Temperature-Dependence of Lipid A Acyl Structure in Psychrobacter cryohalolentis and Arctic Isolates of Colwellia hornerae and Colwellia piezophila.

Lipid A is a fundamental Gram-negative outer membrane component and the essential element of lipopolysaccharide (endotoxin), a potent immunostimulatory molecule. This work describes the metabolic adaptation of the lipid A acyl structure by Psychrobacter cryohalolentis at various temperatures in its facultative psychrophilic growth range, as characterized by MALDI-TOF MS and FAME GC-MS. It also presents the first elucidation of lipid A structure from the Colwellia genus, describing lipid A from strains of Colwellia hornerae and Colwellia piezophila, which were isolated as primary cultures from Arctic fast sea ice and identified by 16S rDNA sequencing.

Object discrimination and reversal learning in infant and juvenile non-human primates in a non-clinical laboratory.

Background: Biopharmaceutical development necessitates use of non-human primates in toxicology, leading to adoption of non-traditional methods including cognitive function assessment.

Methods: A two-object discrimination and reversal test in cynomolgus monkeys (Macaca fascicularis) was performed using a Wisconsin General Testing Apparatus (WGTA). Non-clinical study design and regulatory considerations dictate that infants are raised by their biological mothers until weaning at 6 months.

Developmental and reproductive outcomes in humans and animals after glyphosate exposure: a critical analysis.

Glyphosate is the active ingredient of several widely used herbicide formulations. Glyphosate targets the shikimate metabolic pathway, which is found in plants but not in animals. Despite the relative safety of glyphosate, various adverse developmental and reproductive problems have been alleged as a result of exposure in humans and animals.

Analysis and integration of developmental neurotoxicity and ancillary data into risk assessment: a case study of dimethoate.

Dimethoate is an organophosphate (OP) pesticide used to control a wide variety of insects on agricultural crops and ornamentals. To ensure that dimethoate is used safely, it is important to determine exposure levels that protect against adverse effects at all life stages, including the developing fetus, infant, and child. Based on an analysis of a developmental neurotoxicity (DNT) study, a cholinesterase (ChE) sensitivity study, a cross-fostering study, and several single- and multigenerational reproductive toxicity studies, two potential critical endpoints for dimethoate were identified: brain ChE inhibition (ChEI) in adult females, and pup mortality.

Toxicity of binary chemical munition destruction products: methylphosphonic acid, methylphosphinic acid, 2-diisopropylaminoethanol, DF neutralent, and QL neutralent.

This paper reports the toxicity and environmental impact of neutralents produced from the hydrolysis of binary chemical agent precursor chemicals DF (methylphosphonic difluoride) and QL (2-[bis(1-methylethyl)amino]ethyl ethyl methylphosphonite). Following a literature review of the neutralent mixtures and constituents, basic toxicity tests were conducted to fill data gaps, including acute oral and dermal median lethal dose assays, the Ames mutagenicity test, and ecotoxicity tests. For methylphosphonic acid (MPA), a major constituent of DF neutralent, the acute oral LD(50) in the Sprague-Dawley rat was measured at 1888 mg/kg, and the Ames test using typical tester strains of Salmonella typhimurium and Escherichia coli was negative.

Postnatal growth and morphological development of the brain: a species comparison.

The objective of this report is to summarize the available literature regarding the postnatal growth and morphological development of the brain and compare the timelines for these events between humans and experimental species. While not the primary focus of this report, in acknowledgement of the evident role of maturation of neurotransmitter systems in development, a brief description of the comparative development of the NMDA receptor is included. To illustrate the challenges faced in estimating developmental toxicity potential in humans, the importance of postnatal experience in CNS development is also briefly reviewed.

Mode of action: yolk sac poisoning and impeded histiotrophic nutrition--HBOC-related congenital malformations.

Rodents form an early inverted yolk sac placenta (invYSP) by apposing the yolk sac to the uterine wall. The invYSP supplies nutrients via histiotrophic nutrition involving pinocytosis of materials from uterine gland secretions, lysosomal degradation, and transfer of the products to the embryo. Interference with histiotrophic trafficking through the invYSP by high-molecular-weight molecules (such as trypan blue) causes malformations and resorptions.

Trichloroethylene-contaminated drinking water and congenital heart defects: a critical analysis of the literature.

The organic solvent trichloroethylene (TCE) is a metal degreasing agent and an intermediate in the production of fluorochemicals and polyvinyl chloride. TCE is also a common, persistent drinking water contaminant. Several epidemiological studies have alleged links between TCE exposure during pregnancy and offspring health problems including congenital heart defects (CHDs); however, the results of these studies are inconsistent, difficult to interpret, and involve several confounding factors.

Mechanisms regulating toxicant disposition to the embryo during early pregnancy: an interspecies comparison.

The dose of toxicant reaching the embryo is a critical determinant of developmental toxicity, and is likely to be a key factor responsible for interspecies variability in response to many test agents. This review compares the mechanisms regulating disposition of toxicants from the maternal circulation to the embryo during organogenesis in humans and the two species used predominantly in regulatory developmental toxicity testing, rats and rabbits. These three species utilize fundamentally different strategies for maternal-embryonic exchange during early pregnancy.

Increased DNA methylation in the HoxA5 promoter region correlates with decreased expression of the gene during tumor promotion.

Promoter-region DNA methylation inhibits transcription. A two-stage SENCAR (sensitive to mouse carcinogenesis) mouse skin carcinogenicity model was used to examine gene-specific changes in methylation during skin tumor promotion. Analysis was performed on 7,12-dimethylbenz[a]anthracene (DMBA)-initiated skin promoted with 9, 18, 27, or 36 mg cigarette smoke condensate (CSC) for 9 wk, or 27 mg CSC for 9 wk and sacrificed 6 wk afterwards (recovery group).

The value of DNA methylation analysis in basic, initial toxicity assessments.

DNA methylation is an epigenetic mechanism regulating patterns of gene expression. Our goal was to see if the assessment of DNA methylation might be a useful tool, when used in conjunction with initial, basic in vitro tests, to provide a more informative preliminary appraisal of the toxic potential of chemicals to prioritize them for further evaluation. We sought to give better indications of a compound's toxic potential and its possible mechanism of action at an earlier time and, thereby, contribute to a rational approach of an overall reduction in testing by making improved early decisions.

Progressive alterations in global and GC-rich DNA methylation during tumorigenesis.

DNA methylation plays a key role in the regulation of gene expression, and failure to maintain normal patterns of methylation often contributes to carcinogenesis. We have characterized progressive methylation changes during the promotion stage of carcinogenesis using a SENCAR mouse skin initiation/promotion tumorigenesis model. Mice were initiated with a dermal application of 75 microg dimethylbenz[a]anthracene (DMBA) and promoted with 9, 18, 27, and 36 mg cigarette smoke condensate (CSC) thrice weekly for time periods up to 29 weeks, when a large increase in tumor number was produced by the highest three doses.

Effects of phenobarbital on DNA methylation in GC-rich regions of hepatic DNA from mice that exhibit different levels of susceptibility to liver tumorigenesis.

DNA methylation is an important epigenetic mechanism involved in transcriptional control and altered patterns of methylation may lead to the aberrant gene expression contributing to carcinogenesis. Three groups of mice were used in the current study: the relatively liver-tumor-sensitive C3H/He strain and B6C3F1 stock (C57BL/6xC3H/He), as well as the relatively resistant C57BL/6 strain. For a 2-week period, animals from each group were given drinking water containing a tumor-promoting dose of phenobarbital (PB), a nongenotoxic rodent carcinogen.

Epigenetics and DNA methylation come of age in toxicology.

A wide variety of chemical and physical agents have the potential to produce adverse effects by causing heritable changes to the genome, resulting in heritable alterations in phenotype. These are often assumed to be a consequence of mutation. However, mutagenesis is not the only mechanism underlying heritable alterations to the genome.

Altered DNA methylation: a secondary mechanism involved in carcinogenesis.

This review focuses on the role that DNA methylation plays in the regulation of normal and aberrant gene expression and on how, in a hypothesis-driven fashion, altered DNA methylation may be viewed as a secondary mechanism involved in carcinogenesis. Research aimed at discerning the mechanisms by which chemicals can transform normal cells into frank carcinomas has both theoretical and practical implications. Through an increased understanding of the mechanisms by which chemicals affect the carcinogenic process, we learn more about basic biology while, at the same time, providing the type of information required to make more rational safety assessment decisions concerning their actual potential to cause cancer under particular conditions of exposure.