Health-based cyanotoxin guideline values allow for cyanotoxin-based monitoring and efficient public health response to cyanobacterial blooms.

Human health risks from cyanobacterial blooms are primarily related to cyanotoxins that some cyanobacteria produce. Not all species of cyanobacteria can produce toxins. Those that do often do not produce toxins at levels harmful to human health. Monitoring programs that use identification of cyanobacteria genus and species and enumeration of cyanobacterial cells as a surrogate for cyanotoxin presence can overestimate risk and lead to unnecessary health advisories. In the absence of federal criteria for cyanotoxins in recreational water, the Oregon Health Authority (OHA) developed guideline values for the four most common cyanotoxins in Oregon's fresh waters (anatoxin-a, cylindrospermopsin, microcystins, and saxitoxins). OHA developed three guideline values for each of the cyanotoxins found in Oregon. Each of the guideline values is for a specific use of cyanobacteria-affected water: drinking water, human recreational exposure and dog recreational exposure. Having cyanotoxin guidelines allows OHA to promote toxin-based monitoring (TBM) programs, which reduce the number of health advisories and focus advisories on times and places where actual, rather than potential, risks to health exist. TBM allows OHA to more efficiently protect public health while reducing burdens on local economies that depend on water recreation-related tourism.

Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk.

Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a woman's body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infant's intake of these LPECs may be much greater than his/her mother's average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life. In many cases, current human health risk assessment methods do not account for differences between maternal and infant exposures to LPECs or for lifestage-specific effects of exposure to these chemicals. Because of their persistence and accumulation in body lipids and partitioning into breast milk, LPECs present unique challenges for each component of the human health risk assessment process, including hazard identification, dose-response assessment, and exposure assessment. Specific biological modeling approaches are available to support both dose-response and exposure assessment for lactational exposures to LPECs. Yet, lack of data limits the application of these approaches. The goal of this review is to outline the available approaches and to identify key issues that, if addressed, could improve efforts to apply these approaches to risk assessment of lactational exposure to these chemicals.

The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor.

BACKGROUND: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity and biological activity of dioxins and related chemicals. The AhR influences a variety of processes involved in cellular growth and differentiation, and recent studies have suggested that the AhR is a potential target for immune-mediated diseases. METHODOLOGY/PRINCIPAL FINDINGS: During a screen for molecules that activate the AhR, leflunomide, an immunomodulatory drug presently used in the clinic for the treatment of rheumatoid arthritis, was identified as an AhR agonist. We aimed to determine whether any biological activity of leflunomide could be attributed to a previously unappreciated interaction with the AhR. The currently established mechanism of action of leflunomide involves its metabolism to A771726, possibly by cytochrome P450 enzymes, followed by inhibition of de novo pyrimidine biosynthesis by A771726. Our results demonstrate that leflunomide, but not its metabolite A771726, caused nuclear translocation of AhR into the nucleus and increased expression of AhR-responsive reporter genes and endogenous AhR target genes in an AhR-dependent manner. In silico Molecular Docking studies employing AhR ligand binding domain revealed favorable binding energy for leflunomide, but not for A771726. Further, leflunomide, but not A771726, inhibited in vivo epimorphic regeneration in a zebrafish model of tissue regeneration in an AhR-dependent manner. However, suppression of lymphocyte proliferation by leflunomide or A771726 was not dependent on AhR. CONCLUSIONS: These data reveal that leflunomide, an anti-inflammatory drug, is an agonist of the AhR. Our findings link AhR activation by leflunomide to inhibition of fin regeneration in zebrafish. Identification of alternative AhR agonists is a critical step in evaluating the AhR as a therapeutic target for the treatment of immune disorders.

Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes.

The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), is a novel inducer of adaptive Tregs. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most potent AHR ligand, induces adaptive CD4+CD25+ Tregs during an acute graft-versus-host (GvH) response and prevents the generation of allospecific cytotoxic T lymphocytes. TCDD also suppresses the induction of experimental autoimmune encephalitis in association with an expanded population of Foxp3+ Tregs. In this study, we show that chronic treatment of NOD mice with TCDD potently suppresses the development of autoimmune Type 1 diabetes in parallel with greatly reduced pancreatic islet insulitis and an expanded population of CD4+CD25+Foxp3+ cells in the pancreatic lymph nodes. When treatment with TCDD was terminated after 15 weeks (23 weeks of age), mice developed diabetes over the next 8 weeks in association with lower numbers of Tregs and decreased activation of AHR. Analysis of the expression levels of several genes associated with inflammation, T-cell activation and/or Treg function in pancreatic lymph node cells failed to reveal any differences associated with TCDD treatment. Taken together, the data suggest that AHR activation by TCDD-like ligands may represent a novel avenue for treatment of immune-mediated diseases.

Reduction of myeloid suppressor cell derived nitric oxide provides a mechanistic basis of lead enhancement of alloreactive CD4(+) T cell proliferation.

The persistent environmental toxicant and immunomodulator, lead (Pb), has been proposed to directly target CD4(+) T cells. However, our studies suggest that CD4(+) T cells are an important functional, yet indirect target. In order to identify the direct target of Pb in the immune system and the potential mechanism of Pb-induced immunotoxicity, myeloid suppressor cells (MSCs) were evaluated for their ability to modulate CD4(+) T cell proliferation after Pb exposure. Myeloid suppressor cells regulate the adaptive immune response, in part, by inhibiting the proliferation of CD4(+) T cells. It is thought that the mechanism of MSC-dependent regulation involves the release of the bioactive gas, nitric oxide (NO), blocking cell signaling cascades downstream of the IL-2 receptor and thus preventing T cells from entering cell-cycle. In mixed lymphocyte culture (MLC), increasing numbers of MSCs suppressed T cell proliferation in a dose-dependent manner, and this suppression is strikingly abrogated with 5 microM lead (Pb) treatment. The Pb-sensitive MSC population is CD11b(+), GR1(+)and CD11c(-) and thus phenotypically consistent with MSCs described in other literature. Inhibition of NO-synthase (NOS), the enzyme responsible for the production of NO, enhanced alloreactive T cell proliferation in MLC. Moreover, Pb attenuated NO production in MLC, and exogenous replacement of NO restored suppression in the presence of Pb. Significantly, MSC from iNOS-/- mice were unable to suppress T cell proliferation. An MSC-derived cell line (MSC-1) also suppressed T cell proliferation in MLC, and Pb disrupted this suppression by attenuating NO production. Additionally, Pb disrupted NO production in MSC-1 cells in response to treatment with interferon-gamma (IFN-gamma) and LPS or in response to concanavalin A-stimulated splenocytes. However, neither the abundance of protein nor levels of mRNA for the inducible isoform of NOS (iNOS) were altered with Pb treatment. Taken together these data suggest that Pb abrogates an MSC-dependent suppression of alloreactive T cell proliferation by inhibiting the function, but not the expression of iNOS.

Lead enhances CD4+ T cell proliferation indirectly by targeting antigen presenting cells and modulating antigen-specific interactions.

Although Pb is a well-known immunotoxicant, its mechanism of action is not well understood. Low levels of Pb (approximately 1 microM) markedly enhance the proliferative T cell response in mixed lymphocyte culture (MLC), a process we have termed allo-enhancement. As Pb allo-enhancement occurs whether alloantigen presenting cells (APC) are derived from C57BL/6 or BALB.B10, the allo-reactive T cells involved are likely to be specific for peptide in the context of the IA(b) molecule as the IE molecule is null in H-2(b) mice. Analysis of T cell division in MLC with Pb treatment indicated that there was no significant difference between Pb and non-Pb-treated cultures until day 4 when the frequency of proliferating T cells was much greater than in non-treated cultures. Our data suggest that this increased proliferation is not coupled with increased IL-2 levels in the media as these were actually decreased with Pb treatment and that Pb-induced enhancement in the allo-proliferative response is only partially dependent upon IL-2. Pb allo-enhancement is abrogated when stimulating allo-APCs are paraformaldehyde-fixed, and T cell proliferation stimulated by concanavalin A is not enhanced with Pb treatment, suggesting that the APC is the proximate target of Pb in allo-MLC. Pb allo-enhancement does not occur when T cells respond to irradiated allo-B cells, alone; however, it is restored when syngeneic CD11c-enriched cells are added. Of the CD11c-enriched splenocytes, the fraction that is adherent after 24 h, consistent with macrophages, appears to be the cell type targeted by Pb. Using T cells from DO11.10 transgenic mice, we determined that the effect of Pb is centered around specific p:MHC interactions and that enhanced costimulation is an unlikely mechanism for Pb allo-enhancement.