Thyroid-Hormone–Disrupting Chemicals: Evidence for Dose-Dependent Additivity or Synergism

Endocrine disruption from environmental contaminants has been linked to a broad spectrum of adverse outcomes. One concern about endocrine-disrupting xenobiotics is the potential for additive or synergistic (i.e., greater-than-additive) effects of mixtures. A short-term dosing model to examine the effects of environmental mixtures on thyroid homeostasis has been developed. Prototypic thyroid-disrupting chemicals (TDCs) such as dioxins, polychlorinated biphenyls (PCBs), and poly-brominated diphenyl ethers have been shown to alter thyroid hormone homeostasis in this model primarily by up-regulating hepatic catabolism of thyroid hormones via at least two mechanisms. Our present effort tested the hypothesis that a mixture of TDCs will affect serum total thyroxine (T(4)) concentrations in a dose-additive manner. Young female Long-Evans rats were dosed via gavage with 18 different polyyhalogenated aromatic hydrocarbons [2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin-like PCBs] for 4 consecutive days. Serum total T(4) was measured via radioimmunoassay in samples collected 24 hr after the last dose. Extensive dose–response functions (based on seven to nine doses per chemical) were determined for individual chemicals. A mixture was custom synthesized with the ratio of chemicals based on environmental concentrations. Serial dilutions of this mixture ranged from approximately background levels to 100-fold greater than background human daily intakes. Six serial dilutions of the mixture were tested in the same 4-day assay. Doses of individual chemicals that were associated with a 30% TH decrease from control (ED(30)), as well as predicted mixture outcomes were calculated using a flexible single-chemical-required method applicable to chemicals with differing dose thresholds and maximum-effect asymptotes. The single-chemical data were modeled without and with the mixture data to determine, respectively, the expected mixture response (the additivity model) and the experimentally observed mixture response (the empirical model). A likelihood-ratio test revealed statistically significant departure from dose additivity. There was no deviation from additivity at the lowest doses of the mixture, but there was a greater-than-additive effect at the three highest mixtures doses. At high doses the additivity model underpredicted the empirical effects by 2- to 3-fold. These are the first results to suggest dose-dependent additivity and synergism in TDCs that may act via different mechanisms in a complex mixture. The results imply that cumulative risk approaches be considered when assessing the risk of exposure to chemical mixtures that contain TDCs

National Network of Depression Centers\u27 Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications

The human DEK oncogene regulates DNA damage response signaling and repair

The human DEK gene is frequently overexpressed and sometimes amplified in human cancer. Consistent with oncogenic functions, Dek knockout mice are partially resistant to chemically induced papilloma formation. Additionally, DEK knockdown in vitro sensitizes cancer cells to DNA damaging agents and induces cell death via p53-dependent and -independent mechanisms. Here we report that DEK is important for DNA double-strand break repair. DEK depletion in human cancer cell lines and xenografts was sufficient to induce a DNA damage response as assessed by detection of γH2AX and FANCD2. Phosphorylation of H2AX was accompanied by contrasting activation and suppression, respectively, of the ATM and DNA-PK pathways. Similar DNA damage responses were observed in primary Dek knockout mouse embryonic fibroblasts (MEFs), along with increased levels of DNA damage and exaggerated induction of senescence in response to genotoxic stress. Importantly, Dek knockout MEFs exhibited distinct defects in non-homologous end joining (NHEJ) when compared to their wild-type counterparts. Taken together, the data demonstrate new molecular links between DEK and DNA damage response signaling pathways, and suggest that DEK contributes to DNA repair

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Genome-wide analysis of re-replication initiation and elongation in Saccharomyces cerevisiae

To maintain genomic stability, re-initiation of eukaryotic DNA replication within a single cell cycle is blocked by multiple mechanisms that inactivate or remove replication proteins after G1 phase. Our lab had previously shown that simultaneous deregulation of three replication proteins, ORC, Cdc6 and Mcm2-7, was necessary to cause detectable bulk re-replication in G2/M phase in Saccharomyces cerevisiae. We used microarray comparative genomic hybridization (CGH) to provide a more comprehensive and detailed analysis of re-replication. This genome-wide analysis suggests that re-initiation in G2/M phase primarily occurs at a subset of both active and latent origins, but is independent of chromosomal determinants that specify the timing of origins in S phase. We demonstrate that re-replication can be induced within S phase, but differs in amount and location from re-replication in G2/M phase, illustrating the dynamic nature of DNA replication controls. Finally, we re-examined the issue of mechanistic redundancy and showed that very limited re-replication can be detected by microarray CGH when only two replication proteins are deregulated demonstrating that the mechanisms blocking re-replication are overlapping rather than redundant.Deregulation of these mechanisms leads to incomplete re-replication of the genome and has been shown to cause DNA damage checkpoint activation and double strand breaks. To understand the link between re-replication and DNA damage I performed a genome-wide kinetic analysis of fork progression using microarray CGH. I determined that fork progression was severely impaired during re-replication. During re-replication forks progressed at least five-fold slower than S phase forks and failed to complete duplication of the chromosomes. In addition, analysis of the progression of existing forks suggested that the forks were stalled or collapsed. I next investigated the potential source of this impairment and determined that impaired fork progression was not due to insufficient nucleotides. I also provided evidence that fork progression was impaired even when fork head-to-tail collisions due to multiple rounds of reinitiation were prevented. Thus this impairment is likely occurring at individual forks and is consistent with a model in which replication fork failure during re-replication leads to DNA lesions

Proportions of movements of anglers, ranging from 1x to 10x, among study area watersheds in the study year.

Lines showing the network of linkages among the 66 watersheds (HUC4 Hydrologic Units) that comprise the 12 US states surrounding the Great Lakes and upper Mississippi River basins. Lines between watersheds represent direct connections made by individual anglers fishing in multiple watersheds in the survey year. The multiple direct connections among watersheds demonstrate the potential for introduction and inter-basin spread of aquatic invasive species by anglers along linked pathways. Connecting lines represent the unweighted numbers of anglers among the 2576 survey participants who connected separate watersheds in a single year. Unweighted values, ranging from 1–10, represent proportions of the millions of licensed anglers in the study area. (TIF)</p

Proportions of movements of anglers, ranging from 201x to 300x, among study area watersheds in the study year.

Lines showing the network of linkages among the 66 watersheds (HUC4 Hydrologic Units) that comprise the 12 US states surrounding the Great Lakes and upper Mississippi River basins. Lines between watersheds represent direct connections made by individual anglers fishing in multiple watersheds in the survey year. The multiple direct connections among watersheds demonstrate the potential for introduction and inter-basin spread of aquatic invasive species by anglers along linked pathways. Connecting lines represent the unweighted numbers of anglers among the 2576 survey participants who connected separate watersheds in a single year. Unweighted values, ranging from 201–300, represent proportions of the millions of licensed anglers in the study area; these three major linkages all connect watersheds to large metropolitan centers. (TIF)</p

Movements of anglers among study area counties with >10,000 linkages in the study year.

Connections and estimated magnitudes of movements of anglers among counties in the 13 US states surrounding the Great Lakes and upper Mississippi River basins. The estimated 14,766 links among counties in a single year demonstrate the likelihood of spread by anglers and the potential pathways of transfer of aquatic invasive species. Double-yellow lines represent annual connections between counties numbering from 10,017–15,000, and double-red lines range from 9001–10000 angler trips between counties in a single year. (TIF)</p

Proportions of movements of anglers, ranging from 51x to 100x, among study area watersheds in the study year.

Lines showing the network of linkages among the 66 watersheds (HUC4 Hydrologic Units) that comprise the 12 US states surrounding the Great Lakes and upper Mississippi River basins. Lines between watersheds represent direct connections made by individual anglers fishing in multiple watersheds in the survey year. The multiple direct connections among watersheds demonstrate the potential for introduction and inter-basin spread of aquatic invasive species by anglers along linked pathways. Connecting lines represent the unweighted numbers of anglers among the 2576 survey participants who connected separate watersheds in a single year. Unweighted values, ranging from 51–100, represent proportions of the millions of licensed anglers in the study area. (TIF)</p

Weighted sum of all fishing trips by anglers in the broader Great Lakes region in a single year to counties in 12 US states surrounding the Great Lakes and upper Mississippi River basins.

The estimated numbers of fishing trips with destinations to each of the 1042 individual counties ranged from 1199 (blue), to more than1.95 million (red) in the single year of 2011. Only 148 of the 1042 counties in the study area were not reported as fishing destinations (white).</p