Use of the threshold of toxicological concern (TTC) approach as an alternative tool for regulatory purposes: A case study with an inert ingredient used in pesticide products.

This study investigates the potential of the Threshold of Toxicological Concern (TTC) as an alternative to traditional animal testing in pesticide regulatory risk assessments. The TTC is a principle that establishes exposure threshold values for chemicals with certain structural features, below which there is no appreciable risk to human health. A case study was conducted with α-terpineol, an inert ingredient proposed to be used at low concentrations in pesticide products, to compare a conventional risk assessment using animal data with one using the TTC method.

The relationship between chemical-induced kidney weight increases and kidney histopathology in rats.

The kidney is a major site of chemical excretion, which results in its propensity to exhibit chemically-induced toxicological effects at a higher rate than most other organs. Although the kidneys are often weighed in animal toxicity studies, the manner in which these kidney weight measurements are interpreted and the value of this information in predicting renal damage remains controversial. In this study we sought to determine whether a relationship exists between chemically-induced kidney weight changes and renal histopathological alterations.

Using quantitative structure-activity relationship modeling to quantitatively predict the developmental toxicity of halogenated azole compounds.

Developmental toxicity is a relevant endpoint for the comprehensive assessment of human health risk from chemical exposure. However, animal developmental toxicity data remain unavailable for many environmental contaminants due to the complexity and cost of these types of analyses. Here we describe an approach that uses quantitative structure-activity relationship modeling as an alternative methodology to fill data gaps in the developmental toxicity profile of certain halogenated compounds.

Involvement of the mRNA binding protein CRD-BP in the regulation of metastatic melanoma cell proliferation and invasion by hypoxia.

We have previously shown that the mRNA binding protein CRD-BP is overexpressed in human melanomas, where it promotes cell survival and resistance to chemotherapy. The present study investigates the role of hypoxia, a common characteristic of the tumor microenvironment, in the regulation of CRD-BP expression and melanoma cell responses. We found that hypoxia increases CRD-BP levels in metastatic melanoma cell lines but not in melanocytes or primary melanoma cells.

Inhibition of coding region determinant binding protein sensitizes melanoma cells to chemotherapeutic agents.

We previously reported that malignant melanomas express high levels of the mRNA binding protein coding region determinant binding protein (CRD-BP). This molecule is important for the activation of anti-apoptotic pathways, a mechanism often linked to insensitivity to therapeutics. However, it is not known whether CRD-BP plays a role in the resistance of melanomas to anti-cancer treatment.

TGFβ2-mediated production of hyaluronan is important for the induction of epicardial cell differentiation and invasion.

In the developing heart, the epicardium is a major source of progenitor cells that contribute to the formation of the coronary vessel system. These epicardial progenitors give rise to the different cellular components of the coronary vasculature by undergoing a number of morphological and physiological changes collectively known as epithelial to mesenchymal transformation (EMT). However, the specific signaling mechanisms that regulate epicardial EMT are yet to be delineated.

Involvement of the MEKK1 signaling pathway in the regulation of epicardial cell behavior by hyaluronan.

During embryonic development, cells comprising the outermost layer of the heart or epicardium play a critical role in the formation of the coronary vasculature. Thus, uncovering the molecular mechanisms that govern epicardial cell behavior is imperative to better understand the etiology of cardiovascular diseases. In this study, we investigated the function of hyaluronan (HA), a major component of the extracellular matrix, in the modulation of epicardial signaling.

Size-dependent regulation of Snail2 by hyaluronan: its role in cellular invasion.

Hyaluronan (HA) induces changes in cellular behavior that are crucial during both embryonic development and cancer progression. However, the biological effects of varying sizes of HA and the signal transduction mechanisms that these polymers may activate remain unclear. In this study, we demonstrate that pulse stimulation of mouse embryonic fibroblasts with high-molecular-weight (HMW) HA, but not HA of lower molecular sizes, leads to increases in Snail2 protein which are dependent on NFkappaB activity.

MAP3Ks as central regulators of cell fate during development.

The cytoplasmic serine/threonine kinases transduce extracellular signals into regulatory events that impact cellular responses. The induction of one kinase triggers the activation of several downstream kinases, leading to the regulation of transcription factors to affect gene function. This arrangement allows for the kinase cascade to be amplified, and integrated according to the cellular context.