While it has long been known that inflammation and infection reduce expression of hepatic cytochrome P450 (CYP) genes involved in xenobiotic metabolism and that exposure to xenobiotic chemicals can impair immune function, the molecular mechanisms underlying both of these phenomena have remained largely unknown. Here we show that activation of the nuclear steroid and xenobiotic receptor (SXR) by commonly used drugs in humans inhibits the activity of NF-κB, a key regulator of inflammation and the immune response. NF-κB target genes are upregulated and small bowel inflammation is significantly increased in mice lacking the SXR ortholog pregnane X receptor (PXR), thereby demonstrating a direct link between SXR and drug-mediated antagonism of NF-κB. Interestingly, NF-κB activation reciprocally inhibits SXR and its target genes whereas inhibition of NF-κB enhances SXR activity. This SXR/PXR–NF-κB axis provides a molecular explanation for the suppression of hepatic CYP mRNAs by inflammatory stimuli as well as the immunosuppressant effects of xenobiotics and SXR-responsive drugs. This mechanistic relationship has clinical consequences for individuals undergoing therapeutic exposure to the wide variety of drugs that are also SXR agonists.

Obesity is a worldwide pandemic in adults as well as children and adds greatly to health care costs through its association with type 2 diabetes, metabolic syndrome, cardiovascular disease, and cancers. The prevailing medical view of obesity is that it results from a simple imbalance between caloric intake and energy expenditure. However, numerous other factors are important in the etiology of obesity. The obesogen hypothesis proposes that environmental chemicals termed obesogens promote obesity by acting to increase adipocyte commitment, differentiation, and size by altering metabolic set points or altering the hormonal regulation of appetite and satiety. Many obesogens are endocrine disrupting chemicals that interfere with normal endocrine regulation. Endocrine disrupting obesogens are abundant in our environment, used in everyday products from food packaging to fungicides. In this review, we explore the evidence supporting the obesogen hypothesis, as well as the gaps in our knowledge that are currently preventing a complete understanding of the extent to which obesogens contribute to the obesity pandemic.

A peer-reviewed open access journal published by the National Institute of Environmental Health Sciences

The identification of neurological symptoms caused by vitamin A deficiency pointed to a critical, early developmental role of vitamin A and its metabolite, retinoic acid (RA). The ability of RA to induce post-mitotic, neural phenotypes in various stem cells, in vitro, served as early evidence that RA is involved in the switch between proliferation and differentiation. In vivo studies have expanded this “opposing signal” model, and the number of primary neurons an embryo develops is now known to depend critically on the levels and spatial distribution of RA. The proneural and neurogenic transcription factors that control the exit of neural progenitors from the cell cycle and allow primary neurons to develop are partly elucidated, but the downstream effectors of RA receptor (RAR) signaling (many of which are putative cell cycle regulators) remain largely unidentified. The molecular mechanisms underlying RA-induced primary neurogenesis in anamniote embryos are starting to be revealed; however, these data have been not been extended to amniote embryos. There is growing evidence that bona fide RARs are found in some mollusks and other invertebrates, but little is known about their necessity or functions in neurogenesis. One normal function of RA is to regulate the cell cycle to halt proliferation, and loss of RA signaling is associated with dedifferentiation and the development of cancer. Identifying the genes and pathways that mediate cell cycle exit downstream of RA will be critical for our understanding of how to target tumor differentiation. Overall, elucidating the molecular details of RAR-regulated neurogenesis will be decisive for developing and understanding neural proliferation–differentiation switches throughout development.

The environmental obesogen hypothesis proposes that pre- and postnatal exposure to environmental chemicals contributes to adipogenesis and the development of obesity. Tributyltin (TBT) is an agonist of both retinoid X receptor (RXR) and peroxisome proliferator-activated receptor γ (PPARγ). Activation of these receptors can elevate adipose mass in adult mice exposed to the chemical in utero. Here we show that TBT sensitizes human and mouse multipotent stromal stem cells derived from white adipose tissue [adipose-derived stromal stem cells (ADSCs)] to undergo adipogenesis. In vitro exposure to TBT, or the PPARγ activator rosiglitazone increases adipogenesis, cellular lipid content, and expression of adipogenic genes. The adipogenic effects of TBT and rosiglitazone were blocked by the addition of PPARγ antagonists, suggesting that activation of PPARγ mediates the effect of both compounds on adipogenesis. ADSCs from mice exposed to TBT in utero showed increased adipogenic capacity and reduced osteogenic capacity with enhanced lipid accumulation in response to adipogenic induction. ADSCs retrieved from animals exposed to TBT in utero showed increased expression of PPARγ target genes such as the early adipogenic differentiation gene marker fatty acid-binding protein 4 and hypomethylation of the promoter/enhancer region of the fatty acid-binding protein 4 locus. Hence, TBT alters the stem cell compartment by sensitizing multipotent stromal stem cells to differentiate into adipocytes, an effect that could likely increase adipose mass over time.