Journal of Developmental Origins of Health and Disease最新文献

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased. MASLD notably increases after menopause in women owing to the drastic reduction in estrogen, which regulates lipid metabolism. While prenatal undernutrition leads to hepatic steatosis after birth, whether prenatal undernutrition affects the onset of postmenopausal MASLD remains unknown. Therefore, we examined the impact of early prenatal undernutrition on the predisposition to postmenopausal MASLD in a rat model of menopause. Pregnant female rats were assigned to the control (CNTL) group, while the undernourished (UN) group was fed 40% of the diet of the control group. Furthermore, both groups were assigned to the ovariectomized (CNTL-OVX/UN-OVX) and sham-operated (CNTL-Sham/UN-Sham) groups at 12 weeks of age. Two-way analysis of variance revealed significant main effects of ovariectomy and prenatal undernutrition on body weight and hepatic triglyceride content. Triglycerides accumulated in the liver at 12 and 24 weeks after ovariectomy, while hepatic steatosis was histologically observed at 24 weeks after ovariectomy in UN-OVX rats. Hepatic gene expression analyses showed an interaction effect between prenatal undernutrition × ovariectomy in ESR1 expression; however, PPARα, RXRα, RARα, Raldh1, and Raldh3 expression was not affected by prenatal undernutrition and ovariectomy. These results suggest that early prenatal undernutrition predisposes postmenopausal women to MASLD by uncovering aberrant estrogen signaling, which may be influenced by estrogen reduction.

The impact of maternal nutrition during the peri-conception period on offspring sex remains unclear. Therefore, this study aimed to explore the association between maternal nutritional intake around conception and offspring sex. Data were collected from the Japan Environment and Children's Study, which enrolled 97,510 mother-child pairs. The effect of maternal intake of fats, proteins, and fatty acids on offspring sex was analyzed, adjusting for maternal demographics and lifestyle factors. Overall, maternal intake of total fatty acids, saturated fatty acids (SFAs), polyunsaturated fatty acids (PUFAs), n-3 PUFA, n-6 PUFA, and protein and the ratios of n-6/n-3 and SFA/energy showed no consistent associations with offspring sex.However, further analyses revealed notable patterns related to maternal age and energy intake. Among mothers with high energy intake (≥4,000 kcal/day), higher residual protein intake was associated with increased odds of having a male child (aOR, 1.87; 95% CI, 1.17-2.98). In mothers aged under 20 years, increased n-3 PUFA intake was linked to higher odds of male births, while a higher n-6/n-3 ratio was associated with lower odds of male births. Additionally, among mothers aged 20-35 years, higher n-3 PUFA intake was associated with decreased odds of having a male child (aOR, 0.89; 95% CI, 0.82-0.98).These findings indicate that while no consistent overall relationship was observed, certain maternal nutritional patterns may influence offspring sex, highlighting the need for further research on maternal diet and reproductive outcomes.

Iron deficiency anemia is a major health problem worldwide. Iron is an essential micronutrient in the human body; its demand increases with fetal growth and gestation. Although it has been reported that glucose metabolism is also affected by iron deficiency, only few studies have investigated the influence of iron deficiency during gestation and in offspring. In this study, glucose metabolism in newborns was investigated in terms of maternal iron deficiency prior to pregnancy in a rat model. Briefly, rats were divided into control (CL) and iron deficiency (ID) groups. The levels of serum glucose and insulin and the protein expression of liver GLUT2 in neonates born to dams in the ID group increased. In contrast, the mRNA and protein expression levels of GLUT2 and GLUT4 in the skeletal muscle tended to decrease. In addition, the expression of p-Akt (Thr308), which is involved in GLUT4 membrane translocation, decreased, suggesting that GLUT4 translocation to the plasma membrane may not have been sufficiently promoted. These results suggest that maternal iron deficiency may influence glucose metabolism in neonates and potentially increase the risk of developing metabolic abnormalities and lifestyle-related diseases later in life.

Adverse prenatal conditions can induce intrauterine growth restriction (IUGR) and increase the risk of adulthood metabolic disease. Mechanisms underlying developmentally programmed metabolic disease remain unclear but may involve disrupted postnatal circadian rhythms and kisspeptin signalling. We investigated the impact of maternal hypoxia-induced IUGR on hypothalamic and hepatic expression of clock genes (Bmal1, Per2 and Reverbα), metabolic genes (Pparα, Pparγ and Pgc1α) and kisspeptin genes (Kiss1 and Kiss1r) in adult offspring. Pregnant BALB/c mice were housed in hypoxic conditions (10.5% oxygen) from gestational day 11 to 17.5 and then returned to normoxic conditions until term (gestational day ∼ 21). Control animals were housed in normoxic conditions throughout pregnancy. Offspring were weighed at birth. At 8 weeks of age, body, liver and brain tissues were collected and weighed. Relative clock gene, metabolic gene and kisspeptin signalling gene expression were measured using qPCR. The IUGR offspring were lighter at birth and remained lighter at 8 weeks but with higher brain relative to body weight. The IUGR offspring had decreased hypothalamic Bmal1 and Reverbα expression, but unchanged hepatic clock gene expression and no change in hypothalamic or hepatic Per2 expression, compared with Control offspring. This tissue-specific change in clock gene expression suggests circadian dysregulation. There were no IUGR-related changes to metabolic gene expression in the hypothalamus or liver, but IUGR offspring had increased hypothalamic Kiss1r expression. These results demonstrate IUGR offspring from hypoxia pregnancies show central circadian misalignment and potentially disrupted hypothalamic Kiss1/Kiss1r signalling, which may contribute to developmentally programmed metabolic disease.

This study aimed to investigate the effects of infant formula supplements on Bifidobacterium level in the infant gut through a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs).Systematic review included PubMed, EMBASE, MEDLINE, Scopus, Web of Science, and Cochrane CENTRAL to identify RCTs evaluating the effects of formulas supplemented with prebiotics, probiotics, synbiotics, β-palmitic acid, or combinations of β-palmitic acid with prebiotics on infant gut Bifidobacterium levels. A meta-analysis compared bifidogenic effects to standard formula. The main outcome was the relative abundance (RA) of Bifidobacterium in fecal samples measured by various microbiota assessment techniques, with effect sizes as mean differences and standard deviations. An overall effect estimate was derived using a random-effects model. NMA assessed formula effects using breastfeeding as the reference.Nineteen studies were included. Compared to standard formula, supplementation with prebiotics (p < 0.0001), synbiotics (p < 0.0001), β-palmitic acid (p = 0.0005), or β-palmitic acid combined with prebiotics (p < 0.0001) significantly increased Bifidobacterium levels in the infant gut. Probiotic supplementation showed no significant effect (p = 0.9755). NMA and p-score ranking, comparing formulas to breastmilk, indicated that prebiotic-supplemented formulas with the lowest ranking p-score (0.2764), most closely resembled breastfeeding's bifidogenic effect. However, prebiotics and probiotics were analyzed as broad categories, and group variability may affect outcomes. In conclusion, formula supplementation with prebiotics, synbiotics, β-palmitic acid, or combinations of β-palmitic acid with prebiotics increased the RA of Bifidobacterium in infant's gut, with prebiotic formula most closely mimicking the bifidogenic effects of breastfeeding.

According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, low-birthweight (LBW) infants are programmed to seek additional resources as compensation for early deprivation. However, no study has yet explored this in the context of delay discounting (DD), which refers to the tendency to prefer smaller, immediate rewards over larger, delayed ones. Both prenatal factors, such as LBW, and postnatal factors, including adverse childhood experiences (ACEs) and exposure to natural disasters, may influence DD. To investigate whether LBW children seek larger future rewards, we analyzed LBW's effect on DD, accounting for ACEs and natural disaster exposure. This prospective cohort study involved 167 children from areas affected by the Great East Japan Earthquake (GEJE), with a mean age of 8.3 years at the time of the DD experiment. LBW was assessed in the 2012 baseline questionnaire using the Mother-Child Handbook, along with ACEs prior to the GEJE and traumatic earthquake experiences. In 2014, DD was assessed through a token-based experiment where children allocated tokens for either immediate rewards (one candy per token for "now") or delayed rewards (two candies per token for "one month later"). Our results showed that children with LBW and three or more ACEs exhibited lower DD, while traumatic earthquake experiences were not associated with DD. These findings suggest that children with LBW and multiple ACEs may develop adaptive strategies to seek more resources, indicating a responsive reward system to childhood adversity, even after exposure to a severe natural disaster.

The study aimed to explore the causal effect of maternal prepregnancy body mass index (BMI) on congenital malformations of intestine (CMI). The genome-wide association data of BMI and CMI were obtained via the Mendelian randomization (MR) base platform. Single nucleotide polymorphisms (SNPs) significantly associated with BMI in females were identified and used as instrumental variables, and the causal relationship between BMI in females and CMI was examined using the bidirectional two-sample MR analyses research method. Three statistical methods including inverse-variance weighted (IVW) method, weighted median estimator, and MR-Egger regression were employed. A total of 36 SNPs significantly associated with BMI in females were identified in the study (P < 5 × 10⁻⁸; linkage disequilibrium r² < 0.001). Consistent association between BMI in females and CMI was observed when evaluated by different methods (IVW: odds ratio (OR) 0.364, 95% confidence interval (CI) 0.144–0.922; weighted median estimator: OR 0.395, 95% CI 0.096–1.619; MR-Egger Method: OR 0.244, 95% CI 0.020–2.974), which suggests that BMI in females is negatively associated with increased risk of CMI. The MR analysis provided the strong evidence to indicate that decreasing BMI in females might be causally associated with the risk of CMI.

The developmental origins of health and disease hypothesis suggests that environmental exposures during critical developmental windows increase the risk of disease later in life. Among these, endocrine disruptors (EDs) are particularly concerning due to their ubiquitous presence. The kidneys are highly susceptible to EDs toxicity during the perinatal period; however, long-term effects of ED mixtures on renal structure in aging remain unclear. This study aimed to characterize the renal histoarchitecture of aged rats after perinatal exposure to an ED mixture. Pregnant Sprague-Dawley rats were assigned to two groups: Control (corn oil, 2 ml/kg) and ED Mix (32.11 mg/kg/day of 12 EDs, including phthalates, pesticides, UV filters, bisphenol A, and butylparaben, in corn oil). Exposure occurred from gestational day 7 to postnatal day 21. Offspring were euthanized at postnatal day 440. ED mixture exposure did not affect the organosomatic index. However, ED Mix offspring presented renal lesions, including necrosis and tubular fusion, with a trend toward increased pathological changes. Morphometric analysis revealed enlarged nuclei and increased nuclear perimeters in the cortex and medulla, along with altered cellular organization in glomerular and medullary regions. Collagen organization was disrupted, with increased fibrosis in cortical and medullary compartments and reduced collagen type I and III in glomeruli. These findings indicate that perinatal exposure to an ED mixture alters nuclear phenotype and promotes extracellular matrix remodeling in distinct renal compartments. Such changes suggest long-term impacts on renal structure and function, emphasizing the health risks associated with early-life exposure to complex ED mixtures.

This study aimed to explore the associations between weight gain during infancy with pre-pregnant body mass index (BMI) later in life, focusing on risks of being overweight or underweight. A retrospective cohort study was conducted using data from women (n = 1082) who visited the National Center for Child Health and Development between 2017 and 2021. The participants provided their Maternal and Child Health Handbook, which included records of their own birthweight and weight gain from birth to 1, 3, and 6 months. The infant weight gain was divided into quintiles. Multivariable logistic regression was used to assess the association of weight gain during infancy with pre-pregnant underweight (BMI < 18.5) and overweight (BMI ≥ 25) later in life, adjusting for potential confounders. The current study found that the largest weight gain category (5230-7700 g) by 6 months was associated with a decreased risk of "pre-pregnant underweight," compared to the third weight gain category (4355-4730 g) by 6 months (OR, 0.40; 95% CI, 0.22-0.73). In contrast, no significant association was observed between weight gain category in infancy and being overweight in adulthood. In conclusion, greater weight gain during the first 6 months of life was associated with a reduced risk of "adult underweight," without increasing the risk of being overweight.

The obesogenic maternal environment can lead to cardiac hypertrophy in the offspring. The aim of this study was to investigate whether (-)-epicatechin (Epi) modify the expression of genes related to pathological cardiac hypertrophy (CH), and its physiological pathway, in offspring obese by programing. Four groups of eight male offspring Wistar rats of 110 days were randomly selected to control groups [C and offspring of maternal obesity (MO)] or to Epi groups (C + Epi or MO + Epi). In heart tissue, we evaluated the size of the ventricular walls and cavities, presence of fibrosis, mRNA and protein of Myh6, Myh7, Anp, Bnp, Acta 1, Col1a1, Akt, and Mtor. We observed an increase of the heart weight/body ratio in groups treated with Epi. Only in MO group, heart area and its perimeter were increased, as well as Myh7 and Anp mRNA. We found a significant decrease of fibrosis area in male offspring treatment with Epi. In Epi group Anp mRNA was decreased whilst Anp protein in MO group was increased; further, a decrease in Col1a1 protein was found in MO group. In conclusion, the maternal obesity activates pathological CH markers reactivating fetal cardiac genes involved in histological changes observed in cardiac tissue. Epi treatment decreased the content of collagen area and expression of some fetal cardiac genes participating in this pathway in offspring of maternal obesity.