There is increasing interest in the use of quantitative transcriptomic data to determine benchmark dose (BMD) and estimate a point of departure (POD) for human health risk assessment. Although studies have shown that transcriptional PODs correlate with those derived from apical endpoint changes, there is no consensus on the process used to derive a transcriptional POD. Specifically, the subsets of informative genes that produce BMDs that best approximate the doses at which adverse apical effects occur have not been defined. To determine the best way to select predictive groups of genes, we used published microarray data from dose–response studies on six chemicals in rats exposed orally for 5, 14, 28, and 90 days. We evaluated eight approaches for selecting genes for POD derivation and three previously proposed approaches (the lowest pathway BMD, and the mean and median BMD of all genes). The relationship between transcriptional BMDs derived using these 11 approaches and PODs derived from apical data that might be used in chemical risk assessment was examined. Transcriptional BMD values for all 11 approaches were remarkably aligned with corresponding apical PODs, with the vast majority of toxicogenomics PODs being within tenfold of those derived from apical endpoints. We identified at least four approaches that produce BMDs that are effective estimates of apical PODs across multiple sampling time points. Our results support that a variety of approaches can be used to derive reproducible transcriptional PODs that are consistent with PODs produced from traditional methods for chemical risk assessment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1886-5) contains supplementary material, which is available to authorized users.
The blaR gene of Bacillus licheniformis encodes the signal transducer for induction of the class A beta-lactamase. The protein product, BlaR, has a hydrophilic carboxy region that binds beta-lactams and shows high sequence homology to the class D beta-lactamases, particularly the OXA-2 beta-lactamase of Salmonella typhimurium. The BlaR-beta-lactam complex is stable and may provide the continuing stimulus needed for the prolonged production of the enzyme.
Perfluorooctanesulfonate (PFOS) is one of a class of industrial chemicals known as perfluoroalkyl acids, which have a wide variety of uses as surfactants and stain repellants. The presence of fluorochemical residues in human blood, plasma, or serum from sample populations worldwide is indicative of widespread human exposure. Previous studies demonstrated that PFOS alters fatty acid metabolism in the liver of rodents and that this leads to peroxisome proliferation. This study was undertaken to (1) confirm the effects of PFOS on rat liver, (2) identify additional target organs and systems, and (3) further explore the biochemical and molecular changes associated with PFOS exposure. The results confirmed that liver was a primary target for PFOS. Hepatomegaly, decreased serum triglycerides and cholesterol, and increased expression of the genes for acyl-coenzymeA oxidase 1 (ACOX1) and cytochrome P-450 4A22 (CYP4A22) were indicative of exposure to a peroxisome proliferator. Changes in liver fatty acid profiles included increased total monounsaturated fatty acid levels and decreased total polyunsaturated fatty acids, as well as an increase in linoleic acid levels and a decrease in longer chain fatty acids. These changes were similar to those induced by relatively weak peroxisome proliferators. Disruptions in hepatic fatty acid metabolism may contribute to changes in red blood cell membranes, resulting in increased lysis and cell fragility. Serum thyroid hormone levels were decreased in PFOS-treated rats, while the kidney and cardiovascular systems were not significant targets. Residue analyses indicated that PFOS accumulation in tissues was dose dependent, appearing preferentially in the liver at lower doses but increasing in serum and other organs relative to liver at higher doses.
Perfluorooctanesulfonate (PFOS) is a stable and environmentally persistent metabolic or degradation product of perfluorooctanyl compounds that were manufactured for a variety of industrial and consumer applications. PFOS itself was sold for use as a surfactant. The structurally related contaminants perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), and N-ethyl perfluorooctane sulfonamide (N-EtPFOSA) were shown to suppress immune responses in laboratory rodents. Relatively low doses of PFOS were found to be immunosuppressive in mice. To assess effects of PFOS on the rat immune system at doses known to alter hepatic function, changes in the morphology and function of immune tissues and cells were measured in adult rats exposed to PFOS in their diet for 28 d at levels ranging from 2 to 100 mg PFOS/kg diet (corresponding to approximately 0.14 to 7.58 mg/kg body weight [bw]/d) and compared to those receiving control diet. Body weight reductions were significant in male and female rats exposed to 50 and 100 mg PFOS/kg diet. Liver/body weight was significantly increased in females exposed to 2 mg PFOS/kg diet and in males exposed to 20 mg PFOS/kg diet. Female rats exposed to 100 mg PFOS/kg diet exhibited a significant increase in spleen weight relative to body weight; these changes lacked a histologic correlate and were not observed in males. While thymus weights relative to body weights were not affected, numbers of apoptotic lymphocytes rose in thymus with increasing dietary PFOS. There was a significant dose-related increase in total peripheral blood lymphocyte numbers in female but not male rats. In both genders the percentages of cells within lymphocyte subclasses were altered. There was a significant trend toward increasing T and T-helper (Th) cells and decreasing B cells with higher PFOS dose. Serum total immunoglobulin (Ig) G1 levels were significantly reduced in males exposed to 2 and 20 mg PFOS/kg diet. The ability of male and female rats to mount delayed-type hypersensitivity (DTH) responses to the T-cell-dependent antigen keyhole limpet hemocyanin (KLH) was not altered by PFOS. There was a significant trend toward elevated KLH-specific IgG in serum from male rats exposed to increasing levels of PFOS in diet. Splenic T- and B-cell proliferation in response to ex vivo mitogen exposure was unaffected by exposure to dietary PFOS. In conclusion, changes in immune parameters in rat did not manifest as functional alterations in response to immune challenge with KLH and may be secondary to hepatic-mediated effects of PFOS in this model.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.