PMID- 29935188
OWN - NLM
STAT- MEDLINE
DCOM- 20190411
LR  - 20190901
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Print)
IS  - 0300-483X (Linking)
VI  - 408
DP  - 2018 Sep 1
TI  - Does growth impairment underlie the adverse effects of dexamethasone on 
      development of noradrenergic systems?
PG  - 11-21
LID - S0300-483X(18)30120-3 [pii]
LID - 10.1016/j.tox.2018.06.008 [doi]
AB  - Glucocorticoids are given in preterm labor to prevent respiratory distress but 
      these agents evoke neurobehavioral deficits in association with reduced brain 
      region volumes. To determine whether the neurodevelopmental effects are distinct 
      from growth impairment, we gave developing rats dexamethasone at doses below or 
      within the therapeutic range (0.05, 0.2 or 0.8 mg/kg) at different stages: 
      gestational days (GD) 17-19, postnatal days (PN) 1-3 or PN7-9. In adolescence and 
      adulthood, we assessed the impact on noradrenergic systems in multiple brain 
      regions, comparing the effects to those on somatic growth or on brain region 
      growth. Somatic growth was reduced with exposure in all three stages, with 
      greater sensitivity for the postnatal regimens; brain region growth was impaired 
      to a lesser extent. Norepinephrine content and concentration were reduced 
      depending on the treatment regimen, with a rank order of deficits of PN7-9 > 
      PN1-3 > GD17-19. However, brain growth impairment did not parallel reduced 
      norepinephrine content in magnitude, dose threshold, sex or regional selectivity, 
      or temporal pattern, and even when corrected for reduced brain region weights 
      (norepinephrine per g tissue), the dexamethasone-exposed animals showed subnormal 
      values. Regression analysis showed that somatic growth impairment accounted for 
      an insubstantial amount of the reduction in norepinephrine content, and brain 
      growth impairment accounted for only 12%, whereas specific effects on 
      norepinephrine accounted for most of the effect. The adverse effects of 
      dexamethasone on noradrenergic system development are not simply related to 
      impaired somatic or brain region growth, but rather include specific targeting of 
      neurodifferentiation.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Slotkin, Theodore A
AU  - Slotkin TA
AD  - Department of Pharmacology & Cancer Biology, Duke University Medical Center, 
      Durham, North Carolina, 27710, USA. Electronic address: t.slotkin@duke.edu.
FAU - Ko, Ashley
AU  - Ko A
AD  - Department of Pharmacology & Cancer Biology, Duke University Medical Center, 
      Durham, North Carolina, 27710, USA.
FAU - Seidler, Frederic J
AU  - Seidler FJ
AD  - Department of Pharmacology & Cancer Biology, Duke University Medical Center, 
      Durham, North Carolina, 27710, USA.
LA  - eng
GR  - P42 ES010356/ES/NIEHS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180620
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Glucocorticoids)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - X4W3ENH1CV (Norepinephrine)
SB  - IM
MH  - Adrenergic Neurons/*drug effects/metabolism
MH  - Age Factors
MH  - Animals
MH  - Brain/*drug effects/growth & development/metabolism
MH  - Dexamethasone/*toxicity
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Gestational Age
MH  - Glucocorticoids/*toxicity
MH  - Male
MH  - Neurogenesis/*drug effects
MH  - Norepinephrine/*metabolism
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects
MH  - Rats, Sprague-Dawley
MH  - Sex Factors
PMC - PMC6150779
MID - NIHMS977482
OTO - NOTNLM
OT  - Dexamethasone
OT  - Growth impairment
OT  - Norepinephrine
OT  - Preterm labor
COIS- Conflict of interest statement: TAS has received consultant income in the past 
      three years from Pardieck Law (Seymour, IN) and Walgreen Co. (Deerfield, IL).
EDAT- 2018/06/24 06:00
MHDA- 2019/04/12 06:00
PMCR- 2019/09/01
CRDT- 2018/06/24 06:00
PHST- 2018/04/13 00:00 [received]
PHST- 2018/05/15 00:00 [revised]
PHST- 2018/06/19 00:00 [accepted]
PHST- 2018/06/24 06:00 [pubmed]
PHST- 2019/04/12 06:00 [medline]
PHST- 2018/06/24 06:00 [entrez]
PHST- 2019/09/01 00:00 [pmc-release]
AID - S0300-483X(18)30120-3 [pii]
AID - 10.1016/j.tox.2018.06.008 [doi]
PST - ppublish
SO  - Toxicology. 2018 Sep 1;408:11-21. doi: 10.1016/j.tox.2018.06.008. Epub 2018 Jun 
      20.