The Developmental Origins of Health and Disease (DOHaD) hypothesis highlights the profound impact of early life circumstances on adult health. Prenatal exposure to maternal inflammation, frequently associated with gestational complications like preeclampsia and gestational diabetes, is a significant factor. These complications, despite diverse origins (e.g., maternal obesity, preeclampsia), share a pro-inflammatory profile and lead to comparable long-term offspring health consequences including cardiovascular issues and metabolic dysregulation. This suggests common underlying mechanisms. Maternal inflammation affects fetal programming through alterations in maternal circulating factors and placental biology, impacting fetal growth, cytokine signaling, and oxidative stress. Acute inflammatory insults, like bacterial infections, can also impact fetal development and organogenesis. Lipopolysaccharide (LPS), a component of gram-negative bacteria, is a well-established model for inducing maternal inflammation in rodents, triggering a T helper 1 response. Previous research demonstrates that low-dose LPS exposure at different gestational stages in rodents leads to varying phenotypes in offspring. This study uses a low-dose LPS injection at mid-gestation to model maternal inflammation and examines the combined effects of this prenatal exposure and a subsequent western-style diet (WSD) on offspring cardiovascular, metabolic, and neurological health, recognizing the clinical relevance of WSD in modern diets.

The literature extensively documents the association between maternal inflammation during gestation and adverse long-term health outcomes in offspring. Studies in both humans and animals support this link. The mechanisms underlying these effects are complex and multifaceted, involving altered placental development, changes in circulating maternal factors, and the impact of oxidative stress. The role of cytokines in regulating normal placental development and the consequences of aberrant cytokine signaling are highlighted in previous research. The impact of oxidative stress on fetal programming through DNA damage and lipid peroxidation is also discussed. The administration of lipopolysaccharides (LPS) serves as a widely accepted model for studying maternal inflammation in animal research, simulating an inflammatory response. Rodent studies have shown that prenatal exposure to LPS can result in various phenotypes in offspring, including growth restriction, myocardial fibrosis, and metabolic dysregulation, with the dose and timing of LPS administration being critical.

Pregnant C57BL/6J mice received either a low dose of LPS (25 µg/kg) or saline on gestational day (GD) 10.5. An initial plan to incorporate sFlt-1 adenovirus injection at GD 8.5 to model preeclampsia proved unsuccessful due to inactive adenovirus preparation. From weaning, all offspring were fed a control diet, with half switching to a western-style diet (WSD) from 12 to 24 weeks of age. Maternal plasma metabolomics were analyzed at GD 15.5 using the Biocrates MxP Quant500 kit. Offspring body weight, fat mass (Bruker Minispec), food intake, glucose tolerance, and insulin tolerance were assessed at various time points. Plasma insulin, leptin, and triglycerides were measured using ELISA. Gene expression analysis using qPCR was performed on liver, gonadal white adipose tissue (gWAT), hypothalamus, and cortex. DNA methylation analysis of selected genes in the liver was conducted using PyroMark Q48. Statistical analysis involved three-way ANOVA (repeated measures for body weight, glucose and insulin tolerance tests). MetaboAnalyst 4.0 was used for metabolomics data analysis.

LPS treatment led to a reduced pregnancy success rate and elevated xanthine levels in maternal plasma, indicating oxidative stress. Female offspring exposed to both LPS and WSD exhibited significantly increased body weight, fat mass, and food intake compared to controls. Males exposed to LPS and CTRD showed a significantly increased fat mass at WK24. LPS exposure combined with WSD in females resulted in impaired glucose tolerance and increased fasting leptin levels. Gene expression analysis revealed LPS-induced changes in liver (Lxra, Srebf2, Chrebp) and gWAT (Lxra, Leptin), but no significant changes in DNA methylation. Hypothalamic gene expression showed LPS-associated changes in orexigenic and anorexigenic genes, suggesting a role in regulating food intake. Cortical gene expression analysis revealed LPS-associated changes in microglia and astrocyte homeostasis and activation marker genes, but these changes were not consistent or easy to interpret.

This study demonstrates that a single, low-dose LPS injection during mid-gestation, combined with a WSD later in life, leads to sex-specific, long-term metabolic consequences in mouse offspring. The female-specific excessive weight gain is associated with hyperphagia, impaired glucose tolerance, and increased fasting leptin. Changes in gene expression in the liver, adipose tissue, and hypothalamus support the observed phenotypes. The increased xanthine levels in maternal plasma suggest a role for oxidative stress in mediating these effects. The study highlights the complex interplay between prenatal inflammation and postnatal diet in shaping metabolic health. The female-specific effect warrants further investigation, potentially involving sex hormones or differences in eating behavior.

This research shows that maternal inflammation during mid-gestation, even with a single low-dose LPS exposure, combined with a western-style diet in adulthood, leads to significant and sex-specific changes in offspring body weight and metabolism, primarily affecting females. Altered gene expression in key metabolic tissues and the hypothalamus likely contribute to these changes. Future research should focus on the mechanisms behind the sex-specific effects and explore potential therapeutic interventions.

The study's limitations include the lack of neonatal and behavioral data, analysis of whole hypothalamus and cortex (rather than specific nuclei), and the inability to precisely determine the duration of LPS-induced inflammation due to limited blood sampling after injection. The sample size for hypothalamic analysis was relatively small, potentially limiting the statistical power for detecting subtle effects. Further investigations are needed to elucidate the exact mechanisms involved and to assess the generalizability of the findings to other species and dietary conditions.