paper, we propose the adaption of the carcinogenicity bioassay to integrate additional protocols for comprehensive long-term toxicity assessment that includes developmental exposures and long-term outcomes, capable of generating information on a broad spectrum of different end points.
An integrated study design based on a stepwise process is described that includes the priority end points of the Economic Co-operation and Development and the National Toxicology Program guidelines on carcinogenicity and chronic toxicity and developmental and reproductive toxicity. Integrating a comprehensive set of relevant toxicological end points in a single protocol represents an opportunity to optimize animal use in accordance with the 3Rs (replacement, reduction and refinement). This strategy has the potential to provide sufficient data on multiple windows of susceptibility of specific interest for risk assessments and public health decision-making by including prenatal, lactational, neonatal exposures and evaluating outcomes over the lifespan.
This integrated study design is efficient in that the same generational cohort of rats used for evaluating long-term outcomes can be monitored in satellite parallel experiments to measure biomarkers and other parameters related to system-specific responses including metabolic alterations and endocrine disturbances. Citation: Manservisi F, Babot Marquillas C, Buscaroli A, Huff J, Lauriola M, Mandrioli D, Manservigi M, Panzacchi S, Silbergeld EK, Belpoggi F. 2017. An integrated experimental design for the assessment of multiple toxicological end points in rat bioassays. Environ Health Perspect 125:289-295; http://dx.doi.org/10.1289/EHP419.
PDF
