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Background: An increased risk of lung cancers among asphalt workers has been suggested in epidemiological studies based on large scale statistical analyses., Methods: In a multi-country study of 29,820 male workers employed in road paving, asphalt mixing and roofing, 32,245 ground and building construction workers and 17,757 other workers from Denmark, Finland, France, Germany, Israel, the Netherlands, Norway, and Sweden, with mortality that was documented from 1953-2000. Exposures to bitumen fume, coal tar, 4-6 ring polycyclic aromatic hydrocarbons, organic vapor, diesel exhaust, asbestos, and silica dust were assessed via a job-exposure matrix. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) based on national mortality rates, as well as relative risks (RRs) based on Poisson regression models were calculated., Results: The SMR of lung cancer among workers exposed to bitumen fume (1.08, 95% CI 0.99-1.18) was comparable to that of non-exposed workers (SMR 1.05, 95% CI 0.92-1.19). In a sub-cohort of bitumen-exposed workers without exposure to coal tar, the SMR of lung cancer was 1.23 (95% CI 1.02-1.48). The analysis based on the semi-quantitative, matrix-based exposures in the whole cohort did not suggest an increased lung cancer risk following exposure to bitumen fume. However, in an analysis restricted to road pavers, based on quantitative estimate of bitumen fume exposure, a dose-response was suggested for average level of exposure, applying a 15-year lag, which was marginally reduced after adjustment for co-exposure to coal tar. The results for cancer of the head and neck were similar to those of lung cancer, although they were based on a smaller number of deaths. There was no clear suggestion of an association with bitumen fume for any other neoplasm., Conclusions: The results of the analysis by bitumen fume exposure do not allow us to conclude on the presence or absence of a causal link between exposure to bitumen fume and risk of cancer of the lung and the head and neck., (Copyright 2003 Wiley-Liss, Inc.)

An international cohort of asphalt workers was assembled to study cancer risk after bitumen exposure. This article describes the combination of the exposure assessment with the exposure-response for a quantitative risk assessment for lung cancer mortality within the Dutch component of the study. We identified a retrospective cohort of 3,709 workers with at least one season of employment. Semi-quantitative exposure to bitumen fume was estimated by a job-exposure matrix. Exposure-response relations were fitted by Poisson regression, and excess lifetime risks through age 75 were calculated by a life table method. Working lifetime cumulative exposure to bitumen fume was calculated under different scenarios, representing past and future exposures. For workers with exposures accumulated in the past, excess risks for lung cancer varied from 7.8 to 14.3%. Calculations for future exposures resulted in considerably lower excess risks ranging from 0.6 to 2.6%. The calculated excess risks for lung cancer mortality after working lifetime exposure to bitumen fume depend strongly on when exposure was experienced and to some extent on the exposure-response model chosen, while confounding by smoking cannot be ruled out. Nevertheless, the excess lifetime risk for lung cancer in this Dutch cohort of asphalt workers is above benchmark risks as applied by the Dutch Health Council. Current exposure levels have decreased this risk considerably, but further exposure control may be required.

Otx2, a vertebrate homologue of the Drosophila orthodenticle gene, coordinates two processes in early embryonic development. Not only does it specify cell fate in the anterior regions of the embryo, it also prevents the cells that express it from participating in the convergence extension movements that shape the rest of the body axis. Here we show that, in Xenopus, this latter function is mediated by XclpH3, transcription of which is directly stimulated by Xotx2. XclpH3 is a Xenopus homologue of the mammalian calponin gene, the product of which binds both actin and myosin and prevents the generation of contractile force by actin filaments.

Inductive interactions between different cell layers have an extremely important role in early embryogenesis. One of the most intensively studied and best characterised of these is the induction of neural tissue from ectodermal cells by the dorsal mesoderm. The competence of ectodermal cells to respond to neural induction varies according to dorsal-ventral position; with dorsal ectoderm (much of which forms the neural plate) having a far higher competence. Here we show that overexpression of the nucleotide exchange factor lfc increases ectodermal competence for neural induction as well as the amount of neural tissue in the whole embryo. Lfc is expressed pan ectodermally soon after gastrulation and may respond to an early determinant of dorsal ectoderm.

We have characterised a short (30 base pair) element from the Xenopus Wnt-5a promoter which is nearly identical to one located in the human Wnt-5a promoter, and has the same position relative to the transcription start site. When placed in front of a LacZ gene, this element can reproduce the same expression pattern observed for Wnt-5a at the late gastrula stage. Further we show that gastrula stage Wnt-5a expression is repressed by otx2, something which is reflected by the mutually exclusive expression patterns of these two genes. The isolated promoter sequence contains an OTX- consensus binding site and its' activity in embryos is repressed by ectopically expressed otx2.

Understanding why metazoan Hox/HOM-C genes are expressed in spatiotemporal sequences showing colinearity with their genomic sequence is a central challenge in developmental biology. Here, we studied the consequences of ectopically expressing Hox genes to investigate whether Hox-Hox interactions might help to order gene expression during very early vertebrate embryogenesis. Our study revealed conserved autoregulatory loops for the Hox4 and Hox7 paralogue groups, detected following ectopic expression Hoxb-4 or HOXD4, and Hoxa-7, respectively. We also detected specific induction of 5' posterior Hox genes; Hoxb-5 to Hoxb-9, following ectopic expression of Hoxb-4/HOXD4; Hoxb-8 and Hoxb-9 following ectopic expression of Hoxa-7. Additionally, we observed specific repression of 3' anterior genes, following ectopic expression of Hox4 and Hox7 paralogues. We found that induction of Hoxb-4 and Hoxb-5 by Hoxb-4 can be direct, whereas induction of Hoxb-7 is indirect, suggesting the possibility of an activating cascade. Finally, we found that activation of Hoxb-4 itself and of posterior Hox genes by Hoxb-4 can be both non-cell-autonomous, as well as direct. We believe that our findings could be important for understanding how a highly ordered Hox expression sequence is set up in the early vertebrate embryo.

Several cohort studies of herbicide manufacturing workers have been conducted over the last years. Most of these studies used simple proxies of exposure in the analysis such as a crude grouping in exposure categories based on job titles, presence in certain production areas over a period of time or during an accident, and duration of exposure. Current serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) levels available for a subset of workers can be used to back-extrapolate TCDD levels at the end of exposure using first order kinetic models, and relate TCDD levels to job history using regression models. The regression model obtained can be used to estimate TCDD levels for all cohort members. In this paper, the effect of changes in model assumptions on estimated TCDD levels is explored. TCDD levels are back-extrapolated assuming different values for TCDD half-life. A range of regression models with different sets of exposure determinants is used to relate back-extrapolated TCDD levels to determinants of exposure. These models were used to predict TCDD levels in the epidemiological analysis of data from a Dutch cohort study. The results show that the predicted serum TCDD level is strongly dependent on the assumed half-life. However, the ranking of all individuals on the exposure axis (from low to high) is not affected by changes in the half-life. Predicted serum TCDD levels seem not sensitive to changes in assumption regarding TCDD half-life. Predicted TCDD levels were positively associated with increased (cause specific) mortality.

A retrospective cohort study of workers exposed to phenoxy herbicides, chlorophenols, and contaminants (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other polychlorinated dioxins and furans) has been conducted in a chemical factory in the Netherlands. Male workers exposed to phenoxy herbicides or chlorophenols showed increased relative risks (adjusted for age, calendar period at end of follow-up, and time since first exposure/employment) for total mortality (relative risk (RR)=1.8, 95% confidence interval (CI) 1.2-2.5), cancer mortality (RR=4.1, 95% CI 1.8-9.0), respiratory cancer (RR=7.5, 95% CI 1.0-56.1), non-Hodgkin's lymphoma (RR=1.7, 95% CI 0.2-16.5), and ischemic heart diseases (RR=1.8, 95% CI 0.9-3.6) compared with an internal referent group of nonexposed workers. By using TCDD levels (predicted at the time of maximum exposure), based on extrapolated TCDD levels that were measured in a subset of the cohort, estimated relative risks for workers with medium and high TCDD levels were comparable with risks derived from the simple and earlier applied dichotomous exposure classification. In general, relative risks were highest in the highest category, indicating exposure-related increases in risk with TCDD level. In conclusion, results of this cohort study support the evidence of a high cancer risk in workers exposed to phenoxy herbicides, chlorophenols, and contaminants.

The muscle-myosin heavy-chain (mMHC) gene of Drosophila hydei has been sequenced completely (size 23.3 kb). The sequence comparison with the D. melanogaster mMHC gene revealed that the exon-intron pattern is identical. The protein coding regions show a high degree of conservation (97%). The alternatively spliced exons (3a-b, 7a-d, 9a-c, 11a-e, and 15a-b) display more variations in the number of nonsynonymous and synonymous substitutions than the common exons (2, 4, 5, 6, 8, 10, 12, 13, 14, 16, 17, and 19). The base composition at synonymous sites of fourfold degenerate codons (third position) is not biased in the alternative exons. In the common exons there exists a bias for C and against A. These findings imply that the alternative exons of the Drosophila mMHC gene evolve at a different, in several cases higher, rate than the common ones. The 5' splice junctions and 5' and 3' untranslated regions show a high level of similarity, indicating a functional constraint on these sequences. The intron regions vary considerably in length within one species, but the corresponding introns are very similar in length between the two species and all contain stretches of sequence similarity. A particular example is the first intron, which contains multiple regions of similarity. In the conserved regions of intron 12 (head-tail border) sequences were found which have the potential to direct another smaller mMHC transcript.

The outgrowth of corticospinal tract axons in rat spinal cord primarily occurs during the first postnatal week. Axons originating from a group of layer V pyramidal cell bodies situated in the anterior part of the cerebral sensorimotor cortex project mainly to the cervical gray matter (Joosten et al., Dev. Brain Res., 36 (1987) 121-130). By co-culturing explants of the anterior part of the sensorimotor cortex and of cervical spinal gray matter in 3-D collagen gels, a target-specific directional growth of cortical axons towards the cervical spinal gray explant could be demonstrated. After retrograde filling with the fluorescent tracer 1,1-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI), in vivo as well as in vitro, most of the DiI-labelled cortical neurons were located in layer V of the cortical explant, and were characterized by a pyramidal shape. These data suggest that the cervical spinal gray matter target area becomes innervated by corticospinal axons through the release of a diffusible chemotropic factor.