Assessment of diurnal systemic dose of agrochemicals in regulatory toxicity testing--an integrated approach without additional animal use.

Integrated toxicokinetics (TK) data provide information on the rate, extent and duration of systemic exposure across doses, species, strains, gender, and life stages within a toxicology program. While routine for pharmaceuticals, TK assessments of non-pharmaceuticals are still relatively rare, and have never before been included in a full range of guideline studies for a new agrochemical. In order to better understand the relationship between diurnal systemic dose (AUC(24h)) and toxicity of agrochemicals, TK analyses in the study animals is now included in all short- (excluding acute), medium- and long-term guideline mammalian toxicity studies including reproduction/developmental tests.

Current and future use of genomics data in toxicology: opportunities and challenges for regulatory applications.

Toxicogenomics is the application of toxicology, genetics, molecular biology and environmental health to describe the response of organisms to environmental stimuli. The field of toxicogenomics has developed over the past 15 years mainly due to advances in toxicology, molecular genetics and cell biology. Its prospective use to resolve crucial data gaps and data inconsistencies could improve risk assessment by providing additional data to increase the understanding of mechanisms and modes of action (MOA) and enhance the reliability of dose-response extrapolation.

Prolactin and transforming growth factor-beta signaling exert opposing effects on mammary gland morphogenesis, involution, and the Akt-forkhead pathway.

Both prolactin (PRL) and TGF-beta regulate cell survival in mammary epithelial cells, but their mechanisms of interactions are not known. In primary mammary epithelial cells and the HC11 mouse mammary epithelial cell line, PRL prevented TGF-beta-induced apoptosis, as measured by terminal deoxynucleotidyltransferase dUTP nick-end labeling staining and caspase-3 activation. This effect depended on phosphatidyl inositol triphosphate kinase (PI3K).

Serotonin regulates mammary gland development via an autocrine-paracrine loop.

Mammary gland development is controlled by a dynamic interplay between endocrine hormones and locally produced factors. Biogenic monoamines (serotonin, dopamine, norepinephrine, and others) are an important class of bioregulatory molecules that have not been shown to participate in mammary development. Here we show that mammary glands stimulated by prolactin (PRL) express genes essential for serotonin biosynthesis (tryptophan hydroxylase [TPH] and aromatic amine decarboxylase).

Receptor activator of NF-kappaB ligand induction via Jak2 and Stat5a in mammary epithelial cells.

Prolactin (PRL) is the primary hormone that, in conjunction with local factors, leads to lobuloalveolar development during pregnancy. Recently, receptor activator of NF-kappaB ligand (RANKL) has been identified as one of the effector molecules essential for lobuloalveolar development. The molecular mechanisms by which PRL may induce RANKL expression have not been carefully examined.

Two tandemly linked interferon-gamma-activated sequence elements in the promoter of glycosylation-dependent cell adhesion molecule 1 gene synergistically respond to prolactin in mouse mammary epithelial cells.

Previously, we reported that glycosylation-dependent cell adhesion molecule 1 (GlyCAM 1) was a novel target for prolactin (PRL) in the mouse mammary gland. However, the signaling pathway by which PRL regulates GlyCAM 1 expression has not been specified. In the present study, we showed that PRL induced GlyCAM 1 expression in primary mammary epithelial cells of mice through the Janus kinase 2/signal transducer and activator of transcription 5 (Stat5) pathway.