Page 143 - GPD-3-2

Gene & Protein in Disease Placenta, FASD, and soy

earlier publication only assessed IRS-1 protein expression. chronic ethanol exposure inhibited ASPH expression. In
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In the casein groups, the inhibitory effects of ethanol on addition to reducing its mRNA levels, ethanol inhibits
Irs1 mRNA level corresponded with decreases in protein ASPH protein by increasing GSK-3β activity, leading
concentration. Along with the further demonstration of to its phosphorylation and proteolytic degradation.
2,35
ethanol-reduced Irs2 and Irs4 mRNA levels, it is reasonable The modest but statistically significant increase in ASPH
to conclude that chronic gestational exposure to ethanol protein in the ES group compared with the placentas
broadly inhibits signaling through IRS molecules, thereby from the EC group corresponds with previously reported
contributing to impairments in placentation and fetal reductions in GSK-3β activity. The increased ASPH
1
development. Dietary soy’s broad upregulation of Irs1, Irs2, expression in the placentas of ES dams likely contributed
and Irs4 mRNA levels in ethanol-exposed placental tissue to the normalization of placentation and the prevention of
supports the notion that the corresponding normalization FASD effects.
of impaired placental and fetal development was mediated ASPH functions in part by hydroxylating and activating
by enhanced signaling through these docking proteins. Notch within its epidermal growth factor-like domain.
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However, the interpretation of the data is limited by the Activation of Notch results in cleavage and nuclear
lack of information on IRS-2 and IRS-4 protein expression. localization of the Notch intracellular domain, followed
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For example, although dietary soy elevated Irs1 mRNA to by increased transcription of HES or HEY genes.
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levels above those in the EC, CC, and CS groups, IRS-1 Although ethanol did not reduce Notch expression in
immunoreactivity was suppressed relative to the CC the EC group, dietary soy significantly increased Notch1
and EC groups, suggesting that the capacity to transmit mRNA in the ES group, correspondingly increasing Hes1
downstream signals through IRS-1 may have remained expression. In contrast, the EC group was associated
compromised. Conversely, the lower levels of inhibitory with significantly reduced Hes1 expression. Altogether,
S312 phosphorylation of IRS-1 would have supported these findings suggest that dietary soy enhances insulin/
IRS-1 signaling in ethanol-exposed placentas. The lack IGF signaling through IRS molecules, thereby improving
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of information about the abundances of IRS-2 and IRS4 placentation by increasing ASPH expression and Notch
limits further mechanistic interpretation. However, it can activation of HES1.
be speculated that the combined increases in Irs1, Irs2,
and Irs4 mRNA levels induced by dietary soy in ethanol- 5. Conclusion
exposed samples contributed to the prevention of FASD
and placentation impairments. The combined information from the earlier report and the
present study provides a better mechanistic understanding
ASPH is a downstream target of insulin/IGF of how alcohol exposures during pregnancy impair
signaling. 34,35 Its stimulatory effects on cell motility and placentation and how dietary soy could ameliorate these
invasion, which are essential for placentation, are mediated adverse effects. Future studies should investigate the extent
by catalytic activation of Notch (hydroxylation) and the to which dietary soy interventions at different stages — early
subsequent increase in Hes1 transcription. 4,7,35,36 Previous gestation, later gestation, or pre-gestation — prevent
experiments demonstrated that molecular silencing alcohol-related impairments in placentation and fetal
of ASPH in the placenta inhibits trophoblast motility, development. Recent experimental evidence highlights
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Notch signaling, and fetal growth. Correspondingly, the benefits of postnatal and adolescent-stage dietary
ethanol inhibition of ASPH expression in the placenta is soy in preventing long-term cognitive and motor deficits
associated with impaired placentation and IUGR, along caused by chronic ethanol exposure. The potential
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with inhibition of Notch-1 signaling. Therefore, it was benefits of consuming lower levels of soy or other
of interest to determine if dietary soy positively impacted phytonutrient-rich legumes during pregnancy should be
ASPH expression to mediate enhanced placentation in studied, as a 100% dietary soy protein regimen would be
ethanol-fed dams. extremely challenging to maintain. Furthermore, evidence
The adverse effects of ethanol on insulin and IGF suggests that prenatal dietary soy has beneficial effects on
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signaling can be detected by measuring the expression normal brain development and function and supports
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of downstream molecular targets such as ASPH. 2,21,28 insulin resistance disease states known to be linked to
Previous studies have demonstrated that Asph mRNA neurodegeneration. 40
and protein levels are increased through insulin or IGF Acknowledgments
stimulation. ASPH is abundantly expressed in normal
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placental trophoblasts and plays functional roles in The authors wish to acknowledge the technical assistance
placentation, including implantation, which is crucial of QI and Gilligan, who participated in portions of this
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to fetal development. Consistent with previous reports, research as undergraduate students at Brown University.

Volume 3 Issue 2 (2024) 9 doi: 10.36922/gpd.3113