Transcriptional response of rat frontal cortex following acute In Vivo exposure to the pyrethroid insecticides permethrin and deltamethrin

<p>Abstract</p> <p>Background</p> <p>Pyrethroids are neurotoxic pesticides that interact with membrane bound ion channels in neurons and disrupt nerve function. The purpose of this study was to characterize and explore changes in gene expression that occur in the rat frontal cortex, an area of CNS affected by pyrethroids, following an acute low-dose exposure.</p> <p>Results</p> <p>Rats were acutely exposed to either deltamethrin (0.3 – 3 mg/kg) or permethrin (1 – 100 mg/kg) followed by collection of cortical tissue at 6 hours. The doses used range from those that cause minimal signs of intoxication at the behavioral level to doses well below apparent no effect levels in the whole animal. A statistical framework based on parallel linear (SAM) and isotonic regression (PIR) methods identified 95 and 53 probe sets as dose-responsive. The PIR analysis was most sensitive for detecting transcripts with changes in expression at the NOAEL dose. A sub-set of genes (<it>Camk1g</it>, <it>Ddc</it>, <it>Gpd3</it>, <it>c-fos </it>and <it>Egr1</it>) was then confirmed by qRT-PCR and examined in a time course study. Changes in mRNA levels were typically less than 3-fold in magnitude across all components of the study. The responses observed are consistent with pyrethroids producing increased neuronal excitation in the cortex following a low-dose <it>in vivo </it>exposure. In addition, Significance Analysis of Function and Expression (SAFE) identified significantly enriched gene categories common for both pyrethroids, including some relating to branching morphogenesis. Exposure of primary cortical cell cultures to both compounds resulted in an increase (~25%) in the number of neurite branch points, supporting the results of the SAFE analysis.</p> <p>Conclusion</p> <p>In the present study, pyrethroids induced changes in gene expression in the frontal cortex near the threshold for decreases in ambulatory motor activity <it>in vivo</it>. The penalized regression methods performed similarly in detecting dose-dependent changes in gene transcription. Finally, SAFE analysis of gene expression data identified branching morphogenesis as a biological process sensitive to pyrethroids and subsequent <it>in vitro </it>experiments confirmed this predicted effect. The novel findings regarding pyrethroid effects on branching morphogenesis indicate these compounds may act as developmental neurotoxicants that affect normal neuronal morphology.</p

Carpet-dust chemicals as measures of exposure: Implications of variability

<p>Abstract</p> <p>Background</p> <p>There is increasing interest in using chemicals measured in carpet dust as indicators of chemical exposures. However, investigators have rarely sampled dust repeatedly from the same households and therefore little is known about the variability of chemical levels that exist within and between households in dust samples.</p> <p>Results</p> <p>We analyzed 9 polycyclic aromatic hydrocarbons, 6 polychlorinated biphenyls, and nicotine in 68 carpet-dust samples from 21 households in agricultural communities of Fresno County, California collected from 2003-2005. Chemical concentrations (ng per g dust) ranged from < 2-3,609 for 9 polycyclic aromatic hydrocarbons, from < 1-150 for 6 polychlorinated biphenyls, and from < 20-7,776 for nicotine. We used random-effects models to estimate variance components for concentrations of each of these carpet-dust chemicals and calculated the variance ratio, λ, defined as the ratio of the within-household variance component to the between-household variance component. Subsequently, we used the variance ratios calculated from our data, to illustrate the potential effect of measurement error on the attenuation of odds ratios in hypothetical case-control studies. We found that the median value of the estimated variance ratios was 0.33 (range: 0.13-0.72). Correspondingly, in case-control studies of associations between these carpet-dust chemicals and disease, given the collection of only one measurement per household and a hypothetical odds ratio of 1.5, we expect that the observed odds ratios would range from 1.27 to 1.43. Moreover, for each of the chemicals analyzed, the collection of three repeated dust samples would limit the expected magnitude of odds ratio attenuation to less than 20%.</p> <p>Conclusions</p> <p>Our findings suggest that attenuation bias should be relatively modest when using these semi-volatile carpet-dust chemicals as exposure surrogates in epidemiologic studies.</p

Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia

Background: TheBRCA1c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluateBRCA1c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. Methods: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity aroundBRCA1c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surroundingBRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia. Results: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was similar to 100 generations in Iberia and that it was introduced to South America early during the European colonization period. Conclusions: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening

Critical Consideration of the Multiplicity of Experimental and Organismic Determinants of Pyrethroid Neurotoxicity: A Proof of Concept

Pyrethroids (PYR) are pesticides with high insecticidal activity that may disrupt neuronal excitability in target and nontarget species. The accumulated evidence consistently showed that this neurophysiologic action is followed by alterations in motor, sensorimotor, neuromuscular, and thermoregulatory responses. Nevertheless, there are some equivocal results regarding the potency of PYR in lab animals. The estimation of potency is an important step in pesticide chemical risk assessment. In order to identify the variables influencing neurobehavioral findings across PYR studies, evidence on experimental and organismic determinants of acute PYR-induced neurotoxicity was reviewed in rodents. A comprehensive analysis of these studies was conducted focusing on test material and dosing conditions, testing conditions, animal models, and other determinants such as testing room temperature. Variations in the severity of the neurotoxicity, under lab-controlled conditions, was explained based upon factors including influence of animal species and age, test material features such as chemical structure and stereochemistry, and dosing conditions such as vehicle, route of exposure, and dose volume. If not controlled, the interplay of these factors may lead to large variance in potency estimation. This review examined the scope of acute toxicological data required to determine the safety of pesticide products, and factors and covariates that need to be controlled in order to ensure that predictivity and precaution are balanced in a risk assessment process within a reasonable time-frame, using acute PYR-induced neurotoxicity in rodents as an exemplar.Fil: Wolansky, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Tornero Velez, R.. Environmental Protection Agency; Estados Unido

Temporal association between serum prolactin concentration and exposure to styrene

Background: Previous studies have suggested that occupational exposure to styrene is associated with increased serum levels of the anterior pituitary hormone prolactin (PRL). Aims: To test the hypotheses that: (1) the effect of styrene exposure on PRL secretion is an acute effect, not a subchronic or chronic effect; (2) blood styrene, as a measure of absorbed dose, is a stronger predictor of serum PRL level than personal breathing zone air styrene concentration. Methods: Subjects were recruited from 17 workplaces in the reinforced plastics industry. Personal breathing zone air styrene, whole blood styrene, and serum PRL were measured during one to three sessions, approximately one year apart. Linear multiple regression was used to model the relations between acute (air styrene or blood styrene obtained at same time as PRL), subchronic (average air or blood styrene over two or three sessions), and chronic (years of work in industry or facility times average air styrene over all sessions) indices of styrene exposure and serum PRL. Results: Acute blood styrene concentration was the strongest predictor of serum PRL concentration, with the model predicting a 2.06-fold increase in PRL (95% CI 1.11 to 3.84) for every 10-fold increase in blood styrene. Serum PRL tended to increase with increasing styrene exposure in both men and women; however, women tended to have higher PRL levels. For women, the change in blood styrene between sessions 1 and 2 was a significant predictor of the change in serum PRL between sessions. Conclusions: Results confirm that styrene exposure enhances serum PRL concentrations and support an acute effect of styrene on PRL secretion

Temporal association between serum prolactin concentration and exposure to styrene.

BackgroundPrevious studies have suggested that occupational exposure to styrene is associated with increased serum levels of the anterior pituitary hormone prolactin (PRL).AimsTo test the hypotheses that: (1) the effect of styrene exposure on PRL secretion is an acute effect, not a subchronic or chronic effect; (2) blood styrene, as a measure of absorbed dose, is a stronger predictor of serum PRL level than personal breathing zone air styrene concentration.MethodsSubjects were recruited from 17 workplaces in the reinforced plastics industry. Personal breathing zone air styrene, whole blood styrene, and serum PRL were measured during one to three sessions, approximately one year apart. Linear multiple regression was used to model the relations between acute (air styrene or blood styrene obtained at same time as PRL), subchronic (average air or blood styrene over two or three sessions), and chronic (years of work in industry or facility times average air styrene over all sessions) indices of styrene exposure and serum PRL.ResultsAcute blood styrene concentration was the strongest predictor of serum PRL concentration, with the model predicting a 2.06-fold increase in PRL (95% CI 1.11 to 3.84) for every 10-fold increase in blood styrene. Serum PRL tended to increase with increasing styrene exposure in both men and women; however, women tended to have higher PRL levels. For women, the change in blood styrene between sessions 1 and 2 was a significant predictor of the change in serum PRL between sessions.ConclusionsResults confirm that styrene exposure enhances serum PRL concentrations and support an acute effect of styrene on PRL secretion

Predictors of occupational exposure to styrene and styrene‐7,8‐oxide in the reinforced plastics industry

To identify demographic and work related factors that predict blood levels of styrene and styrene‐7,8‐oxide (SO) in the fibreglass reinforced plastics (FRP) industry