PMID- 31734307
OWN - NLM
STAT- MEDLINE
DCOM- 20210122
LR  - 20211204
IS  - 1873-6823 (Electronic)
IS  - 0741-8329 (Print)
IS  - 0741-8329 (Linking)
VI  - 84
DP  - 2020 May
TI  - Maternal iron nutriture modulates placental development in a rat model of fetal 
      alcohol spectrum disorder.
PG  - 57-66
LID - S0741-8329(19)30196-X [pii]
LID - 10.1016/j.alcohol.2019.11.003 [doi]
AB  - Prenatal alcohol exposure (PAE) causes developmental abnormalities known as fetal 
      alcohol spectrum disorder (FASD). Maternal iron status modulates the severity of 
      these defects in the offspring. Because the placenta is central in supporting 
      fetal development, we investigated whether maternal iron status similarly 
      modulates alcohol's effects in the placenta. We hypothesized that PAE causes 
      placental insufficiency by decreasing placental weight and efficiency, and we 
      hypothesized that these are worsened by maternal iron deficiency (ID) and 
      alleviated by dietary iron fortification (IF). We also determined whether altered 
      placental iron flux and inflammatory balance contribute to placental 
      insufficiency. Pregnant Long-Evans rats consumed an iron-deficient (ID; 2-6 ppm), 
      iron-sufficient (IS; 100 ppm), or iron-fortified (IF; 500 ppm) diet. Alcohol 
      (5 g/kg body weight) or isocaloric maltodextrin (MD) was gavaged daily from 
      gestational day (GD) 13.5-19.5. Placental outcomes were evaluated on GD20.5. PAE 
      reduced fetal weight (p < 0.0001), placental weight (p = 0.0324), and placental 
      efficiency (p = 0.0043). PAE downregulated placental transferrin receptor 
      (p = 0.0032); it also altered placental Il1b and Tnf expression and the Il6:Il10 
      ratio (p = 0.0337, 0.0300, and 0.0034, respectively) to generate a response 
      favoring inflammation. ID-PAE further reduced fetal growth and placental 
      efficiency and induced a heightened pro-inflammatory placental profile. IF did 
      not rescue the alcohol-reduced fetal weight, but it normalized placental 
      efficiency and decreased placental inflammation. These placental cytokines 
      correlated with fetal and placental growth, and explained 45% of the variability 
      in fetal weight and 20% of the variability in placental efficiency. In summary, 
      alcohol induces placental insufficiency and is associated with a pro-inflammatory 
      cytokine profile exacerbated by maternal ID and mitigated by maternal IF. Because 
      the placenta is closely linked to intrauterine growth, the placental 
      insufficiency reported here may correlate with the lower birth weights in a 
      subgroup of individuals who experienced PAE.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Kwan, Sze Ting Cecilia
AU  - Kwan STC
AD  - Nutrition Research Institute, University of North Carolina at Chapel Hill, 
      Kannapolis, NC, 28081, United States.
FAU - Kezer, Camille A
AU  - Kezer CA
AD  - Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, 
      53706, United States.
FAU - Helfrich, Kaylee K
AU  - Helfrich KK
AD  - Nutrition Research Institute, University of North Carolina at Chapel Hill, 
      Kannapolis, NC, 28081, United States.
FAU - Saini, Nipun
AU  - Saini N
AD  - Nutrition Research Institute, University of North Carolina at Chapel Hill, 
      Kannapolis, NC, 28081, United States.
FAU - Huebner, Shane M
AU  - Huebner SM
AD  - Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, 
      53706, United States.
FAU - Flentke, George R
AU  - Flentke GR
AD  - Nutrition Research Institute, University of North Carolina at Chapel Hill, 
      Kannapolis, NC, 28081, United States.
FAU - Kling, Pamela J
AU  - Kling PJ
AD  - Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, 53715, 
      United States.
FAU - Smith, Susan M
AU  - Smith SM
AD  - Nutrition Research Institute, University of North Carolina at Chapel Hill, 
      Kannapolis, NC, 28081, United States; Department of Nutritional Sciences, 
      University of Wisconsin-Madison, Madison, WI, 53706, United States. Electronic 
      address: Susan_Smith@unc.edu.
LA  - eng
GR  - R01 AA011085/AA/NIAAA NIH HHS/United States
GR  - F32 AA021311/AA/NIAAA NIH HHS/United States
GR  - F32 AA027121/AA/NIAAA NIH HHS/United States
GR  - T32 DK007686/DK/NIDDK NIH HHS/United States
GR  - R01 AA022999/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20191114
PL  - United States
TA  - Alcohol
JT  - Alcohol (Fayetteville, N.Y.)
JID - 8502311
RN  - 0 (Cytokines)
RN  - 0 (Iron, Dietary)
RN  - 3K9958V90M (Ethanol)
SB  - IM
MH  - Animals
MH  - Cytokines/*metabolism
MH  - Disease Models, Animal
MH  - Ethanol/*administration & dosage
MH  - Female
MH  - *Fetal Alcohol Spectrum Disorders
MH  - Inflammation
MH  - *Iron Deficiencies
MH  - Iron, Dietary/*administration & dosage
MH  - *Maternal Nutritional Physiological Phenomena
MH  - Placentation/*drug effects
MH  - Pregnancy
MH  - Rats
MH  - Rats, Long-Evans
PMC - PMC7131893
MID - NIHMS1556129
OTO - NOTNLM
OT  - Fetal development
OT  - Inflammatory cytokines
OT  - Iron
OT  - Placental insufficiency
OT  - Prenatal alcohol exposure
COIS- Declaration of Interest: None
EDAT- 2019/11/18 06:00
MHDA- 2021/01/23 06:00
PMCR- 2021/05/01
CRDT- 2019/11/18 06:00
PHST- 2019/08/28 00:00 [received]
PHST- 2019/11/01 00:00 [revised]
PHST- 2019/11/04 00:00 [accepted]
PHST- 2019/11/18 06:00 [pubmed]
PHST- 2021/01/23 06:00 [medline]
PHST- 2019/11/18 06:00 [entrez]
PHST- 2021/05/01 00:00 [pmc-release]
AID - S0741-8329(19)30196-X [pii]
AID - 10.1016/j.alcohol.2019.11.003 [doi]
PST - ppublish
SO  - Alcohol. 2020 May;84:57-66. doi: 10.1016/j.alcohol.2019.11.003. Epub 2019 Nov 14.