Epigenome‐wide DNA methylation analysis implicates neuronal and inflammatory signaling pathways in adult murine hepatic tumorigenesis following perinatal exposure to bisphenol A

Developmental exposure to the endocrine‐active compound bisphenol A (BPA) has been linked to epigenotoxic and potential carcinogenic effects in rodent liver, prostate, and mammary glands. A dose‐dependent increase in hepatic tumors in 10‐month mice perinatally exposed to one of three doses of BPA (50 ng, 50 µg, or 50 mg BPA/kg chow) was previously reported. These tumors represent early‐onset disease and lack classical sexual dimorphism in incidence. Here, adult epigenome‐wide liver DNA methylation profiles to identify gene promoters associated with perinatal BPA exposure and disease in 10‐month mice with and without liver tumors were investigated. Mice with hepatic tumors showed 12,822 (1.8%) probes with differential methylation as compared with non‐tumor animals, of which 8,656 (67.5%) were hypomethylated. A significant enrichment of differential methylation in Gene Ontology (GO) terms and biological processes related to morphogenesis and development, and epigenomic alteration were observed. Pathway enrichment revealed a predominance of hypermethylated neuronal signaling pathways linked to energy regulation and metabolic function, supporting metabolic consequences in the liver via BPA‐induced disruption of neuronal signaling pathways. Hypothesis‐driven pathway analysis revealed mouse and human genes linked to BPA exposure related to intracellular Jak/STAT and MAPK signaling pathways. Taken together, these findings are indicators of the relevance of the hepatic tumor phenotype seen in BPA‐exposed mice to human health. This work demonstrated that epigenome‐wide discovery experiments in animal models were effective tools for identification and understanding of paralagous epimutations salient to human disease. Environ. Mol. Mutagen. 57:435–446, 2016. © 2016 Wiley Periodicals, Inc.     

EPA‐Registered Repellents for Mosquitoes Transmitting Emerging Viral Disease

In many parts of the United States, mosquitoes were previously nuisance pests. However, they now represent a potential threat in the spread of viral diseases. The Aedes aegypti, Aedes albopictus, and Culex species mosquitoes are endemic to the United States and together may transmit a variety of viral diseases of growing concern, including West Nile virus, chikungunya, dengue fever, and Zika virus. The Centers for Disease Control and Prevention and the Environmental Protection Agency (EPA) recommend N,N‐diethyl‐meta‐toluamide (DEET) as a first‐line mosquito repellent, but for patients refusing to use DEET or other conventional repellents, guidance is limited to any EPA‐registered product. Therefore, we conducted a systematic review of the literature to identify which EPA‐registered personal mosquito repellent provides the best protection from A. aegypti, A. albopictus, and Culex spp. mosquitoes. We abstracted data from 62 published reports of EPA‐registered mosquito repellents. The conventional repellent picaridin has the strongest data to support its use as a second‐line agent, while IR3535 and oil of lemon eucalyptus are reasonably effective natural products. Citronella, catnip, and 2‐undecanone offer limited protection or have limited data. These results can be used by pharmacists and other health care professionals to advise patients on the selection of an EPA‐registered mosquito repellent. Regardless of the repellent chosen, it is vital for patients to follow all instructions/precautions in the product labeling to ensure safe and effective use.     

Localization of Burkholderia cepacia Complex Bacteria in Cystic Fibrosis Lungs and Interactions with Pseudomonas aeruginosa in Hypoxic Mucus

The localization of Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) lungs, alone or during coinfection with Pseudomonas aeruginosa, is poorly understood. We performed immunohistochemistry for Bcc and P. aeruginosa bacteria on 21 coinfected or singly infected CF lungs obtained at transplantation or autopsy. Parallel in vitro experiments examined the growth of two Bcc species, Burkholderia cenocepacia and Burkholderia multivorans, in environments similar to those occupied by P. aeruginosa in the CF lung. Bcc bacteria were predominantly identified in the CF lung as single cells or small clusters within phagocytes and mucus but not as “biofilm-like structures.” In contrast, P. aeruginosa was identified in biofilm-like masses, but densities appeared to be reduced during coinfection with Bcc bacteria. Based on chemical analyses of CF and non-CF respiratory secretions, a test medium was defined to study Bcc growth and interactions with P. aeruginosa in an environment mimicking the CF lung. When test medium was supplemented with alternative electron acceptors under anaerobic conditions, B. cenocepacia and B. multivorans used fermentation rather than anaerobic respiration to gain energy, consistent with the identification of fermentation products by high-performance liquid chromatography (HPLC). Both Bcc species also expressed mucinases that produced carbon sources from mucins for growth. In the presence of P. aeruginosa in vitro, both Bcc species grew anaerobically but not aerobically. We propose that Bcc bacteria (i) invade a P. aeruginosa-infected CF lung when the airway lumen is anaerobic, (ii) inhibit P. aeruginosa biofilm-like growth, and (iii) expand the host bacterial niche from mucus to also include macrophages.     

Closely related bird species demonstrate flexibility between beak morphology and underlying developmental programs

The astonishing variation in the shape and size of bird beaks reflects a wide range of dietary specializations that played an important role in avian diversification. Among Darwin’s finches, ground finches (Geospiza spp.) have beaks that represent scaling variations of the same shape, which are generated by alterations in the signaling pathways that regulate growth of the two skeletal components of the beak: the prenasal cartilage (pnc) and the premaxillary bone (pmx). Whether this developmental mechanism is responsible for variation within groups of other closely related bird species, however, has remained unknown. Here, we report that the Caribbean bullfinches (Loxigilla spp.), which are closely related to Darwin’s finches, have independently evolved beaks of a novel shape, different from Geospiza, but also varying from each other only in scaling. However, despite sharing the same beak shape, the signaling pathways and tissues patterning Loxigilla beaks differ among the three species. In Loxigilla noctis, as in Geospiza, the pnc develops first, shaped by Bmp4 and CaM signaling, followed by the development of the pmx, regulated by TGFβIIr, β-catenin, and Dkk3 signaling. In contrast, beak morphogenesis in Loxigilla violacea and Loxigilla portoricensis is generated almost exclusively by the pmx through a mechanism in which Ihh and Bmp4 synergize to promote expansion of bone tissue. Together, our results demonstrate high flexibility in the relationship between morphology and underlying developmental causes, where different developmental programs can generate identical shapes, and similar developmental programs can pattern different shapes.     

Constitutively low expression of collagen XIII alpha 1 may help explain the vulnerability of the inferior rectus muscle to thyroid-associated ophthalmopathy

Thyroid-associated ophthalmopathy (TAO) has a predilection for inferior rectus muscle that has never been explained. We conducted immunohistochemical staining for the soluble cleaved form of collagen XIII alpha 1 (COL13A1) and found constitutively low expression of COL13A1 in normal human inferior rectus muscles and moderate expression of COL13A1 in normal human medial rectus muscles. COL13A1 is known to be essential to development and maintenance of neuromuscular junctions and there is some evidence to suggest it may help support normal immune function. The combination of constitutively low expression of COL13A1, high physiological and metabolic demands, and consequentially relatively high exposure to stressors via the blood stream may help explain the particular vulnerability of inferior rectus to TAO compared to other extraocular muscles.