Abstract
Copper (Cu)-deficiency-induced teratogenicity is characterized by major cardiac, brain, and vascular anomalies; however, the underlying mechanisms are poorly understood. Cu deficiency decreases superoxide dismutase activity and increases superoxide anions, which can interact with nitric oxide (NO), reducing the NO pool size. Given the role of NO as a developmental signaling molecule, we tested the hypothesis that low NO levels, secondary to Cu deficiency, represent a developmental challenge. Gestation day 8.5 embryos from Cu-adequate (Cu+) or Cu-deficient (Cu-) dams were cultured for 48 h in Cu+ or Cu- medium, respectively. We report that NO levels were low in conditioned medium from Cu-/Cu- embryos and yolk sacs, compared to Cu+/Cu+ controls under basal conditions and with NO synthase (NOS) agonists. The low NO production was associated with low endothelial NOS phosphorylation at serine 1177 and cyclic guanosine-3′,5′-monophosphate (cGMP) concentrations in the Cu-/Cu- group. The altered NO levels in Cu-deficient embryos are functionally significant, as the administration of the NO donor DETA/NONOate increased cGMP and ameliorated embryo and yolk sac abnormalities. These data support the concept that Cu deficiency limits NO availability and alters NO-dependent signaling, which contributes to abnormal embryo and yolk sac development.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1639-1648 |
| Number of pages | 10 |
| Journal | Free Radical Biology and Medicine |
| Volume | 43 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 15 2007 |
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Keywords
- Copper deficiency
- Cyclic GMP
- Embryo development
- Free radicals
- Nitric oxide
- Nutrition
- Oxidative stress
- Pregnancy
- Superoxide dismutase
- Yolk sac
ASJC Scopus subject areas
- Medicine(all)
- Toxicology
- Clinical Biochemistry
Cite this
Low nitric oxide : a key factor underlying copper-deficiency teratogenicity. / Yang, Soo Jin; Keen, Carl L; Lanoue, Louise; Rucker, Robert B.; Uriu-Adams, Janet Y.
In: Free Radical Biology and Medicine, Vol. 43, No. 12, 15.12.2007, p. 1639-1648.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Low nitric oxide
T2 - a key factor underlying copper-deficiency teratogenicity
AU - Yang, Soo Jin
AU - Keen, Carl L
AU - Lanoue, Louise
AU - Rucker, Robert B.
AU - Uriu-Adams, Janet Y.
PY - 2007/12/15
Y1 - 2007/12/15
N2 - Copper (Cu)-deficiency-induced teratogenicity is characterized by major cardiac, brain, and vascular anomalies; however, the underlying mechanisms are poorly understood. Cu deficiency decreases superoxide dismutase activity and increases superoxide anions, which can interact with nitric oxide (NO), reducing the NO pool size. Given the role of NO as a developmental signaling molecule, we tested the hypothesis that low NO levels, secondary to Cu deficiency, represent a developmental challenge. Gestation day 8.5 embryos from Cu-adequate (Cu+) or Cu-deficient (Cu-) dams were cultured for 48 h in Cu+ or Cu- medium, respectively. We report that NO levels were low in conditioned medium from Cu-/Cu- embryos and yolk sacs, compared to Cu+/Cu+ controls under basal conditions and with NO synthase (NOS) agonists. The low NO production was associated with low endothelial NOS phosphorylation at serine 1177 and cyclic guanosine-3′,5′-monophosphate (cGMP) concentrations in the Cu-/Cu- group. The altered NO levels in Cu-deficient embryos are functionally significant, as the administration of the NO donor DETA/NONOate increased cGMP and ameliorated embryo and yolk sac abnormalities. These data support the concept that Cu deficiency limits NO availability and alters NO-dependent signaling, which contributes to abnormal embryo and yolk sac development.
AB - Copper (Cu)-deficiency-induced teratogenicity is characterized by major cardiac, brain, and vascular anomalies; however, the underlying mechanisms are poorly understood. Cu deficiency decreases superoxide dismutase activity and increases superoxide anions, which can interact with nitric oxide (NO), reducing the NO pool size. Given the role of NO as a developmental signaling molecule, we tested the hypothesis that low NO levels, secondary to Cu deficiency, represent a developmental challenge. Gestation day 8.5 embryos from Cu-adequate (Cu+) or Cu-deficient (Cu-) dams were cultured for 48 h in Cu+ or Cu- medium, respectively. We report that NO levels were low in conditioned medium from Cu-/Cu- embryos and yolk sacs, compared to Cu+/Cu+ controls under basal conditions and with NO synthase (NOS) agonists. The low NO production was associated with low endothelial NOS phosphorylation at serine 1177 and cyclic guanosine-3′,5′-monophosphate (cGMP) concentrations in the Cu-/Cu- group. The altered NO levels in Cu-deficient embryos are functionally significant, as the administration of the NO donor DETA/NONOate increased cGMP and ameliorated embryo and yolk sac abnormalities. These data support the concept that Cu deficiency limits NO availability and alters NO-dependent signaling, which contributes to abnormal embryo and yolk sac development.
KW - Copper deficiency
KW - Cyclic GMP
KW - Embryo development
KW - Free radicals
KW - Nitric oxide
KW - Nutrition
KW - Oxidative stress
KW - Pregnancy
KW - Superoxide dismutase
KW - Yolk sac
UR - http://www.scopus.com/inward/record.url?scp=36248999362&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36248999362&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2007.08.031
DO - 10.1016/j.freeradbiomed.2007.08.031
M3 - Article
C2 - 18037129
AN - SCOPUS:36248999362
VL - 43
SP - 1639
EP - 1648
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
IS - 12
ER -