Docosahexaenoic Acid Increases the Pro-Resolving Brain Lipid Mediators of Inflammation in Rat Pups Prenatally Exposed to Alcohol
Abstract
1. Introduction
2. Materials and Methods
2.1. Control Group (N = 6)
2.2. Alcohol Groups
2.2.1. Low-Dose (LD) Alcohol at 1.6 g Alcohol/kg/day (N = 5)
2.2.2. High-Dose (HD) Alcohol at 2.4 g Alcohol/kg/day (N = 5)
2.2.3. High Dose Alcohol + DHA (HD/DHA) at 2.4 g Alcohol/kg/day + DHA at 1250 mg/kg/day (N = 5)
2.2.4. Gavage Feeding
2.2.5. Delivery of the Dams and Pups
2.2.6. Brain Lipid Analysis
2.2.7. Statistical Analysis
3. Results
3.1. Birth Weight
3.2. Dam Weights
3.3. Placental Weights
3.4. Brain Lipid Mediators of Inflammation
3.4.1. Pro-Inflammatory Brain Lipid Mediators
- Legend: Control = olive oil + maltose/dextrin;
- Low-dose alcohol = 1.6 g/kg/day alcohol + olive oil;
- High-dose alcohol = 2.4 g/kg/day alcohol + olive oil;
- Alcohol + DHA = alcohol (2.4 g/kg/day) + DHA (1250 mg/kg).
- The low-dose alcohol group was not significantly lower than the control in the four pro-inflammatory lipid mediators.
- The high-dose alcohol group was significantly lower than the control in LTB4 and PGE2 (Figure 2).
- The high-dose alcohol + DHA group was significantly lower than the control in LTB4, PGF2α, and TXB2.
- High-dose alcohol was significantly lower than low-dose alcohol in LTB4.
- High-dose alcohol + DHA was not significantly different compared to high-dose alcohol in any of the pro-inflammatory lipid mediators.
3.4.2. Pro-Resolving Brain Lipid Mediators
- Legend: control = olive oil + maltose/dextrin;
- Low-dose alcohol = 1.6 g/kg/day alcohol + olive oil;
- High-dose alcohol = 2.4 g/kg/day alcohol + olive oil;
- Alcohol + DHA = alcohol (2.4 g/kg/day) + DHA (1250 mg/kg).
- The low-dose alcohol group was significantly higher than the control in LAX5 and 4-HDoHE.
- The high-dose alcohol group was significantly lower than the control in 4-HDoHE and 17-HDoHE. Alcohol + DHA was significantly higher than the control in LXA5, MaR1n-3 DPA, and 4-HDoHE.
- High-dose alcohol was significantly lower than low-dose alcohol in LXA5, 4-HDoHE, and 17-HDoHE and vs. the control in 4-HDoHE and 17-HDoHE.
- High-dose alcohol combined with DHA, compared to high-dose alcohol alone, showed a significant increase in LXA5 and MaR1 (n-3 DPA), and a two- to three-fold rise in 4-HDoHE (7.163 vs. 2.155 ng/mg, p < 0.001) and 17-HDoHE levels (0.850 vs. 0.317 ng/mg, p < 0.001), despite the high alcohol dose.
4. Discussion
5. Limitations
- (1).
- This paper is essentially an exploratory study that demonstrates the response of pro-inflammatory and pro-resolving brain lipid mediators to alcohol, and the protective role of DHA. However, as an exploratory study, it is not comprehensive and many biomarkers of alcohol-induced degeneration—such as caspase 3 and 9 activation, DNA fragmentation, nuclear disruption, and pro-inflammatory cytokines like TNF-α, IL-1β, and TGF-β—are not included. Similarly, exploring the relationship with FASD phenotypes and brain pathology was beyond the initial aims of this study. Nonetheless, the research, especially its findings on the beneficial effects of DHA on pro-resolving brain lipid mediators, provides a foundation for future studies. These future investigations could offer valuable insight into the mechanisms of alcohol toxicity and potential treatment strategies in relation to prevention of the serious fetal and infant sequelae associated with maternal alcoholism. The Special Issue on “The Biological Impacts of Fetal Alcohol Exposure” aims to “bring together cutting-edge research from a range of disciplines to deepen our understanding of how prenatal alcohol exposure affects fetal development and long-term health outcomes”. Furthermore, despite decades of research, many questions remain about how alcohol disrupts critical biological processes during gestation, and how these disruptions result in the clinical features seen in Fetal Alcohol Spectrum Disorders (FASDs). We hope our study, though exploratory, aligns well with these goals.
- (2).
- Adverse sex-specific responses to prenatal alcohol are known, such as in cognitive control [51], performance in differential tasks [52], and neuroimmune function [53]. Unfortunately, we were unable to determine the sex of the pups in this study, due to the difficulty we encountered in accurately measuring the anogenital distance in the extremely small pups. Molecular sex determination using Spry gene PCR determination on tissues has been suggested, and we can explore this option on frozen brain tissues of the pups, once funding becomes available.
- (3).
- The present study of brain lipid mediators in the pups is only the first step in assessing the beneficial effects of DHA in mitigating the adverse impacts of alcohol on the fetal brain. Demonstrating an improvement in pups’ behavior is also necessary. We have an ongoing follow-up study using the same protocol which examines the anxiety behavior in rat pups at 6 weeks of postnatal age. Preliminary observations indicate that female rats perform better than male pups in the anxiety tests, which highlights the importance of sex.
- (4).
- We could not determine sex and measure brain alcohol concentrations in the rat pups, nor blood alcohol concentrations in the dams, which are important factors that can directly reflect fetal brain exposure and response to alcohol. These factors will be determined in future studies.
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
FASD | Fetal alcohol spectrum disorder |
FAS | Fetal alcohol syndrome |
PILMs | Pro-inflammatory lipid mediators |
LTB4 | Leukotriene B4 |
PGE2 | ProstaglandinE2 |
PGF2 | Prostaglandin F2α |
TXB2 | Thromboxane B2 |
PRLMs | Pro-resolving lipid mediators |
LXA5 | Lipoxin A5 |
4-HDoHE | 4-Hydroxydocosahexaenoic acid |
17-HDoHE | 17-Hydroxydocosahexaenoic acid |
MaR1n-3 DPA | 7R,14S-dihydroxy-docosapentaenoic acid |
PUFA | Polyunsaturated fatty acid |
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95% Confidence Interval | ||||||
---|---|---|---|---|---|---|
Group | N (Dams) | n (Pups) | Mean Birth Weight (g) | SD | Lower Bound | Upper Bound |
Control | 6 | 48 | 3.06 | 0.25 | 2.80 | 3.32 |
LD | 5 | 38 | 3.08 | 0.29 | 2.72 | 3.44 |
HD | 5 | 40 | 4.10 * | 0.25 | 3.79 | 4.41 |
HD/DHA | 4 | 32 | 3.54 ** | 0.17 | 3.27 | 3.82 |
Weight (Grams) of the Dams on Day 8 and Day 20 | ||||
---|---|---|---|---|
Day 8 | N | Mean | Std. Deviation | Std. Error |
Control | 6 | 234.67 | 11.13 | 4.544 |
LD | 5 | 251.0 | 17.916 | 8.012 |
HD | 5 | 240.6 | 14.1 | 6.306 |
HD/DHA | 4 | 234.8 | 12.377 | 5.535 |
Day 20 | ||||
Control | 6 | 327.67 | 31.443 | 12.837 |
LD | 5 | 343 | 45.591 | 20.389 |
HD | 5 | 345.2 | 28.217 | 12.619 |
HD/DHA | 4 | 321.2 | 39.915 | 17.85 |
ANOVA Day 8 | p = 0.235 | |||
ANOVA Day 20 | p = 0.746 |
Treatment Group | N | n | Mean Placental Weight (g) | SD | 95% Confidence Interval | |
---|---|---|---|---|---|---|
Lower Bound | Upper Bound | |||||
Control | 6 | 48 | 0.49 | 0.08 | 0.46 | 0.51 |
LD | 5 | 38 | 0.59 | 0.12 | 0.55 | 0.63 |
HD | 5 | 40 | 0.57 | 0.07 | 0.55 | 0.59 |
HD/DHA | 4 | 32 | 0.58 | 0.10 | 0.55 | 0.61 |
Duncan’s Test a,b | |||
---|---|---|---|
Group | N | Subset for Alpha = 0.05 | |
1 | 2 | ||
Control | 48 | 0.485 | |
High dose | 40 | 0.568 | |
DHA/alcohol | 32 | 0.581 | |
Low dose | 38 | 0.592 | |
Sig. | 1.000 | 0.275 |
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Ostrea, E.M., Jr.; Yadav, D.; Cheng, C.T.; Kisseih, E.D.; Maddipati, K.R.; Thomas, R.L. Docosahexaenoic Acid Increases the Pro-Resolving Brain Lipid Mediators of Inflammation in Rat Pups Prenatally Exposed to Alcohol. Life 2025, 15, 1530. https://doi.org/10.3390/life15101530
Ostrea EM Jr., Yadav D, Cheng CT, Kisseih ED, Maddipati KR, Thomas RL. Docosahexaenoic Acid Increases the Pro-Resolving Brain Lipid Mediators of Inflammation in Rat Pups Prenatally Exposed to Alcohol. Life. 2025; 15(10):1530. https://doi.org/10.3390/life15101530
Chicago/Turabian StyleOstrea, Enrique M., Jr., Deepak Yadav, Charlie T. Cheng, Esther D. Kisseih, Krishna R. Maddipati, and Ronald L. Thomas. 2025. "Docosahexaenoic Acid Increases the Pro-Resolving Brain Lipid Mediators of Inflammation in Rat Pups Prenatally Exposed to Alcohol" Life 15, no. 10: 1530. https://doi.org/10.3390/life15101530
APA StyleOstrea, E. M., Jr., Yadav, D., Cheng, C. T., Kisseih, E. D., Maddipati, K. R., & Thomas, R. L. (2025). Docosahexaenoic Acid Increases the Pro-Resolving Brain Lipid Mediators of Inflammation in Rat Pups Prenatally Exposed to Alcohol. Life, 15(10), 1530. https://doi.org/10.3390/life15101530