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Maternal diet disrupts the placenta-brain axis in a sex-specific manner
Alexis M Ceasrine1, Benjamin A Devlin1, Jessica L Bolton2
1Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
Insights
Maternal high-fat diets cause inflammation, impacting male offspring brain development and increasing susceptibility to neurological disorders. This study reveals a sex-specific mechanism involving microglia and serotonin.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- High maternal weight and diet are linked to offspring neurodevelopmental disorders.
- Sex biases exist in these disorders, but underlying mechanisms are poorly understood.
Purpose of the Study:
- To investigate sex-specific mechanisms by which maternal diet influences offspring susceptibility to neurological disorders.
- To elucidate the role of inflammation and microglial signaling in mediating these effects.
Main Methods:
- Utilized a maternal high-fat diet model in mice.
- Analyzed fetal tissue for endotoxin accumulation and inflammation.
- Investigated macrophage Toll-like receptor 4 (TLR4) signaling and microglial phagocytosis of serotonin (5-HT) neurons.
- Performed bulk sequencing on human placental and fetal brain samples.
Main Results:
- Maternal high-fat diet induced endotoxin accumulation and perinatal inflammation, leading to sex-specific behavioral outcomes.
- In male offspring, increased TLR4 signaling caused excessive microglial phagocytosis of 5-HT neurons, reducing 5-HT bioavailability.
- Sex-specific transcriptome-wide changes were observed in human placental and brain tissues correlating with maternal triglyceride levels.
- Fetal brain 5-HT levels decreased with increasing placental triglycerides in male mice and humans.
Conclusions:
- Maternal diet impacts offspring neuropsychiatric disorder susceptibility via a microglia-dependent, sex-specific mechanism.
- Inflammation and altered serotonin signaling in male offspring are key mediators.
- Findings highlight the critical role of maternal nutrition in neurodevelopment and sex-specific disease risk.
Abstract:
High maternal weight is associated with detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression and communicative disorders. Despite widespread acknowledgement of sex biases in the development of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we show that a maternal high-fat diet causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation contributes to sex-specific behavioural outcomes in offspring. In male offspring exposed to a maternal high-fat diet, increased macrophage Toll-like receptor 4 signalling results in excess microglial phagocytosis of serotonin (5-HT) neurons in the developing dorsal raphe nucleus, decreasing 5-HT bioavailability in the fetal and adult brains. Bulk sequencing from a large cohort of matched first-trimester human samples reveals sex-specific transcriptome-wide changes in placental and brain tissue in response to maternal triglyceride accumulation (a proxy for dietary fat content). Further, fetal brain 5-HT levels decrease as placental triglycerides increase in male mice and male human samples. These findings uncover a microglia-dependent mechanism through which maternal diet can impact offspring susceptibility for neuropsychiatric disorder development in a sex-specific manner.
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