Mary K Walker

University of New Mexico, Albuquerque, NM, United States

Are you Mary K Walker?

Claim your profile

Publications (31)95.61 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Dibenzo[def,p]chrysene (DBC) is a potent environmental carcinogen in rodents, fish, and human cells examined in culture. There are numerous similarities between the patterns of cytochrome P-450 (P450) activation of DBC and its covalent binding to DNA and proteins with another polycyclic aromatic hydrocarbon (PAH), 7,12-dimethylbenz[a]anthracene (DMBA). Our lab has previously shown that DMBA produces immunosuppression in rodents and human cell systems. Therefore, the purpose of these studies was to examine the immunotoxicity of DBC in a rodent model that was found to be sensitive to the immunosuppressive effects of DMBA. Data showed that DBC had similar potency to DMBA in producing suppression of a T-dependent antibody response (TDAR) and altered spleen cell subsets in a similar manner as DMBA when DMBA was given by gavage for 5 d in corn oil to mice at doses of 1-100 mg/kg total cumulative doses. T-cell-independent antigen (TNP-Ficoll) responses were quantitatively less sensitive to DBC suppression. It was also found that as with DMBA, DBC produced a persistent immunosuppression, which lasted for at least 4 wk following dosing with a novel pill method for self-administration of DBC. In conclusion, DBC appears to possess many of the same characteristics of DMBA in terms of its immunotoxicity.
    Journal of Toxicology and Environmental Health Part A 01/2013; 76(1):16-24. · 1.73 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: In vitro cytochrome P4501A1 (CYP1A1) metabolizes omega-3 polyunsaturated fatty acids (n-3 PUFAs); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily to 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP), respectively. These metabolites have been shown to mediate vasodilation via increases in nitric oxide (NO) and activation of potassium channels. We hypothesized that genetic deletion of CYP1A1 would reduce vasodilatory responses to n-3 PUFAs, but not the metabolites, and increase blood pressure (BP) due to decreases in NO. We assessed BP by radiotelemetry in CYP1A1 wildtype (WT) and knockout (KO) mice±NO synthase (NOS) inhibitor. We also assessed vasodilation to acetylcholine (ACh), EPA, DHA, 17,18-EEQ and 19,20-EDP in aorta and mesenteric arterioles. Further, we assessed vasodilation to an NO donor and to DHA±inhibitors of potassium channels. CYP1A1 KO mice were hypertensive, compared to WT, (mean BP in mmHg, WT 103±1, KO 116±1, n=5/genotype, p<0.05), and exhibited a reduced heart rate (beats per minute, WT 575±5; KO 530±7; p<0.05). However, BP responses to NOS inhibition and vasorelaxation responses to ACh and an NO donor were normal in CYP1A1 KO mice, suggesting that NO bioavailability was not reduced. In contrast, CYP1A1 KO mice exhibited significantly attenuated vasorelaxation responses to EPA and DHA in both the aorta and mesenteric arterioles, but normal vasorelaxation responses to the CYP1A1 metabolites, 17,18-EEQ and 19,20-EDP, and normal responses to potassium channel inhibition. Taken together these data suggest that CYP1A1 metabolizes n-3 PUFAs to vasodilators in vivo and the loss of these vasodilators may lead to increases in BP.
    Toxicology and Applied Pharmacology 09/2012; 264(3):351-60. · 3.98 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Oral gavage dosing can induce stress and potentially confound experimental measurements, particularly when blood pressure and heart rate are endpoints of interest. Thus, we developed a pill formulation that mice would voluntarily consume and tested the hypothesis that pill dosing would be significantly less stressful than oral gavage. C57Bl/6 male mice were singly housed and on four consecutive days were exposed to an individual walking into the room (week 1, control), a pill being placed into the cage (week 2), and a dose of water via oral gavage (week 3). Blood pressure and heart rate were recorded by radiotelemetry continuously for 5h after treatment, and feces collected 6-10h after treatment for analysis of corticosterone metabolites. Both pill and gavage dosing significantly increased mean arterial pressure (MAP) during the first hour, compared to control. However, the increase in MAP was significantly greater after gavage and remained elevated up to 5h, while MAP returned to normal within 2h after a pill. Neither pill nor gavage dosing significantly increased heart rate during the first hour, compared to control; however, pill dosing significantly reduced heart rate while gavage significantly increased heart rate 2-5h post dosing. MAP and heart rate did not differ 24h after dosing. Lastly, only gavage dosing significantly increased fecal corticosterone metabolites, indicating a systemic stress response via activation of the hypothalamic-pituitary-adrenal axis. These data demonstrated that this pill dosing method of mice is significantly less stressful than oral gavage.
    Toxicology and Applied Pharmacology 02/2012; 260(1):65-9. · 3.98 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Endogenous estrogens mediate protective effects in the cardiovascular system, affecting both endothelium-dependent and endothelium-independent mechanisms. Previous studies have suggested that nonselective estrogen receptor agonists such as endogenous estrogens inhibit endothelium-dependent vasoconstriction; however, the role of estrogen receptors in this response has not yet been clarified. This study investigated whether the intracellular transmembrane G protein-coupled estrogen receptor (GPER) regulates vascular reactivity in mice. Effects of chronic deficiency (using mice lacking the GPER gene) and acute inhibition (using the GPER-selective antagonist G15) on endothelium-dependent and endothelium-independent vascular reactivity, and the effects of GPER deficiency on vascular gene expression and structure were investigated. We found that chronic GPER deficiency is associated with increased endothelial prostanoid-mediated vasoconstriction but has no effect on endothelial nitric oxide bioactivity, gene expression of endothelial nitric oxide synthase and thromboxane prostanoid (TP) receptor, or vascular structure. GPER deletion also increases TP receptor-mediated contraction. Acute GPER blockade enhances endothelium-dependent contractions and reduces endothelial nitric oxide bioactivity. Contractions in response to TP receptor activation are unaffected by G15. In conclusion, this study identifies GPER as the first estrogen receptor with inhibitory activity on endothelium-dependent contractility. These findings may be important for understanding and treating diseases associated with increased endothelial vasoconstrictor prostanoid activity such as hypertension and obesity.
    Hypertension 12/2011; 59(2):507-12. · 6.87 Impact Factor
  • Source
    Larry N Agbor, Khalid M Elased, Mary K Walker
    [show abstract] [hide abstract]
    ABSTRACT: Hypotension in aryl hydrocarbon receptor knockout mice (ahr(-/-)) is mediated, in part, by a reduced contribution of angiotensin (Ang) II to basal blood pressure (BP). Since AHR is highly expressed in endothelial cells (EC), we hypothesized that EC-specific ahr(-/-) (ECahr(-/-)) mice would exhibit a similar phenotype. We generated ECahr(-/-) mice by crossing AHR floxed mice (ahr(fx/fx)) to mice expressing Cre recombinase driven by an EC-specific promoter. BP was assessed by radiotelemetry prior to and following an acute injection of Ang II or chronic treatment with an angiotensin converting enzyme inhibitor (ACEi). ECahr(-/-) mice were hypotensive (ECahr(+/+): 116.1±1.4; ECahr(-/-): 107.4±2.0 mmHg, n=11, p<0.05) and exhibited significantly different responses to Ang II and ACEi. While Ang II increased BP in both genotypes, the increase was sustained in ECahr(+/+), whereas the increase in ECahr(-/-) mice steadily declined. Area under the curve analysis showed that Ang II-induced increase in diastolic BP (DBP) over 30 min was significantly lower in ECahr(-/-) mice (ECahr(+/+) 1297±223 mmHg/30 min; ECahr(-/-)(AUC): 504±138 mmHg/30 min, p<0.05). In contrast, while ACEi decreased BP in both genotypes, the subsequent rise in DBP after treatment was significantly delayed in the ECahr(-/-) mice. ECahr(-/-) mice also exhibited reduced vascular and adipose Ang II type 1 receptor (AT1R) expression, and reduced aortic Ang II-dependent vasoconstriction in the presence of vascular adipose. Taken together these data suggest that hypotension in ECahr(-/-) mice results from reduced vascular responsiveness to Ang II that is influenced by AT1R expression and adipose.
    Biochemical pharmacology 06/2011; 82(5):514-23. · 4.25 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: There were no signs of overt toxicity in sexually mature female lake trout (Salvelinus namaycush) exposed to either a control or a 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-containing diet for 11 wk prior to spawning. At spawning the maternally derived egg TCDD concentrations were 42 ± 4 and 43 ± 6% of the maternal skeletal muscle TCDD concentration on a lipid and wet weight basis, respectively. Egg TCDD concentrations of 233–387 pg TCDD/g egg (wet weight) resulted in nonviable oocytes, while concentrations of 50–152 pg/g resulted in a dose-related increase in sac fry mortality associated with yolk sac edema, craniofacial alterations, and arrested development, resembling blue-sac disease. The dose–response relationship for sac fry mortality associated with blue-sac disease was essentially identical to that observed when fertilized lake trout eggs were exposed to either waterborne or injected TCDD. The no and lowest observable adverse effect levels for sac fry mortality were 23 and 50 pg/g (maternal egg exposure), 34 and 40 pg/g (waterborne egg exposure), and 44 and 55 pg/g (egg injection). LD50s, based on egg TCDD concentration, were 58 (36–90), 69 (64–75), and 80 (68–91) pg/g (95% fiducial limits) following egg exposure via maternal, waterborne, or injection routes, respectively.
    Canadian Journal of Fisheries and Aquatic Sciences 04/2011; 51(6):1410-1419. · 2.32 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Lake trout (Salvelinus namaycush) eggs containing [3H]TCDD concentrations from 0 to 302 parts per trillion (ppt) were observed through the fry stage for TCDD metabolism, elimination, and toxicity. All radioactive residues extracted from eggs and sac fry were due to TCDD; no metabolites were detected. [3H]TCDD was not eliminated from eggs and sac fry, but was rapidly eliminated from fry (t1/2, 35–37 d). Hatchability was less at egg TCDD concentrations ; however, the greatest TCDD-related mortality occurred during the sac fry stage. In all TCDD groups (34–302 ppt), sac fry that died developed subcutaneous yolk sac edema prior to death, resembling blue-sac disease. The development of yolk sac edema preceded sac fry mortality, and the severity of edema varied directly with cumulative mortality. Based on TCDD concentrations in the egg resulting from a 48-h exposure, the no observable adverse effect level (NOAEL) for mortality was 34 ppt and the lowest observable adverse effect level (LOAEL) was 55 ppt. The TCDD concentration in eggs that caused 50% mortality above control at swim-up (LD50) was 65 ppt. Lake trout sac fry exposed as eggs are more sensitive to the lethal effects of TCDD than any mammalian, avian, or fish species investigated thus far.
    Canadian Journal of Fisheries and Aquatic Sciences 04/2011; 48(5):875-883. · 2.32 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: National Health and Nutrition Examination Survey data show an association between hypertension and exposure to dioxin-like halogenated aromatic hydrocarbons (HAHs). Furthermore, chronic exposure of mice to the prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces reactive oxygen species (ROS), endothelial dysfunction, and hypertension. Because TCDD induces cytochrome P4501A1 (CYP1A1) and CYP1A1 can increase ROS, we tested the hypothesis that TCDD-induced endothelial dysfunction and hypertension are mediated by CYP1A1. CYP1A1 wild-type (WT) and knockout (KO) mice were fed one control or TCDD-containing pill (180 ng TCDD/kg, 5 days/week) for 35 days (n = 10-14/genotype/treatment). Blood pressure was monitored by radiotelemetry, and liver TCDD concentration, CYP1A1 induction, ROS, and aortic reactivity were measured at 35 days. TCDD accumulated to similar levels in livers of both genotypes. TCDD induced CYP1A1 in endothelium of aorta and mesentery without detectable expression in the vessel wall. TCDD also induced superoxide anion production, measured by NADPH-dependent lucigenin luminescence, in aorta, heart, and kidney of CYP1A1 WT mice but not KO mice. In contrast, TCDD induced hydrogen peroxide, measured by amplex red assay, to similar levels in aorta of CYP1A1 WT and KO mice but not in heart or kidney. TCDD reduced acetylcholine-dependent vasorelaxation in aortic rings of CYP1A1 WT mice but not in KO mice. Finally, TCDD steadily increased blood pressure after 15 days, which plateaued after 25 days (+20 mmHg) in CYP1A1 WT mice but failed to alter blood pressure in KO mice. These results demonstrate that CYP1A1 is required for TCDD-induced cardiovascular superoxide anion production, endothelial dysfunction, and hypertension.
    Toxicological Sciences 10/2010; 117(2):537-46. · 4.33 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Sleep apnea (SA) is defined as intermittent respiratory arrest during sleep and affects up to 20% of the adult population. SA is also associated with an increased incidence of hypertension and peripheral vascular disease. Exposing rodents to intermittent hypoxia during sleep mimics the cyclical hypoxia/normoxia of SA. We have previously shown that in mice and rats intermittent hypoxia induces ET-1 upregulation and systemic hypertension. Furthermore, intermittent hypoxia (IH) in mice increases nuclear factor of activated T cells isoform 3 (NFATc3) transcriptional activity in aorta and mesenteric arteries, whereas the calcineurin/NFAT inhibitor cyclosporin A prevents IH-induced hypertension. More importantly, NFATc3 knockout (KO) mice do not develop IH-induced hypertension. The goals of this study were to determine the role of NFATc3 in IH-induced arterial remodeling and whether IH-induced NFATc3 activation is mediated by ET-1. Oral administration of both a dual (bosentan) and a selective endothelin receptor type A antagonist (PD155080) during 2 days of IH exposure attenuated NFAT activation in aorta and mesenteric arteries. Rho kinase inhibition with fasudil also prevented IH-induced NFAT activation. Mesenteric artery cross-sectional wall thickness was increased by IH in wild-type (WT) and vehicle-treated mice but not in bosentan-treated and NFATc3 KO mice. The arterial remodeling in mesenteric arteries after IH was characterized by increased expression of the hypertrophic NFATc3 target smooth muscle-alpha-actin in WT but not in KO mice. These results indicate that ET-1 is an upstream activator of NFATc3 during intermittent hypoxia, contributing to the resultant hypertension and increased wall thickness.
    AJP Heart and Circulatory Physiology 08/2010; 299(2):H356-63. · 3.63 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: It has been postulated that fetal vascular abnormalities in aryl hydrocarbon receptor null (ahr(-/-)) mice may alter cardiovascular homeostasis in adulthood. We tested the hypothesis that blood pressure regulation in adult heterozygous mice (ahr(+/-)) would be normal, compared to ahr(-/-) mice, since no vascular abnormalities have been reported in the heterozygote animals. Mean arterial blood pressure (MAP) was measured using radiotelemetry prior to and during treatment with inhibitors of the autonomic nervous system, nitric oxide synthase (NOS), angiotensin converting enzyme (ACE), or endothelin-1 A receptor (ET(A)). Also, indices of renin-angiotensin system (RAS) activation were measured. ahr(+/-) and ahr(-/-) mice were normotensive and hypotensive, respectively, compared to wild-type (ahr(+/+)) littermates. Responses of all genotypes to autonomic nervous system inhibition were normal. ahr(+/-) mice responded normally to NOS inhibition, while the responses of ahr(-/-) mice were significantly blunted. In contrast, ahr(+/-) mice were significantly more responsive to inhibition of ACE, an ET(A) antagonist, or both, while ahr(-/-) mice were significantly less responsive to ACE inhibition and more responsive to an ET(A) antagonist. ahr(+/-) mice also exhibited significant increases in plasma renin and ACE activity, plasma sodium, and urine osmolality, indicative of RAS activation. Thus, normotension in ahr(+/-) mice appears to be maintained by increased RAS and ET-1 signaling, while hypotension in ahr(-/-) mice may result from decreased RAS signaling. In conclusion, despite the lack of overt fetal vascular abnormalities in ahr(+/-) mice, the loss of a single ahr allele has a significant effect on blood pressure regulation.
    Biochemical pharmacology 03/2010; 80(2):197-204. · 4.25 Impact Factor
  • Robin E. Jung, Mary K. Walker
    [show abstract] [hide abstract]
    ABSTRACT: We exposed anuran eggs and tadpoles to vehicle control (0.7% acetone) or waterborne [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 24 h (American toad, 0.003-30 μg/L; leopard frog, 3 μg/L; green frog, 0.3-100 μg/L) and subsequently raised them in clean water. Neither American toads nor green frogs exhibited TCDD-related mortality, but leopard frogs showed significantly increased (10%) mortality over controls. Eggs and tadpoles eliminated TCDD relatively quickly compared with published data for other vertebrates, with t1/2 of 1 to 5 d (American toad), 2 to 7 d (leopard frog), and 4 to 6 d (green frog). Elimination rates were slowest for tadpoles fed nothing, fastest for those fed a low-fat diet, and intermediate for those fed a high-fat diet. Although not significant, American toads exposed to ⩾0.03 μg TCDD/L appeared to metamorphose earlier, and those exposed to higher TCDD treatments appeared to metamorphose at a larger body mass than controls. Comparisons of these results with studies of fish early life stages suggest that anuran eggs and tadpoles eliminate TCDD more rapidly and are 100- to 1,000-fold less sensitive to its deleterious effects during development. These differences may be related to differences in metabolic rate, patterns of lipid storage and utilization, and aryl hydrocarbon receptor binding and signal transduction.
    Environmental Toxicology and Chemistry 10/2009; 16(2):230 - 240. · 2.62 Impact Factor
  • Mary K. Walker, Richard E. Peterson
    [show abstract] [hide abstract]
    ABSTRACT: The sensitivity of early life stages of brook trout (Salvelinus fontinalis) to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity was investigated. Newly fertilized eggs were exposed for 48 h to water containing either acetone or a range of concentrations of [3H]TCDD dissolved in acetone. Eggs were then transferred to TCDD-free water and observed through development. TCDD concentrations of 101 to 470 pg/g in the eggs caused dose-related increases in sac-fry mortality associated with yolk-sac edema, hemorrhages, and arrested development. These signs of TCDD-induced toxicity resemble blue-sac disease. The NOELs and LOELs for sac-fry mortality were 135 and 185 pg TCDD/g egg, respectively, whereas the LD50 and LD100 (95% fiducial limits) were 200 (179-215) and 324 (283-488) pg/g egg, respectively. The time course and signs of TCDD toxicity to brook trout during early development are essentially identical to those observed in both rainbow trout and lake trout following TCDD exposure of their eggs via water or injection, and in lake trout exposed to maternally derived TCDD. Brook trout sac fry are intermediate in sensitivity to TCDD-induced lethality compared to lake trout and rainbow trout.
    Environmental Toxicology and Chemistry 10/2009; 13(5):817 - 820. · 2.62 Impact Factor
  • Phillip G Kopf, Mary K Walker
    [show abstract] [hide abstract]
    ABSTRACT: The developing cardiovascular system is a sensitive target of many environmental pollutants, including dioxins, dioxin-like polychlorinated biphenyls (PCBs), and some pesticides such as methyl parathion. Laboratory research has utilized a variety of vertebrate models to elucidate potential mechanisms that mediate this cardioteratogenicity and to establish the sensitivity of different species for predicting potential risk to environmental and human health. Studies of dioxin and dioxin-like PCBs have illustrated that piscine, avian, and mammalian embryos exhibit cardiovascular structural changes and functional deficits, although the specific characteristics vary among the individual models. Piscine models typically exhibit reduced blood flow, altered heart looping, and reduced heart size and contraction rate. The chick embryo exhibits extensive cardiac dilation, thinner ventricle walls, and reduced responsiveness to chronotropic stimuli, while the murine embryo exhibits reduced heart size. It is notable that in all models the dioxin-associated cardioteratogenicity is associated with increases in cardiovascular apoptosis and decreases in cardiocyte proliferation. While the cardiotertogenicity in piscine and avian species is associated with overt morbidity and mortality, that is not the case for the murine embryo. However, murine offspring exposed during development to dioxin exhibit cardiac hypertrophy and an increased sensitivity to a second cardiovascular insult in adulthood. Thus, although the mammalian embryo is less sensitive to cardiovascular defects by dioxin and dioxin-like compounds, developmental exposure increases the risk of cardiovascular disease later in life. The impact of developmental exposure to dioxin-like chemicals on human cardiovascular disease susceptibility is not known. However, recent animal research has confirmed human epidemiology studies that dioxin exposure in adulthood is associated with hypertension and cardiovascular disease.
    Journal of Environmental Science and Health Part C Environmental Carcinogenesis & Ecotoxicology Reviews 10/2009; 27(4):276-85. · 3.23 Impact Factor
  • Source
    Phillip G Kopf, Janice K Huwe, Mary K Walker
    [show abstract] [hide abstract]
    ABSTRACT: The mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the incidence of human cardiovascular disease are not known. We investigated the degree to which cardiovascular disease develops in mice following subchronic TCDD exposure. Adult male C57BL/6 mice were dosed with vehicle or 300 ng TCDD/kg by oral gavage three times per week for 60 days. Blood pressure was recorded by radiotelemetry and aortic endothelial function was assessed by acetylcholine-induced vasorelaxation. Mean arterial pressure of TCDD-exposed mice was increased significantly by day 4 and between days 7-10, 25-35, and 45-60 with two periods of normalization on days 11-24 and days 36-39. Consistent with a prolonged period of systemic hypertension, heart weight was increased and was associated with concentric left ventricular hypertrophy. Significant increases in superoxide production also were observed in the kidney, heart, and aorta of TCDD-exposed mice. Furthermore, increased aortic superoxide resulted in endothelial dysfunction as demonstrated by significant impairment of acetylcholine-induced vasorelaxation in TCDD-exposed mice, which was restored by tempol, a superoxide dismutase (SOD) mimetic. Our model is the first to definitely demonstrate that sustained AhR activation by TCDD increases blood pressure and induces cardiac hypertrophy, which may be mediated, in part, by increased superoxide.
    Cardiovascular toxicology 11/2008; 8(4):181-93. · 2.56 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that mediates induction of metabolic enzymes and toxicity of certain environmental pollutants. Although AHR knockout (KO) mice develop cardiac hypertrophy, conflicting reports associate this pathology with hypotension or endothelin (ET)-1-dependent hypertension. Because hypertension occurred at modest altitude, we tested the hypothesis that loss of AHR increases the sensitivity to hypoxia-induced ET-1, contributing to systemic hypertension. We found that AHR KO mice were hypertensive at modest altitude (1632 m) but hypotensive at low altitude (225 m). When AHR KO mice residing at 1632 m were exposed to the partial pressure of inspired oxygen (PIO(2)) at sea level for 11 days, blood pressure declined to levels measured at 225 m. Although plasma ET-1 in AHR KO mice was significantly elevated at 1632 m and decreased at 225 m and sea level PIO(2), pulmonary prepro-ET-1 mRNA was significantly reduced at 1632 m and decreased further at 225 m and sea level PIO(2). Blood gas analysis revealed that AHR KO mice were hypoxemic, hypercapnic, and acidotic at 1632 m, values that were attenuated and normalized after 24 hours and 11 days under sea level PIO(2), respectively. Lastly, AHR inactivation in endothelial cells by small interfering RNA significantly reduced basal prepro-ET-1 mRNA but did not alter hypoxia-induced expression. Our studies establish the AHR KO mouse as a model in which modest decreases in PIO(2) lead to hypoxemia, increased plasma ET-1, and systemic hypertension without increased pulmonary prepro-ET-1 mRNA expression.
    Hypertension 04/2008; 51(3):803-9. · 6.87 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The mouse heart is a target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during fetal development, and microarray analysis demonstrates significant changes in expression of cardiac genes involved in extracellular matrix (ECM) remodeling. We tested the hypothesis that developmental TCDD exposure would disrupt cardiac ECM expression and be associated with changes in cardiac morphology in adulthood. In one study, time-pregnant C57BL/6 mice were dosed with corn oil or 1.5, 3.0, or 6.0 microg TCDD/kg on gestation day (GD) 14.5 and sacrificed on GD 17.5, when changes in fetal cardiac mRNA expression were analyzed using quantitative PCR. TCDD induced mRNA expression of genes associated with ECM remodeling (matrix metalloproteinase 9 and 13, preproendothelin-1 [preproET-1]), cardiac hypertrophy (atrial natriuretic peptide, beta-myosin heavy chain, osteopontin), and aryl hydrocarbon receptor (AHR) activation (cytochrome P4501A1, AHR repressor). Further, all TCDD-induced changes required the AHR since gene expression was not altered in AHR knockout fetuses. In a second study, time-pregnant mice were treated with corn oil or 6.0 microg TCDD/kg on GD 14.5, and male offspring were assessed for changes in cardiac gene expression and cardiac and renal morphology at 3 months. All TCDD-induced changes in cardiac gene expression observed fetally, except for preproET-1, remained induced in the hearts of adult male offspring. Adult male offspring of TCDD-exposed dams also displayed cardiac hypertrophy, decreased plasma volume, and mild hydronephrosis. These results demonstrate that in utero and lactational TCDD exposures alter cardiac gene expression and cardiac and renal morphology in adulthood, which may increase the susceptibility to cardiovascular dysfunction.
    Toxicological Sciences 03/2008; 101(2):321-30. · 4.33 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: In utero and lactational exposure of mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to cardiac hypertrophy and hydronephrosis in adulthood. We tested the hypothesis that perinatal TCDD exposure increases the susceptibility to cardiovascular disease when offspring are exposed to a common cardiovascular disease risk factor, angiotensin II (Ang II). Pregnant C57BL/6N mice were exposed to corn oil (control) or 6.0 microg/kg TCDD on gestation day 14.5. Male offspring were then exposed to a subpressor (0.1 mg/kg/day) or pressor (0.7 mg/kg/day) dose of Ang II at 3.5 months and cardiac morphology and blood pressure analyzed, respectively. Perinatal TCDD exposure increased left ventricular cavity dilation during diastole, and wall thickness during diastole and systole. While Ang II stimulated an increase in wall thickness, the degree of increase was equivalent between control and TCDD offspring. In contrast, perinatal TCDD exposure did not alter basal blood pressure. However, Ang II increased systolic blood pressure more rapidly and to a greater degree in TCDD offspring. Further, Ang II stimulated renal myofibroblast differentiation and collagen deposition to a greater degree, and tended to increase procollagen I mRNA in TCDD offspring, compared to controls. These data suggest that perinatal TCDD exposure increases the susceptibility of offspring to renal fibrosis and hypertension in adulthood.
    Cardiovascular Toxicology 02/2008; 8(3):145-54. · 2.35 Impact Factor
  • Source
    Nan Zhang, Mary K Walker
    [show abstract] [hide abstract]
    ABSTRACT: Endothelial cells are a target of halogenated aromatic hydrocarbon toxicity following aryl hydrocarbon receptor (AHR) activation. Further, evidence suggests that AHR has a physiological function in endothelial cells in the absence of exogenous ligands. Understanding these "normal" functions of AHR may help to reveal the mechanisms that contribute to the toxicity of xenobiotic ligands. Thus, this study focused on the crosstalk between hypoxia and AHR in the absence of exogenous ligands. Constitutive CYP1A1 mRNA was measured by real time PCR in human pulmonary microvascular endothelial cells exposed to hypoxia (1 or 2.5% O2), 25 nM AHR siRNA, 25 nM hypoxia-inducible factor (HIF)-2alpha siRNA, or their combinations. Hypoxia significantly induced known hypoxia-regulated genes, and this induction was highly attenuated by HIF-2alpha siRNA, suggesting that HIF-2alpha is a primary mediator of hypoxic responses in these cells. Hypoxia also significantly reduced CYP1A1 mRNA and this reduction was also attenuated by HIF-2alpha siRNA. As expected, AHR siRNA significantly reduced constitutive CYP1A1 mRNA. While the combination of hypoxia plus AHR siRNA reduced CYP1A1 mRNA more than either treatment alone, the reduction was less than additive, suggesting that hypoxia and AHR deficiency may share a common pathway in reducing CYP1A1 expression. Finally, hypoxia significantly reduced AHR mRNA and this reduction was completely prevented by HIF-2alpha siRNA. In conclusion, constitutive CYP1A1 mRNA expression is dependent on AHR and is reduced by hypoxia via a HIF-2alpha-dependent mechanism, which may be mediated by a HIF-2alpha-dependent reduction of AHR expression.
    Cardiovascular Toxicology 02/2007; 7(4):282-90. · 2.35 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ETA receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, beta-myosin heavy chain (beta-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ETA receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and beta-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ETA receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.
    Toxicology and Applied Pharmacology 05/2006; 212(2):127-35. · 3.98 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of the AhR results in cardiac hypertrophy that is mediated primarily by endothelin-1 (ET-1); ET-1 has been implicated in the elevation of reactive oxygen species (ROS) in the heart, which are thought to contribute to several cardiovascular disorders, including cardiac hypertrophy. Thus, we tested the novel hypothesis that ET-1 induces ROS in AhR null mice via ET(A) receptor activation. We first confirmed the presence of ROS in the hearts of AhR null mice by measuring superoxide (O2*-)-dependent oxidation of dihydroethidium. Ethidium fluorescence was increased 10-fold in the hearts of AhR null mice, compared to the wild type. Then, to elucidate whether ET-1 mediated the increase in ROS, mice were chronically treated with 100 ng/kg/day of the ET(A) receptor antagonist BQ-123. In AhR null mice, BQ-123 significantly reduced elevated plasma 8-isoprostane, a systemic end product of phospholipid oxidation by ROS, and cardiac thiobarbituric acid reactive substances (TBARS), a nonspecific assessment of ROS production. Furthermore, BQ-123 reduced both cardiac lucigenin chemiluminescence and cardiac mRNA expression of NAD(P)H oxidase subunits gp91phox, p47phox, and p67phox in AhR null mice below the levels observed in wild-type mice. These findings demonstrate that ET-1 activation of ET(A) receptors mediates an increase in ROS that is associated with cardiac hypertrophy in AhR null mice. In addition, the ET-1-mediated increase in ROS appears to be initiated via increased NAD(P)H oxidase activity.
    Toxicological Sciences 12/2005; 88(1):265-73. · 4.33 Impact Factor

Publication Stats

670 Citations
95.61 Total Impact Points


  • 2003–2012
    • University of New Mexico
      • • Department of Pharmaceutical Sciences
      • • College of Pharmacy
      • • Department of Pediatrics
      • • School of Medicine
      Albuquerque, NM, United States
    • United States Environmental Protection Agency
      • Mid-Continent Ecology Division
      Washington, D. C., DC, United States
  • 1991–2009
    • University of Wisconsin, Madison
      • School of Pharmacy
      Madison, MS, United States
  • 2005
    • Bates College
      Lewiston, Maine, United States
  • 1992
    • University of Wisconsin - Oshkosh
      Oshkosh, Wisconsin, United States