The transcriptional co-repressor SEED DORMANCY 4-LIKE (AtSDR4L) promotes the embryonic-to-vegetative transition in Arabidopsis thaliana.

Repression of embryonic traits during the seed-to-seedling phase transition requires the inactivation of master transcription factors associated with embryogenesis. How the timing of such inactivation is controlled is unclear. Here, we report on a novel transcriptional co-repressor, Arabidopsis thaliana SDR4L, that forms a feedback inhibition loop with the master transcription factors LEC1 and ABI3 to repress embryonic traits post-imbibition. LEC1 and ABI3 regulate their own expression by inducing AtSDR4L during mid to late embryogenesis. AtSDR4L binds to sites upstream of LEC1 and ABI4, and these transcripts are upregulated in Atsdr4l seedlings. Atsdr4l seedlings phenocopy a LEC1 overexpressor. The embryonic traits of Atsdr4l can be partially rescued by impairing LEC1 or ABI3. The penetrance and expressivity of the Atsdr4l phenotypes depend on both developmental and external cues, demonstrating the importance of AtSDR4L in seedling establishment under suboptimal conditions.

Arabidopsis thaliana SEED DORMANCY 4-LIKE regulates dormancy and germination by mediating the gibberellin pathway.

The molecular mechanisms underlying seed dormancy and germination are not fully understood. Here, we show that Arabidopsis thaliana SEED DORMANCY 4-LIKE (AtSdr4L) is a novel specific regulator of dormancy and germination. AtSdr4L encodes a protein with an unknown biochemical function that is localized in the nucleus and is expressed specifically in seeds. Loss of function of AtSdr4L results in increased seed dormancy. The germination of freshly harvested seeds of the Atsdr4l mutant is insensitive to gibberellin (GA). After-ripened mutant seeds are hypersensitive to the GA biosynthesis-inhibitor paclobutrazol but show unaltered sensitivity to abscisic acid. Several GA biosynthesis genes and GA-regulated cell wall remodeling genes are down-regulated in the mutant in both dormant and after-ripened seeds. These results suggest that the Atsdr4l mutation causes both decreased GA biosynthesis and reduced responses. In addition, a genetic analysis indicated that AtSdr4L is epistatic to DELAY OF GERMINATION1 (DOG1) for dormancy and acts upstream of RGA-LIKE 2 (RGL2) in the GA pathway. We propose that AtSdr4L regulates seed dormancy and germination by mediating both the DOG1 and GA pathways.

A quantitative comparison of points of departure between 28-day and 90-day repeated dose studies with a proposed extrapolation factor.

The influence of exposure duration on chemical toxicity has important implications for risk assessment. Although a default 10-fold extrapolation factor is commonly applied when the toxicological dataset includes a subchronic (90-day) study but lacks studies of chronic duration, little consensus has been reached on an appropriate extrapolation factor to apply when the dataset includes a 28-day study but lacks studies of longer durations. The goal of the present assessment was to identify a 28-day to 90-day extrapolation factor by analyzing distributions of ratios of No-Observed-Adverse-Effect Levels (NOAELs) and Benchmark Doses (BMDs) derived from 28-day and 90-day studies. The results of this analysis suggest that a default 10-fold extrapolation factor in chemical risk assessment applications is sufficient to account for the uncertainty associated with evaluating human health risk based on results from a 28-day study in the absence of results from a 90-day study. This analysis adds significantly to the growing body of literature interpreting the influence of exposure duration on chemical toxicity that will likewise facilitate discussions on the future state of testing requirements in the international regulatory community.

Approaches to advancing quantitative human health risk assessment of environmental chemicals in the post-genomic era.

The contribution of genomics and associated technologies to human health risk assessment for environmental chemicals has focused largely on elucidating mechanisms of toxicity, as discussed in other articles in this issue. However, there is interest in moving beyond hazard characterization to making more direct impacts on quantitative risk assessment (QRA)--i.e., the determination of toxicity values for setting exposure standards and cleanup values. We propose that the evolution of QRA of environmental chemicals in the post-genomic era will involve three, somewhat overlapping phases in which different types of approaches begin to mature. The initial focus (in Phase I) has been and continues to be on "augmentation" of weight of evidence--using genomic and related technologies qualitatively to increase the confidence in and scientific basis of the results of QRA. Efforts aimed towards "integration" of these data with traditional animal-based approaches, in particular quantitative predictors, or surrogates, for the in vivo toxicity data to which they have been anchored are just beginning to be explored now (in Phase II). In parallel, there is a recognized need for "expansion" of the use of established biomarkers of susceptibility or risk of human diseases and disorders for QRA, particularly for addressing the issues of cumulative assessment and population risk. Ultimately (in Phase III), substantial further advances could be realized by the development of novel molecular and pathway-based biomarkers and statistical and in silico models that build on anticipated progress in understanding the pathways of human diseases and disorders. Such efforts would facilitate a gradual "reorientation" of QRA towards approaches that more directly link environmental exposures to human outcomes.

Lead, mercury, and cadmium exposure and attention deficit hyperactivity disorder in children.

BACKGROUND: There is limited research examining the relationship between lead (Pb) exposure and medically diagnosed attention deficit hyperactivity disorder (ADHD) in children. The role of mercury (Hg) and cadmium (Cd) exposures in ADHD development is even less clear. OBJECTIVES: To examine the relationship between Pb, Hg, and Cd and ADHD in children living inside and outside a Lead Investigation Area (LIA) of a former lead refinery in Omaha, NE. METHODS: We carried out a case-control study with 71 currently medically diagnosed ADHD cases and 58 controls from a psychiatric clinic and a pediatric clinic inside and outside of the LIA. The participants were matched on age group (5-8, 9-12 years), sex, race (African American or Caucasians and others), and location (inside or outside LIA). We measured whole blood Pb, total Hg, and Cd using inductively coupled plasma mass spectrometry. RESULTS: Inside the LIA, the 27 cases had blood Pb geometric mean (GM) 1.89 µg/dL and the 41 controls had 1.51 µg/dL. Outside the LIA, the 44 cases had blood Pb GM 1.02 µg/dL while the 17 controls had 0.97 µg/dL. After adjustment for matching variables and maternal smoking, socioeconomic status, and environmental tobacco exposure, each natural log unit blood Pb had an odds ratio of 2.52 with 95% confidence interval of 1.07-5.92. Stratification by the LIA indicated similar point estimate but wider CIs. No associations were observed for Hg or Cd. CONCLUSIONS: Postnatal Pb exposure may be associated with higher risk of clinical ADHD, but not the postnatal exposure to Hg or Cd.

Evaluation of ATSDR's MRL and EPA's RfCs/RfDs: Similarities, Differences, and Rationales.

Objectives: The Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA) derive minimal risk levels (MRLs) and reference concentrations and doses (RfCs and RfDs), respectively, for environmental contaminants to help identify potential health risks to exposed populations. MRLs, RfDs, and RfCs involve similar derivation methods, but the values sometimes differ for the same chemical. The objectives of this manuscript are to quantitatively assess similarities and differences between MRLs, RfCs, and RfDs, qualitatively describe how a number of factors can influence the development of the health guidance values (HGVs) and identify ongoing collaborations and opportunities for increased coordination of efforts. Materials and Methods: We collected MRLs and RfCs/RfDs, assessment date, and description of the derivation process from ATSDR's toxicological profiles and EPA's Integrated Risk Information System (IRIS) and Office of Pesticide Program (OPP) and identified reasons for differences between MRLs and RfCs/RfDs. Results: The most frequent types of differences in values that we found in our analysis included use of different methodologies, use of different studies, and/or completion of a more recent chemical evaluation. These can stem from differences in scientific judgement. Conclusion: To avoid confusion when disparate HGVs occur between government agencies, a keen understanding of these differences can be helpful for appropriate risk characterization and communication when applying HGVs.

Flame retardant tris(1,3-dichloro-2-propyl)phosphate (TDCPP) toxicity is attenuated by N-acetylcysteine in human kidney cells.

Prolonged exposure to the flame retardants found in many household products and building materials is associated with adverse developmental, reproductive, and carcinogenic consequences. While these compounds have been studied in numerous epidemiological and animal models, less is known about the effects of flame retardant exposure on cell function. This study evaluated the toxicity of the commonly used fire retardant tris(1,3-dichloro-2-propyl)phosphate (TDCPP) in cell line derived from the kidney, a major tissue target of organohalogen toxicity. TDCPP inhibited cell growth at lower concentrations (IC50 27 µM), while cell viability and toxicity were affected at higher concentrations (IC50 171 µM and 168 µM, respectively). TDCPP inhibited protein synthesis and caused cell cycle arrest, but only at higher concentrations. Additionally, the antioxidant N-acetylcysteine (NAC) reduced cell toxicity in cells treated with TDCPP, suggesting that exposure to TDCPP increased oxidative stress in the cells. In summary, these data show that low concentrations of TDCPP result in cytostasis in a kidney cell line, whereas higher concentrations induce cell toxicity. Furthermore, TDCPP toxicity can be attenuated by NAC, suggesting that antioxidants may be effective countermeasures to some organohalogen exposures.

Assessment of the potential health risks associated with the aluminium, arsenic, cadmium and lead content in selected fruits and vegetables grown in Jamaica.

Thirteen Jamaican-grown food crops - ackee (Blighia sapida), banana (Musa acuminate), cabbage (Brassica oleracea), carrot (Daucus carota), cassava (Manihot esculenta), coco (Xanthosoma sagittifolium), dasheen (Colocasia esculenta), Irish potato (Solanum tuberosum), pumpkin (Cucurbita pepo), sweet pepper (Capsicum annuum), sweet potato (Ipomoea batatas), tomato (Solanum lycopersicum) and turnip (Brassica rapa) - were analysed for aluminium, arsenic, cadmium and lead by atomic absorption spectrophotometry and instrumental neutron activation analysis. The fresh weight mean concentrations in these food crops (4.25-93.12 mg/kg for aluminium; 0.001-0.104 mg/kg for arsenic; 0.015-0.420 mg/kg for cadmium; 0.003-0.100 mg/kg for lead) were used to calculate the estimated daily intake (EDI), target hazard quotient (THQ), hazard index (HI) and target cancer risk (TCR) for arsenic, associated with dietary exposure to these potentially toxic elements. Each food type had a THQ and HI < 1 indicating no undue non-carcinogenic risk from exposure to a single or multiple potentially toxic elements from the same food. The TCR for arsenic in these foods were all below 1 × 10-4, the upper limit used for acceptable cancer risk. There is no significant health risk to the consumer associated with the consumption of these Jamaican-grown food crops.

Serum concentrations of polychlorinated biphenyls (PCBs) in participants of the Anniston Community Health Survey.

Serum concentrations of 35 ortho-substituted polychlorinated biphenyl congeners (PCBs) were measured in 765 adults from Anniston, Alabama, where PCBs were manufactured between 1929 and 1971. As part of the Anniston Community Health Survey (ACHS), demographic data, questionnaire information, and blood samples were collected from participants in 2005-2007. Forty-six percent of study participants were African-American, 70% were female, and the median age was 56 years. The median concentration of the sum of 35 PCB congeners (ΣPCBs) was 528 ng/g lipid, with a 90th percentile of 2,600 ng/g lipid, minimum of 17.0 ng/g lipid, and maximum of 27,337 ng/g lipid. The least square geometric mean ΣPCBs was more than 2.5 times higher for African-American participants than for White participants (866 ng/g lipid vs. 331 ng/g lipid); this difference did not change materially after adjustment for age, sex, body mass index (BMI) and current smoking. In spite of large differences in absolute PCB levels, relative contributions of individual congeners to ΣPCBs were quite similar between race groups. Nevertheless, while percent contributions to ΣPCBs for most of the most abundant penta- to heptachlorobiphenyls were higher among African-Americans, the percentages were higher in Whites for the lower-chlorinated PCBs 28 and 74 and for octa- to decachlorinated PCBs. No major differences were observed in geometric mean ΣPCBs between women and men when adjusted for age, race, BMI and current smoking (516 ng/g lipid vs. 526 ng/g lipid). Principal component analysis revealed groups of co-varying congeners that appear to be determined by chlorine substitution patterns. These congener groupings were similar between ACHS participants and the National Health and Nutrition Examination Survey (NHANES) 2003-04 sample of the general United States population, despite ACHS participants having serum concentrations of ΣPCBs two to three times higher than those in comparable age and race groups from NHANES.

MRNA and miRNA expression patterns associated to pathways linked to metal mixture health effects.

Metals are a threat to human health by increasing disease risk. Experimental data have linked altered miRNA expression with exposure to some metals. MiRNAs comprise a large family of non-coding single-stranded molecules that primarily function to negatively regulate gene expression post-transcriptionally. Although several human populations are exposed to low concentrations of As, Cd and Pb as a mixture, most toxicology research focuses on the individual effects that these metals exert. Thus, this study aims to evaluate global miRNA and mRNA expression changes induced by a metal mixture containing NaAsO2, CdCl2, Pb(C2H3O2)2·3H2O and to predict possible metal-associated disease development under these conditions. Our results show that this metal mixture results in a miRNA expression profile that may be responsible for the mRNA expression changes observed under experimental conditions in which coding proteins are involved in cellular processes, including cell death, growth and proliferation related to the metal-associated inflammatory response and cancer.

Taiwan food scandal: the illegal use of phthalates as a clouding agent and their contribution to maternal exposure.

In 2011 the Taiwan Food and Drug Administration reported that plasticizers di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP), endocrine disruptors, were illegally added to clouding agents used in foods and beverages. 965 products were found contaminated, of which 206 were exported to 22 countries. This study's purpose was to obtain English names for 28 contaminated products for which DEHP levels were reported, calculate estimated average daily intake (mg/kg/day) for a 50 kg woman consuming one portion, and compare to U.S. and E.U. guidelines for daily intake. We found that drinking just one bottle (500 ml) of sports drinks would result in an average DEHP intake of 0.14 mg/kg bw/day (range 0.091-0.341), which exceeds by several fold government guidelines (0.02-0.06 mg/kg bw/day). One (2 g) serving from 4/14 samples of contaminated dietary supplements exceeds the guideline of 0.02 mg/kg bw/day. In conclusion, consuming even one portion of tainted drinks and some powders would lead to daily intake of DEHP that greatly exceeds established safety guidelines, raising concerns about potential adverse effects, particularly reproductive tract development in the male fetus. Global distribution of DEHP-contaminated and other adulterated products should prompt governments to become proactive in food safety regulations and chemical testing.