Effects of pollution on human growth and development: an introduction

Pollution is a worldwide problem and its potential to influence the physiology of human populations is great. Studies of human growth and development in relation to pollution have increased in number and quality since the mid-twentieth century. Many studies have found that some pollutants have detrimental effects on human growth, particularly prenatal growth. The heavy metal, lead, is commonly found in human populations and is related to smaller size at birth and studies have reported decrements that range up to about 200 grams. Noise stress from transportation sources also is related to reduced prenatal growth with somewhat smaller decrements reported. Studies of humans exposed to polychlorinated biphenyls, one of the persistent organic pollutants, have reduced size at birth, advanced sexual maturation and altered hormone levels related to thyroid regulation. Thus different pollutants exert effects through different physiological pathways. However, some studies have not observed these effects, which indicates that the situation is complex and requires further study with better study designs. Determining the effects of pollutants on human physiology and growth is difficult as it requires fairly large numbers of subjects who are not purposely exposed but for whom exposure can be measured. These effects of pollutants and the mechanisms of effect require further study to understand and, it is hoped, to blunt or block any detrimental effects on human health and well-being.     

Fluid Flow-induced Soluble Vascular Endothelial Growth Factor Isoforms Regulate Actin Adaptation in Osteoblasts

Although load-induced mechanical signals play a key role in bone formation and maintenance of bone mass and structure, the cellular mechanisms involved in the translation of these signals are still not well understood. Recent identification of a novel flow-induced mechanosignaling pathway involving VEGF in osteoblasts and the known VEGF regulation of actin reorganization in various cell types has led us to hypothesize that fluid shear stress-induced Vegf up-regulation underlies the actin cytoskeleton adaptation observed in osteoblasts during mechanotransduction. Our results show that MC3T3-E1 cells secrete significant VEGF in response to 5 h of pulsatile fluid shear stress (PFSS; 5 dynes/cm² at 1 Hz), whereas expression of VEGF receptors (VEGFR-1, VEGFR-2, or NRP1) is unaffected. These receptors, in particular VEGFR-2, participate in PFSS-induced VEGF release. Exposure to flow-conditioned medium or exogenous VEGF significantly induces stress fiber formation in osteoblasts that is comparable with PFSS-induced stress fiber formation, whereas VEGF knockdown abrogates this response to PFSS, thereby providing evidence that flow-induced VEGF release plays a role in actin polymerization. Using neutralizing antibodies against the receptors and VEGF isoforms, we found that soluble VEGFs, in particular VEGF₁₆₄, play a crucial role in transient stress fiber formation during osteoblast mechanotransduction, most likely through VEGFR-2 and NRP1. Based on these data we conclude that flow-induced VEGF release from osteoblasts regulates osteoblast actin adaptation during mechanotransduction and that VEGF paracrine signaling may provide potent cross-talk among bone cells and endothelial cells that is essential for fracture healing, bone remodeling, and osteogenesis.     

Autoantibodies Against an Extracellular Peptide of the GluR3 Subtype of AMPA Receptors Activate Both Homomeric and Heteromeric AMPA Receptor Channels

Autoantibodies to the GluR3-subtype of AMPA/glutamate receptors are found in the sera and cerebrospinal fluid of some individuals with epilepsy. They could possibly play a role in the pathophysiology of epilepsy since anti-GluR3 sera display glutamatergic agonist activity. We have investigated here the ability of affinity-purified antibodies (Abs) directed against the immunogenic peptide GluR3B (amino-acid 372–395) to interact with and activate recombinant GluR3-receptor channels expressed by Xenopus oocytes. We report here that the affinity-purified anti-GluR3B Abs directly activate GluR3-containing homomeric and heteromeric AMPA receptor complexes without the requirement of neuronal, glial or blood ancillary molecules. We present some of the properties of the purified anti-GluR3B Abs and discuss the possible physiological or pathological consequences of their activation of glutamate receptors.     

Antifouling activity of synthesized peptide analogs of the sponge metabolite barettin

Barettin (cyclo [(6-bromo-8-en-tryptophan) arginine]), a diketopiperazine isolated from the marine sponge Geodia barretti, is a potent inhibitor of barnacle larvae settlement with an EC50-value of 0.9 microM. In the present study, 14 analogs of barettin and its structural congener dipodazine were synthezised and tested for their ability to inhibit larval settlement. Two of the analogs have an intact barettin skeleton. The remaining analogs have a dipodazine skeleton (a diketopiperazine where arginine is replaced with glycine). Six of the tested synthetic analogs displayed significant settlement inhibition with the most potent inhibitor being benzo[g]dipodazine, which displayed even stronger activity than barettin (EC50-value 0.034 microM). The effect of benzo[g]dipodazine was also shown to be readily reversible, when cyprids were transferred to filtered seawater (FSW).     

Towards compendia of negative genetic association studies: an example for Alzheimer disease

Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004–April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) β-amyloid (Aβ) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.     

Connexin43 and pannexin1 channels in osteoblasts: who is the "hemichannel"?

Osteoblasts sense and respond to mechanical stimuli in a process involving influx and release of large ions and signaling molecules. Unapposed gap junction hemichannels formed of connexin43 (Cx43) have been proposed as a major route for such exchange, in particular for release of ATP and prostaglandin E₂ (PGE₂) in osteocytes. However, we have found that Cx43-null osteoblasts have unaltered, mechanically induced PGE₂ release and ATP-induced YoPro dye uptake. In contrast, PGE₂ release in response to fluid shear stress is abolished in P2X₇ receptor (P2X₇R)–null osteoblasts, and ATP-induced dye uptake is attenuated following treatment of wild-type cells with a P2X₇R or Pannexin1 (Panx1) channel blocker. These data indicate that Panx1 channels, in concert with P2X₇R, likely form a molecular complex that performs the hemichannel function in osteoblast mechanosignaling.     

Characteristics of hummocked and non-hummocked Colorado riparian areas and wetlands

Several hummock formation theories exist in the scientific literature, but are rarely mentioned in management publications where only one or two other theories are stressed. Our objectives were to identify and describe the edaphic, climatic, topographic and vegetation characteristics of riparian areas and wetlands in Colorado that do and do not support hummocks, and to classify hummocked sites according to hummock characteristics. 25 natural resource professionals throughout Colorado identified ten sites each that were a mix of hummocked and non-hummocked in proportion to their local abundance, from which 40 hummocked and 40 non-hummocked sites were randomly selected for sampling. Plant functional group canopy cover was determined using Daubenmire cover classes. Soil samples were collected and numerous site characteristics were recorded. Hummock size, shape and density were measured at hummocked sites. Forward model selection and multiple logistic regression were used to determine relationships between site characteristics and odds of hummock occurrence. Mean winter precipitation, mean annual temperature and forb cover were negatively related to odds of hummock occurrence while soil silt content and plant species richness were positively related to odds of hummock occurrence. Cluster analysis resulted in three groups of hummocked sites with differing hummock morphology, vegetation and climatic characteristics. Differential frost heave and plant biomass accumulation were likely involved in hummock formation at sites examined for this study, but conditions expected to occur following cryoexpulsion of clasts were not observed.     

The effect of alternative mating tactics on the fertilization success of a hermaphroditic seabass

In the simultaneously hermaphroditic marine fish, Serranus subligarius, male role individuals are known to pair spawn, group spawn and streak spawn. While the effects of these common mating tactics on mating success in the male role have been well studied, their consequences for the reproductive success of the individuals taking the female role have received little attention. To investigate those consequences, I observed mating behaviors and quantified fertilization success in natural and experimental settings during the summers of 2005-2008 at three sites with different local population densities. I observed focal individuals in 15-min increments and recorded the total number of spawns, number of streak spawns, size of participating spawners, and fertilization rate. The occurrence of small-sized individuals in the local population is associated with higher frequencies of streaking behavior; these small fish are most often first-year individuals reaching sexual maturity late in the spawning season (August/September). Spawns that included one or more streak spawners had a significantly lower average fertilization rate (89?%) than pair spawns without a streak spawner (97?%). This pattern was confirmed with a field manipulation experiment in which spawning events that included streakers again showed lower fertilization rates (93?%) than spawning events that did not include streakers (98?%). These lower fertilization rates occurred despite the fact that spawns that included multiple males produced, on average, 20?% more sperm than produced in spawns with only a single male. These results indicate that females incur a significant fitness cost when streakers invade a spawning event, a cost not attributable to sperm limitation or any direct effects on the female.     

Lipid environment modulates the development of acute tolerance to ethanol in Caenorhabditis elegans

The development of tolerance to a drug at the level of the neuron reflects a homeostatic mechanism by which neurons respond to perturbations of their function by external stimuli. Acute functional tolerance (AFT) to ethanol is a fast compensatory response that develops within a single drug session and normalizes neuronal function despite the continued presence of the drug. We performed a genetic screen to identify genes required for the development of acute functional tolerance to ethanol in the nematode C. elegans. We identified mutations affecting multiple genes in a genetic pathway known to regulate levels of triacylglycerols (TAGs) via the lipase LIPS-7, indicating that there is an important role for TAGs in the development of tolerance. Genetic manipulation of lips-7 expression, up or down, produced opposing effects on ethanol sensitivity and on the rate of development of AFT. Further, decreasing cholesterol levels through environmental manipulation mirrored the effects of decreased TAG levels. Finally, we found that genetic alterations in the levels of the TAG lipase LIPS-7 can modify the phenotype of gain-of-function mutations in the ethanol-inducible ion channel SLO-1, the voltage- and calcium-sensitive BK channel. This study demonstrates that the lipid milieu modulates neuronal responses to ethanol that include initial sensitivity and the development of acute tolerance. These results lend new insight into studies of alcohol dependence, and suggest a model in which TAG levels are important for the development of AFT through alterations of the action of ethanol on membrane proteins.     

Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR)?=?1.03, 95% CI 1.00-1.06, p?=?0.023). There was evidence for heterogeneity in the ORs among studies (I(2)?=?49.3%; p?=?<0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR?=?0.89, 95%CI 0.80-1.00, p?=?0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.