Effects of acute alcohol intoxication in the second trimester of pregnancy on development of the murine fetal lung

doi:10.1016/j.ajog.2007.06.031

American Journal of Obstetrics and Gynecology

Volume 197, Issue 3, September 2007, Pages 269.e1-269.e4

Presented at the 27th Annual Clinical Meeting of the Society for Maternal–Fetal Medicine, San Francisco, CA, Feb. 5-10, 2007.

https://doi.org/10.1016/j.ajog.2007.06.031 Get rights and content

Objective

We hypothesized that administration of alcohol during the second trimester of gestation at the pseudoglandular phase of lung development might lead to aberrant differentiation and growth, similar to that seen in congenital cystic adenomatoid malformation in human. We further hypothesized that these effects would be apparent morphologically and by altered Hoxb5 expression.

Study Design

C57BL/6J mice, exposed to ethanol at embryonic day (E) 11.5 to E13.5, which corresponds to the pseudoglandular stage of lung development, were examined at E18.5. The lungs were analyzed histologically by immunostaining.

Results

The average body and lung weight of alcohol-exposed (AE) fetuses were lower than those of control fetuses, the reduction in lung mass being more than the body weight. Histology showed that AE lungs were less developed and exhibited higher expression of Hoxb5 in AE lungs than controls.

Conclusion

Alcohol exposure at E13.5 affected fetal lung development, with delayed differentiation and increased Hoxb5.

Section snippets

Alcohol exposure

For timed matings, the day of the detection of the vaginal plug was considered embryonic day (E) 0.5, and the developmental stage was determined according to Theiler.¹¹ Pregnant C57BL/6J mice, a strain known to be susceptible to ethanol¹² were injected intraperitoneally with 2 doses of either 25% ethanol (3.75 g/kg; alcohol exposed [AE]) or with Ringer’s solution (controls [C]) at a 4-hour interval at day 11.5, 12.5, and 13.5 of gestation (E11.5, E12.5, and E13.5). The animals quickly recovered

The resorption rate, body weight, and lung weight of the alcohol-exposed fetuses compared with control fetuses

The pregnant C57BL/6J mice were injected intraperitoneally with either ethanol (alcohol exposed-AE) or Ringer’s solution (control) during specific gestation stages (E11.5, E12.5, and E13.5), and fetuses were retrieved at E18.5 (AE: E11.5, n = 25; E12.5, n = 31; E13.5, n = 73; C: E11.5, n = 9; E12.5 n = 7; and E13.5, n = 24). As shown in the Table, we observed that the AE mice exhibited a higher embryonic resorption rate, regardless of the gestation stage that they were exposed to the alcohol,

Comment

In the present study, we showed that high acute alcohol exposure at the pseudoglandular development phase of lungs does in fact affect lung development. The disproportionate reduction in the mass of the AE lungs as compared with the C lungs suggested that lung might be particularly sensitive to the acute alcohol exposure during this period of time; that is, during the pseudoglandular phase. Furthermore, the morphologic analysis showed that at the same gestational stage, the AE lungs were

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Role of zinc insufficiency in fetal alveolar macrophage dysfunction and RSV exacerbation associated with fetal ethanol exposure
2019, Alcohol
Citation Excerpt :
It is well established that in utero alcohol exposure has negative outcomes for the developing fetus (Akison, Kuo, Reid, Boyd, & Moritz, 2018; Gottesfeld, 1998). Although the lung has received little attention as a target of fetal alcohol exposure, growing evidence shows that the developing lung is also vulnerable to alcohol-induced toxicity and long-term consequences (Gauthier et al., 2010; Gauthier, Ping, et al., 2005; Lazic et al., 2011; Ping et al., 2007; Sozo et al., 2009; Wang, Gomutputra, Wolgemuth, & Baxi, 2007). As noted above, fetal alcohol exposure is associated with alarming increased odds of developing late onset sepsis and bronchopulmonary dysplasia in very low birthweight newborns (Gauthier et al., 2016), which has its own adverse consequences.
We previously reported that maternal alcohol use significantly increases the risk of sepsis in premature and term newborns. In the mouse, fetal ethanol exposure results in an immunosuppressed phenotype for the alveolar macrophage (AM) and decreases bacterial phagocytosis. In pregnant mice, ethanol decreased AM zinc homeostasis, which contributed to immunosuppression and impaired AM phagocytosis. In this study, we explored whether ethanol-induced zinc insufficiency extended to the pup AMs and contributed to immunosuppression and exacerbated viral lung infections.
C57BL/6 female mice were fed a liquid diet with 25% ethanol-derived calories or pair-fed a control diet with 25% of calories as maltose-dextrin. Some pup AMs were treated in vitro with zinc acetate before measuring zinc pools or transporter expression and bacteria phagocytosis. Some dams were fed additional zinc supplements in the ethanol or control diets, and then we assessed pup AM zinc pools, zinc transporters, and the immunosuppressant TGFβ1. On postnatal day 10, some pups were given intranasal saline or respiratory syncytial virus (RSV), and then AM RSV phagocytosis and the RSV burden in the airway lining fluid were assessed.
Fetal ethanol exposure decreased pup AM zinc pools, zinc transporter expression, and bacterial clearance, but in vitro zinc treatments reversed these alterations. In addition, the expected ethanol-induced increase in TGFβ1 and immunosuppression were associated with decreased RSV phagocytosis and exacerbated RSV infections. However, additional maternal zinc supplements blocked the ethanol-induced perturbations in the pup AM zinc homeostasis and TGFβ1 immunosuppression, thereby improving RSV phagocytosis and attenuating the RSV burden in the lung.
These studies suggest that, despite normal maternal dietary zinc intake, in utero alcohol exposure results in zinc insufficiency, which contributes to compromised neonatal AM immune functions, thereby increasing the risk of bacterial and viral infections.
Maternal Alcohol Use During Pregnancy and Associated Morbidities in Very Low Birth Weight Newborns
2016, American Journal of the Medical Sciences
Citation Excerpt :
LOS in VLBW infants is known to be associated with an increased risk of adverse outcomes such as BPD or death.33 Multiple animal models suggest that in utero alcohol also alters the development of the lung,5,6,34-37 but no clinical data have been reported regarding pulmonary outcomes of alcohol-exposed newborns, particularly those born prematurely. In the current study population, we did not find a significance effect of alcohol exposure on the individual outcomes of BPD or neonatal death.
We hypothesized that maternal alcohol use occurs in pregnancies that end prematurely and that in utero alcohol exposure is associated with an increased risk of morbidities of premature newborns.
In an observational study of mothers who delivered very low birth weight newborns (VLBW) ≤1,500 g, maternal alcohol use was determined via a standardized administered questionnaire. We compared the effect of maternal drinking on the odds of developing late-onset sepsis (LOS), bronchopulmonary dysplasia (BPD), death, BPD or death, days on oxygen or any morbidity (either LOS, BPD or death). The effect of drinking amounts (light versus heavy) was also evaluated.
A total of 129 subjects who delivered 143 VLBW newborns were enrolled. Approximately 1 in 3 (34%) subjects reported drinking alcohol during the first trimester (“exposed”). Within the exposed group, 15% reported drinking ≥7 drinks/week (“heavy”) and 85% of the subjects reported drinking <7 drinks/week (“light”). When controlling for maternal age, drug or tobacco use during pregnancy and neonatal gestational age, any drinking increased the odds of BPD or death and any morbidity. Furthermore, light or heavy drinking increased the odds of BPD or death and any morbidity, whereas heavy drinking increased the odds of LOS.
In utero alcohol exposure during the first trimester occurred in 34% of VLBW newborns. Maternal drinking in the first trimester was associated with significantly increased odds of neonatal morbidity. Further studies are warranted to determine the full effect of in utero alcohol exposure on the adverse outcomes of VLBW premature newborns.
Prenatal alcohol exposure and childhood atopic disease: A Mendelian randomization approach
2014, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Although there is some evidence for a protective effect of alcohol on allergic airway inflammation and airway hyperresponsiveness in an adult mouse model of allergic asthma,3 the mechanisms underlying such an effect and the relevance of these observations to the inception of asthma after prenatal exposure in humans are unclear. In addition, other animal data indicate detrimental effects of prenatal exposure on fetal lung growth and development.4-6 The findings for hay fever, if real, would be expected to be mediated through an effect on atopy, yet we did not find similar negative associations between reported intake and atopy or IgE.
Alcohol consumption in western pregnant women is not uncommon and could be a risk factor for childhood atopic disease. However, reported alcohol intake may be unreliable, and associations are likely to be confounded.
We aimed to study the relation between prenatal alcohol exposure and atopic phenotypes in a large population-based birth cohort with the use of a Mendelian randomization approach to minimize bias and confounding.
In white mothers and children in the Avon Longitudinal Study of Parents and Children (ALSPAC) we first analyzed associations between reported maternal alcohol consumption during pregnancy and atopic outcomes in the offspring measured at 7 years of age (asthma, wheezing, hay fever, eczema, atopy, and total IgE). We then analyzed the relation of maternal alcohol dehydrogenase (ADH)1B genotype (rs1229984) with these outcomes (the A allele is associated with faster metabolism and reduced alcohol consumption and, among drinkers, would be expected to reduce fetal exposure to ethanol).
After controlling for confounders, reported maternal drinking in late pregnancy was negatively associated with childhood asthma and hay fever (adjusted odds ratio [OR] per category increase in intake: 0.91 [95% CI, 0.82-1.01] and 0.87 [95% CI, 0.78-0.98], respectively). However, maternal ADH1B genotype was not associated with asthma comparing carriers of A allele with persons homozygous for G allele (OR, 0.98 [95% CI, 0.66-1.47]) or hay fever (OR, 1.11 [95% CI, 0.71-1.72]), nor with any other atopic outcome.
We have found no evidence to suggest that prenatal alcohol exposure increases the risk of asthma or atopy in childhood.
Poisoning the developing lung
2013, Paediatric Respiratory Reviews
Perinatal exposure to alcohol: Implications for lung development and disease
2013, Paediatric Respiratory Reviews
Citation Excerpt :
In rats, foetal alcohol impairs lung development resulting in inhibition of cellular growth and hypoplastic lungs.24 In mice, foetal alcohol during the second trimester at the pseudo glandular stage of lung development resulted in decreased lung mass and delayed lung maturation.25 These effects of in utero alcohol were also associated with increased expression of the homeobox-containing gene Hoxb5 which is critical for bronchiolar patterning and airway branching morphogenesis during the saccular phase of development.
In utero alcohol exposure dramatically increases the risk of premature delivery. However, the majority of premature and term newborns exposed to alcohol remain undetected by medical caregivers. There is a desperate need for reliable and accurate biomarkers of alcohol exposure for the term and premature newborn population. The inability to identify the exposed newborn severely limits our understanding of alcohol's pathophysiological effects on developing organs such as the lung. This chapter will review potential advancements in future biomarkers of alcohol exposure for the newborn population. We will discuss alcohol's effects on redox homeostasis and cellular development of the neonatal lung. Finally, we will present the evidence describing in utero alcohol's derangement of innate and adaptive immunity and risk for infectious complications in the lung. Continued investigations into the identification and understanding of the mechanisms of alcohol-induced alterations in the premature lung will advance the care of this vulnerable patient population.
The effects of low-moderate dose prenatal ethanol exposure on the fetal and postnatal rat lung
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: Cite this article as: Wang X, Gomutputra P, Wolgemuth DJ, et al. Effects of acute alcohol intoxication in the second trimester of pregnancy on development of the murine fetal lung. Am J Obstet Gynecol 2007;197:269.e1-269.e4.

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SMFM paperEffects of acute alcohol intoxication in the second trimester of pregnancy on development of the murine fetal lung

Objective

Study Design

Results

Conclusion

Section snippets

Alcohol exposure

The resorption rate, body weight, and lung weight of the alcohol-exposed fetuses compared with control fetuses

Comment

Int J Gynaecol Obstet

Am J Obstet Gynecol

Mech Dev

J Pediatr Surg

Mech Dev

Fetal alcohol spectrum disorder

CMAJ

Effect of intrauterine ethanol exposure on fetal lung growth

Pediatr Res

Congenital cystic adenomatoid malformation in the fetus: a hypothesis of its development

Fetal Diagn Ther

SMFM paper
Effects of acute alcohol intoxication in the second trimester of pregnancy on development of the murine fetal lung