George R. Hoffmann

One-to-one coupling of glacial climate variability in Greenland and Antarctica.

Precise knowledge of the phase relationship between climate changes in the two hemispheres is a key for understanding the Earth’s climate dynamics. For the last glacial period, ice core studies have revealed strong coupling of the largest millennial-scale warm events in Antarctica with the longest Dansgaard–Oeschger events in Greenland through the Atlantic meridional overturning circulation. It has been unclear, however, whether the shorter Dansgaard–Oeschger events have counterparts in the shorter and less prominent Antarctic temperature variations, and whether these events are linked by the same mechanism. Here we present a glacial climate record derived from an ice core from Dronning Maud Land, Antarctica, which represents South Atlantic climate at a resolution comparable with the Greenland ice core records. After methane synchronization with an ice core from North Greenland, the oxygen isotope record from the Dronning Maud Land ice core shows a one-to-one coupling between all Antarctic warm events and Greenland Dansgaard–Oeschger events by the bipolar seesaw6. The amplitude of the Antarctic warm events is found to be linearly dependent on the duration of the concurrent stadial in the North, suggesting that they all result from a similar reduction in the meridional overturning circulation.

Validity of the temperature reconstruction from water isotopes in ice cores

Well-documented present-day distributions of stable water isotopes (HDO and H218O) show the existence, in middle and high latitudes, of a linear relationship between the mean annual isotope content of precipitation (δD and δ18O) and the mean annual temperature at the precipitation site. Paleoclimatologists have used this relationship, which is particularly well obeyed over Greenland and Antarctica, to infer paleotemperatures from ice core data. There is, however, growing evidence that spatial and temporal isotope/surface temperature slopes differ, thus complicating the use of stable water isotopes as paleothermometers. In this paper we review empirical estimates of temporal slopes in polar regions and relevant information that can be inferred from isotope models: simple, Rayleigh-type distillation models and (particularly over Greenland) general circulation models (GCMs) fitted with isotope tracer diagnostics. Empirical estimates of temporal slopes appear consistently lower than present-day spatial slopes and are dependent on the timescale considered. This difference is most probably due to changes in the evaporative origins of moisture, changes in the seasonality of the precipitation, changes in the strength of the inversion layer, or some combination of these changes. Isotope models have not yet been used to evaluate the relative influences of these different factors. The apparent disagreement in the temporal and spatial slopes clearly makes calibrating the isotope paleothermometer difficult. Nevertheless, the use of a (calibrated) isotope paleothermometer appears justified; empirical estimates and most (though not all) GCM results support the practice of interpreting ice core isotope records in terms of local temperature changes.

Hormesis predicts low-dose responses better than threshold models.

This study evaluated characteristics of the concentration-response relationships of chemicals from the U.S. National Cancer Institute (NCI) Yeast Anticancer Drug Screen database with respect to the threshold and the hormetic dose-response models. The database reported concentration-response studies of 2189 chemicals from a broad range of chemical classes. The biological end point was growth in 13 strains of yeast (Saccharomyces cerevisiae), most of which contain genetic alterations affecting DNA repair or cell cycle control. The analysis was limited to studies that satisfied a priori entry criteria for evaluation, including having two or more concentrations in the nontoxic zone (below a Benchmark Dose). The mean growth response compared to untreated controls of these doses was significantly greater than 100% in all 13 yeast strains, ranging from ~105% to ~111%. Under a threshold model, one would expect values more closely approximating 100%. Moreover, the distribution of responses below the BMD5 for chemicals was shifted upwardly from the expectations of a threshold model for all strains. These results indicate that for the chemicals and yeast strains studied, the responses are more consistent with a hormetic model than a threshold model, and they strengthen previous results presented by Calabrese et al. (2006, Toxicol. Sci. 94:368–378). Taken together, the analyses provide strong evidence for hormesis, a phenomenon with a broad range of biomedical and toxicological implications.

A PERSPECTIVE ON THE SCIENTIFIC, PHILOSOPHICAL, AND POLICY DIMENSIONS OF HORMESIS

The hormesis concept has broad implications for biology and the biomedical sciences. This perspective on hormesis concentrates on toxicology and toxicological risk assessment and secondarily explores observations from other fields. It considers the varied manifestations of hormesis in the context of a broad family of biological stress responses. Evidence for hormesis is reviewed, and the hormesis model is contrasted with more widely accepted dose-response models in toxicology: a linear nonthreshold (LNT) model for mutagenesis and carcinogenesis, and a threshold model for most other toxicologic effects. Scientific, philosophical, and political objections to the hormesis concept are explored, and complications in the hormesis concept are analyzed. The review concludes with a perspective on the current state of hormesis and challenges that the hormesis model poses for risk assessment.

Hormesis in high-throughput screening of antibacterial compounds in E coli.

This article assesses the response below a toxicological threshold for 1888 antibacterial agents in Escherichia coli, using 11 concentrations with twofold concentration spacing in a high-throughput study. The data set had important strengths such as low variability in the control (2%—3% SD), a repeat measure of all wells, and a built-in replication. Bacterial growth at concentrations below the toxic threshold is significantly greater than that in the controls, consistent with a hormetic concentration response. These findings, along with analyses of published literature and complementary evaluations of concentration-response model predictions of low-concentration effects in yeast, indicate a lack of support for the broadly and historically accepted threshold model for responses to concentrations below the toxic threshold.

Higher frequency of chromosome aberrations in late-arising first-division metaphases than in early-arising metaphases after exposure of human lymphocytes to X-rays in G0.

Purpose : To determine whether metaphases arising at different times after mitogen stimulation of G 0 lymphocytes differ in frequencies of X-ray-induced chromosome aberrations. Materials and methods : Human G 0 lymphocytes from peripheral blood exposed to 0, 1.5 or 3.0 Gy X-rays were stimulated to divide with the mitogen phytohaemagglutinin (PHA). First-division metaphases were distinguished from second and third divisions by chromatid labelling with 5-bromodeoxyuridine (BUdR) and staining with Giemsa or DAPI. Cultures harvested 48, 70 and 94 h after mitogen stimulation were analysed for unstable aberrations on Giemsa-stained slides and for stable and unstable aberrations by fluorescence in situ hybridization (FISH) with painting probes for chromosomes 1, 2 and 4. Results : Frequencies of aberrations declined at the later culture periods, as expected on the basis of unstable aberrations being lost in mitotic division. When scoring was restricted to first-division metaphases, however, aberration frequencies were higher in 94-h cultures than in 48-h cultures. Conclusions : Frequencies of radiation-induced chromosome aberrations in first-division metaphases increase with culture time after mitogen stimulation. Possible explanations for this finding are a delay of damaged cells in mitogenic response or progression through divisions and heterogeneity among lymphocytes in culture kinetics and radiosensitivity. The data argue against the common assumption that all first-division cells are equivalent as indicators of radiation-induced chromosome aberrations.

Analysis by FISH of the spectrum of chromosome aberrations induced by X-rays in G0 human lymphocytes and their fate through mitotic divisions in culture.

The induction, distribution, and persistence of chromosome aberrations in human lymphocytes exposed to X‐rays in G0 were analyzed in 48‐, 70‐, and 94‐hr cultures by conventional metaphase analysis and painting of chromosomes 1, 2, and 4 by FISH. All cells that had been scored by FISH were relocated to determine by differential staining of chromatids whether they had passed through 1, 2, or ≥3 divisions. FISH revealed a dose‐dependent induction of stable and unstable aberrations, while chromatid labeling showed mitotic lag caused by irradiation in G0. Relative to their DNA contents, there was a small but significant overrepresentation of chromosome 4 and underrepresentation of chromosome 2 among the aberrations involving chromosomes 1, 2, and 4. FISH slightly underestimated the genomic frequency of unstable aberrations measured by conventional metaphase analysis. There was a slight excess of translocations relative to dicentrics, but the data are compatible with the 1:1 ratio expected from cytogenetic theory. Many of the translocations were apparently incomplete (i.e., nonreciprocal). Incomplete translocations were more frequent at higher X‐ray dose and in first division, suggesting that they may be associated with complex damage and are more apt to be lost in mitosis than complete translocations. Among the incomplete translocations, t(Ab) outnumbered t(Ba) — a difference ascribable to the FISH technique. Aberration frequencies declined as the cells divided in culture. The overall decline in the frequency of aberrant cells (≈29% per cell generation) reflects a rapid decline in dicentrics and fragments (≈60% per cell generation) and the relative stability of translocations. The frequency of translocation‐bearing cells underwent a modest decline in culture (≈13% per cell generation). Environ. Mol. Mutagen. 33:94–110, 1999

Mutagenicity of acridines in a reversion assay based on tetracycline resistance in plasmid pBR322 in Escherichia coli.

The mutagenicity of a series of acridine compounds was studied in an assay based on the reversion of mutations in the tetracycline-resistance gene (tet) of plasmid pBR322 in Escherichia coli. Mutations that restore the tetracycline-resistant phenotype were detected in tetracycline-sensitive strains carrying mutant plasmids. Mutations that revert by +2, +1, -1 and -2 frameshift mutations and by base-pair substitutions were used to analyze the mutagenicity of two simple acridines, two acridine mustards, and a nitroacridine. The simple acridines (9-aminoacridine and quinacrine) effectively induced -1 frameshifts and weakly induced +1 frameshifts. The acridine mustards (quinacrine mustard and ICR-191) were more potent inducers of -1 and +1 frameshifts than the simple acridines. Reactive acridines, including both the mustards and the nitroacridine Entozon, were effective inducers of -2 frameshifts but the simple acridines were not. The two classes of reactive acridines differed from one another, in that the mustards were better inducers of +1 frameshifts than Entozon, whereas Entozon was a particularly potent inducer of -2 frameshifts. None of the compounds induced +2 frameshifts, and the induction of base-pair substitutions was negligible. These results confirm and extend studies showing that adduct-forming acridines are stronger frameshift mutagens than simple intercalating acridines and that the acridines differ from one another not only in overall mutagenic potency but also in the prevalence of different classes of frameshift mutations.

MODULATION OF BLEOMYCIN-INDUCED MITOTIC RECOMBINATION IN YEAST BY THE AMINOTHIOLS CYSTEAMINE AND WR-1065

The cancer chemotherapy drug bleomycin (BLM) is a potent inducer of genetic damage in a wide variety of assays. The radioprotectors cysteamine (CSM) and WR-1065 have been shown in previous studies to potentiate the induction of micronuclei and chromosome aberrations by BLM in Go human lymphocytes. By contrast, WR-1065 is reported to reduce the induction of hprt mutations by BLM in Chinese hamster cells. To elucidate the basis for these interactions, we examined the effects of CSM and WR-1065 on the induction of mitotic gene conversion by BLM in the yeast Saccharomyces cerevisiae. Treatment with BLM causes a dose-dependent increase in the frequency of mitotic gene conversion and gene mutations. Unlike its potentiation of BLM in G0 lymphocytes, WR-1065 protected against the recombinagenicity of BLM in yeast. CSM was also strongly antirecombinagenic under some conditions., but the nature of the interaction depended strongly on the treatment conditions. Under hypoxic conditions, cysteamine protected against BLM, but under oxygenrich conditions CSM potentiated the genetic activity og BLM. The protective effect of aminothiols against BLM may be ascribed to the depletion of oxygen required for the activation of BLM and the processing of BLM-induced damage. Aminothiols may potentiatc the effect of BLM by acting as an electron source for the activation of BLM and/or by causing conformational alterations that make DNA more accessible tc BLM. The results indicate that aminothiols have a strong modulating influence on the genotoxicity of BLM in yeast as they do in other genetic assays. Moreover, the modulation differs markedly depending on physiological conditions. Thus, yeast assays help to explain why aminothiols have been observed to potentiate BLM in some genetic systems and to protect against it in others.

Potentiation of bleomycin by the aminothiol WR-1065 in assays for chromosomal damage in G0 human lymphocytes

The aminothiol radioprotector WR-1065 potentiates the induction of chromosome aberrations and micronuclei by the chemotherapy drug bleomycin in G(0) human lymphocytes. Potentiation by 5 mM WR-1065 was observed at bleomycin concentrations from 0.1 to 100 micrograms/ml in a 2-h treatment. The frequencies of micronuclei induced by bleomycin in the presence of WR-1065 reached that of 500-fold higher concentrations of bleomycin alone. The potential therapeutic implications of these findings are discussed.