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.

Niacin increases adiponectin and decreases adipose tissue inflammation in high fat diet-fed mice.

AIMS: To determine the effects of niacin on adiponectin and markers of adipose tissue inflammation in a mouse model of obesity. MATERIALS AND METHODS: Male C57BL/6 mice were placed on a control or high-fat diet (HFD) and were maintained on such diets for the duration of the study. After 6 weeks on the control or high fat diets, vehicle or niacin treatments were initiated and maintained for 5 weeks. Identical studies were conducted concurrently in HCA2 (-/-) (niacin receptor(-/-)) mice. RESULTS: Niacin increased serum concentrations of the anti-inflammatory adipokine, adiponectin by 21% in HFD-fed wild-type mice, but had no effect on lean wild-type or lean or HFD-fed HCA2 (-/-) mice. Niacin increased adiponectin gene and protein expression in the HFD-fed wild-type mice only. The increases in adiponectin serum concentrations, gene and protein expression occurred independently of changes in expression of PPARγ C/EBPα or SREBP-1c (key transcription factors known to positively regulate adiponectin gene transcription) in the adipose tissue. Further, niacin had no effect on adipose tissue expression of ERp44, Ero1-Lα, or DsbA-L (key ER chaperones involved in adiponectin production and secretion). However, niacin treatment attenuated HFD-induced increases in adipose tissue gene expression of MCP-1 and IL-1ß in the wild-type HFD-fed mice. Niacin also reduced the expression of the pro-inflammatory M1 macrophage marker CD11c in HFD-fed wild-type mice. CONCLUSIONS: Niacin treatment attenuates obesity-induced adipose tissue inflammation through increased adiponectin and anti-inflammatory cytokine expression and reduced pro-inflammatory cytokine expression in a niacin receptor-dependent manner.

Plasma phenylalanine concentrations are associated with hepatic iron content in a murine model for phenylketonuria.

Individuals with phenylketonuria (PKU) have been reported to have altered trace mineral status. In this study, we evaluated in a murine PKU model whether protein level and level of phenylalanine (PHE) restriction could modulate iron, copper, and zinc status. Fifty-four male weanling PKU and control mice were assigned to receive for 56 days an elemental low or normal protein diet; PKU mice also were assigned to receive PHE restriction (treated) or no restriction (untreated). PHE-restricted mice consumed a prescribed dietary PHE to maintain plasma PHE concentrations between 120 and 480 micromol/L. PHE-unrestricted and control mice received equal amounts of dietary PHE. Intestinal and hepatic copper, iron, and zinc were measured at day 56 and fecal minerals measured at baseline and day 56. Mean plasma PHE concentrations were significantly greater in PKU PHE-unrestricted versus PKU PHE-restricted mice and control mice. Mean intestinal weights when normalized for body weight were significantly greater in PKU mice versus control mice. PKU PHE-unrestricted mice had significantly lower hepatic copper and zinc than PKU PHE-restricted mice, and significantly greater hepatic iron than control and PKU PHE-restricted mice. PKU PHE-unrestricted mice on a low protein diet had hepatic iron concentrations about 1.5 times that of the other mice. Fecal iron concentrations in all mice were significantly greater at day 56 than at baseline. No animal group effects or protein level effects were found for fecal copper, iron, or zinc contents. We conclude that hyperphenylalaninemia alters the metabolism of iron, copper, and zinc in PKU mice.

Non-anemic iron depletion, oral iron supplementation and indices of copper status in college-aged females.

OBJECTIVES: Indices of copper status, specifically serum copper and ceruloplasmin concentrations and erythrocyte superoxide dismutase activity, and iron status, including serum ferritin, transferrin receptors, hemoglobin and hematocrit, were studied in 27 college-aged females with adequate iron versus low iron stores. METHODS: Serum copper and ceruloplasmin concentrations, erythrocyte superoxide dismutase activity, serum ferritin, transferrin receptors, hemoglobin and hematocrit were studied in 15 females with non-anemic iron depletion before and after five weeks of iron supplementation and in 12 healthy iron-adequate females aged 19 to 28 years. RESULTS: Mean hemoglobin, hematocrit and ferritin concentrations of the control group (144 +/- 11 g/L, 43 +/- 3% and 38 +/- 15 micro g/L, respectively) were significantly higher than those of the iron depleted group prior to supplementation (134 +/- 9 g/L, 39 +/- 2% and 11 +/- 6 micro g/L, respectively). The serum transferrin receptor to serum ferritin ratio was significantly greater for the iron depleted group prior to supplementation (890 +/- 753) versus the control group (151 +/- 61). Mean serum copper and ceruloplasmin concentrations and erythrocyte superoxide dismutase activity of the iron-adequate control group (20.0 +/- 5.7 micro mol/L, 463 +/- 142 mg/L and 527 +/- 124 U/mL, respectively) were significantly higher than those of the iron depleted group (12.4 +/- 3.8 micro mol/L, 350 +/- 108 mg/L and 353 +/- 186 U/mL, respectively) prior to supplementation. Following iron supplementation, hematocrit and ferritin concentrations of the iron depleted group significantly increased to 42 +/- 3% and 26 +/- 8 micro g/L, respectively. Mean serum transferrin receptor concentrations and the serum transferrin receptor to ferritin ratios significantly decreased in the iron depleted group following supplementation (6.1 +/- 1.6 mg/L to 4.6 +/- 1.5 mg/L and 890 +/- 753 to 198 +/- 114, respectively). Iron supplementation also significantly increased the mean serum copper concentration to 14.2 +/- 5.4 micro mol/L and, in subjects with serum ferritin concentrations