Characterization of Activation of the Hypothalamic-Pituitary-Adrenal Axis by the Herbicide Atrazine in the Female Rat.

Atrazine (ATR) is a commonly used pre-emergence and early postemergence herbicide. Rats gavaged with ATR and its chlorometabolites desethylatrazine (DEA) and deisopropylatrazine (DIA) respond with a rapid and dose-dependent rise in plasma corticosterone, whereas the major chlorometabolite, diaminochlorotriazine (DACT), has little or no effect on corticosterone levels. In this study, we investigated the possible sites of ATR activation of the hypothalamic-pituitary-adrenal (HPA) axis. ATR treatment had no effect on adrenal weights but altered adrenal morphology. Hypophysectomized rats or rats under dexamethasone suppression did not respond to ATR treatment, suggesting that ATR does not directly stimulate the adrenal gland to induce corticosterone synthesis. Immortalized mouse corticotrophs (AtT-20) and primary rat pituitary cultures were treated with ATR, DEA, DIA, or DACT. None of the compounds induced an increase in ACTH secretion or potentiated ACTH release in conjunction with CRH on ACTH release. In female rats gavaged with ATR, pretreatment with the CRH receptor antagonist astressin completely blocked the ATR-induced rise in corticosterone concentrations, implicating CRH release in ATR-induced HPA activation. Intracerebroventricular infusion of ATR, DEA, and DIA but not DACT at concentrations equivalent to peak plasma concentrations after gavage dosing resulted in an elevation of plasma corticosterone concentrations. However, ATR did not induce c-Fos immunoreactivity in the paraventricular nucleus of the hypothalamus. These results indicate that ATR activates the HPA axis centrally and requires CRH receptor activation, but it does not stimulate cellular pathways associated with CRH neuronal excitation.

Vaccination coverage among foreign-born and U.S.-born adolescents in the United States: Successes and gaps - National Immunization Survey-Teen, 2012-2014.

BACKGROUND: An overall increase has been reported in vaccination rates among adolescents during the past decade. Studies of vaccination coverage have shown disparities when comparing foreign-born and U.S.-born populations among children and adults; however, limited information is available concerning potential disparities in adolescents. METHODS: The National Immunization Survey-Teen is a random-digit-dialed telephone survey of caregivers of adolescents aged 13-17 years, followed by a mail survey to vaccination providers that is used to estimate vaccination coverage among the U.S. population of adolescents. Using the National Immunization Survey-Teen data, we assessed vaccination coverage during 2012-2014 among adolescents for routinely recommended vaccines for this age group (≥1 dose tetanus and diphtheria toxoids and acellular pertussis [Tdap] vaccine, ≥1 dose quadrivalent meningococcal conjugate [MenACWY] vaccine, ≥3 doses human papillomavirus [HPV] vaccine) and for routine childhood vaccination catch-up doses (≥2 doses measles, mumps, and rubella [MMR] vaccine, ≥2 doses varicella vaccine, and ≥3 doses hepatitis B [HepB] vaccine). Vaccination coverage prevalence and vaccination prevalence ratios were estimated. RESULTS: Of the 58,090 respondents included, 3.3% were foreign-born adolescents. Significant differences were observed between foreign-born and U.S.-born adolescents for insurance status, income-to-poverty ratio, education, interview language, and household size. Foreign-born adolescents had significantly lower unadjusted vaccination coverage for HepB (89% vs. 93%), and higher coverage for the recommended ≥3 doses of HPV vaccine among males, compared with U.S.-born adolescents (22% vs. 14%). Adjustment for demographic and socioeconomic factors accounted for the disparity in HPV but not HepB vaccination coverage. CONCLUSIONS: We report comparable unadjusted vaccination coverage among foreign-born and U.S.-born adolescents for Tdap, MenACWY, MMR, ≥2 varicella. Although coverage was high for HepB vaccine, it was significantly lower among foreign-born adolescents, compared with U.S.-born adolescents. HPV and ≥2-dose varicella vaccination coverage were low among both groups.

Understanding the structural requirements for activators of the Kef bacterial potassium efflux system.

The potassium efflux system, Kef, protects bacteria against the detrimental effects of electrophilic compounds via acidification of the cytoplasm. Kef is inhibited by glutathione (GSH) but activated by glutathione-S-conjugates (GS-X) formed in the presence of electrophiles. GSH and GS-X bind to overlapping sites on Kef, which are located in a cytosolic regulatory domain. The central paradox of this activation mechanism is that GSH is abundant in cells (at concentrations of ∼10-20 mM), and thus, activating ligands must possess a high differential over GSH in their affinity for Kef. To investigate the structural requirements for binding of a ligand to Kef, a novel fluorescent reporter ligand, S-{[5-(dimethylamino)naphthalen-1-yl]sulfonylaminopropyl} glutathione (DNGSH), was synthesized. By competition assays using DNGSH, complemented by direct binding assays and thermal shift measurements, we show that the well-characterized Kef activator, N-ethylsuccinimido-S-glutathione, has a 10-20-fold higher affinity for Kef than GSH. In contrast, another native ligand that is a poor activator, S-lactoylglutathione, exhibits a similar Kef affinity to GSH. Synthetic ligands were synthesized to contain either rigid or flexible structures and investigated as ligands for Kef. Compounds with rigid structures and high affinity activated Kef. In contrast, flexible ligands with similar binding affinities did not activate Kef. These data provide insight into the structural requirements for Kef gating, paving the way for the development of a screen for potential therapeutic lead compounds targeting the Kef system.

Peripheral ghrelin stimulates feeding behavior and positive energy balance in a sciurid hibernator.

Hibernators exhibit a robust circannual cycle of body mass gain and loss primarily mediated by food intake, but the pathways controlling food intake in these animals have not been fully elucidated. Ghrelin is an orexigenic hormone that increases feeding in all mammals studied so far, but has not until recently been studied in hibernators. In other mammals, ghrelin stimulates feeding through phosphorylation and activation of AMP-activated protein kinase (AMPK). Activation of AMPK phosphorylates and deactivates acetyl Co-A carboxylase (ACC), a committed step in fatty acid synthesis. In order to determine the effects of exogenous ghrelin on food intake and metabolic factors (i.e. non-esterified fatty acids (NEFAs), and hypothalamic AMPK and ACC) in hibernators, ghrelin was peripherally injected into ground squirrels in all four seasons. Changes in food intake and body mass were recorded over a 2-6 hour period post injections, and squirrels were euthanized. Brains and blood were removed, and Western blots were performed to determine changes in phosphorylation of hypothalamic AMPK and ACC. A colorimetric assay was used to determine changes in concentration of serum NEFAs. We found that food intake, body mass, and locomotor activity significantly increased with ghrelin injections versus saline-injected controls, even in animals injected during their aphagic winter season. Injected ghrelin was correlated with increased phosphorylation of AMPK, but didn't have an effect on ACC in winter. Ghrelin-injected animals also had increased levels of serum NEFAs compared with saline controls. This study is the first to show an effect of injected ghrelin on a hibernator.