A Link between Prenatal Stage of Life during the Great Chinese Famine and Subsequent Depressive Symptoms among Middle-Aged and Older Adults.

Prenatal malnutrition may increase the risk of depressive symptoms in adulthood. This study investigated the association between prenatal exposure to malnutrition with risk of depressive symptoms in middle-aged and older adults using the Chinese Great Famine of 1959-1961 as a natural experiment. Data were obtained from the China Health and Retirement Longitudinal Study baseline survey (2011). A total of 5391 individuals born from 1956 to 1965 were included in the study. Depressive symptoms were ascertained via the Center for Epidemiological Studies Depression Scale short form. Famine severity was measured using the cohort size shrinkage index. Difference-in-differences models were used to explore the association between prenatal famine exposure and later-life depressive symptoms. Compared with the post-famine cohort (1963-1965), famine cohorts (1959-1962) were 4.74 times (95% CI = 1.28-8.20) as likely to develop depressive symptoms. The stratified analysis found that prenatal exposure to famine was associated with depressive symptoms in rural residents but not those living in urban areas. In rural females, prenatal malnutrition was associated with a higher risk of depressive symptoms. However, there was no significant association between prenatal malnutrition and depressive symptoms in rural males. Our results indicated that prenatal malnutrition may contribute to a higher risk for depressive symptoms in later life among female rural residents.

Gene coexpression network analysis reveals perirenal adipose tissue as an important target of prenatal malnutrition in sheep.

We have previously demonstrated that pre- and early postnatal malnutrition in sheep induced depot- and sex-specific changes in adipose morphological features, metabolic outcomes, and transcriptome in adulthood, with perirenal (PER) as the major target followed by subcutaneous (SUB) adipose tissue. We aimed to identify coexpressed and hub genes in SUB and PER to identify the underlying molecular mechanisms contributing to the early nutritional programming of adipose-related phenotypic outcomes. Transcriptomes of SUB and PER of male and female adult sheep with different pre- and early postnatal nutrition histories were used to construct networks of coexpressed genes likely to be functionally associated with pre- and early postnatal nutrition histories and phenotypic traits using weighted gene coexpression network analysis. The modules from PER showed enrichment of cell cycle regulation, gene expression, transmembrane transport, and metabolic processes associated with both sexes' prenatal nutrition. In SUB (only males), a module of enriched adenosine diphosphate metabolism and development correlated with prenatal nutrition. Sex-specific module enrichments were found in PER, such as chromatin modification in the male network but histone modification and mitochondria- and oxidative phosphorylation-related functions in the female network. These sex-specific modules correlated with prenatal nutrition and adipocyte size distribution patterns. Our results point to PER as a primary target of prenatal malnutrition compared to SUB, which played only a minor role. The prenatal programming of gene expression and cell cycle, potentially through epigenetic modifications, might be underlying mechanisms responsible for observed changes in PER expandability and adipocyte-size distribution patterns in adulthood in both sexes.

Prenatal over- and undernutrition differentially program small intestinal growth, angiogenesis, absorptive capacity, and endocrine function in sheep.

The aim was to test the hypothesis that prenatal under- and overnutrition in late gestation can program small intestinal (SI) growth, angiogenesis, and endocrine function to predispose for a hyperabsorptive state, thereby increasing the susceptibility to the adverse effects of an early postnatal obesogenic diet. Twin-pregnant ewes were exposed to adequate (NORM), LOW (50% of NORM), or HIGH (150% energy and 110% protein of NORM) diets through the last trimester (term ~147 days). From 3 days to 6 months of age, their lambs were fed either a moderate (CONV) or a high-carbohydrate high-fat (HCHF) diet. At 6 months of age, responses in plasma metabolites and insulin to refeeding after fasting were determined and then different segments of the SI were sampled at autopsy. Prenatal overnutrition impacts were most abundant in the duodenum where HIGH had increased villus amplification factor and lowered villi thickness with increased IRS-1 and reduced GH-R expressions. In jejunum, HIGH lambs had an increased expression of Lactate gene and amplified when exposed to HCHF postnatally. Specifically, in LOW, sensitivity to HCHF was affected in ileum. Thus, the mismatching LOW-HCHF nutrition increased expressions of angiogenic genes (VEGF, VEGF-R1, ANGPT1, RTK) and increased mucosa layer (tunica mucosa) thickness but reduced muscle layer (Tunica muscularis) thickness. The SI is a target of prenatal nutritional programming, where late gestation overnutrition increased and shifted digestive capacity for carbohydrates toward the jejunum, whereas late gestation undernutrition predisposed for ileal angiogenesis and carbohydrate and fat hyperabsorptive capacity upon subsequent exposure to postnatal obesogenic diet.

Effects of maternal stress and nutrient restriction during gestation on offspring neuroanatomy in humans.

Cognitive and mental health are major determinants of quality of life, allowing integration into society at all ages. Human epidemiological and animal studies indicate that in addition to genetic factors and lifestyle, prenatal environmental influences may program neuropsychiatric disorders in later life. While several human studies have examined the effects of prenatal stress and nutrient restriction on brain function and mental health in later life, potentially mediating effects of prenatal stress and nutrient restriction on offspring neuroanatomy in humans have been studied only in recent years. Based on neuroimaging and anatomical data, we comprehensively review the studies in this emerging field. We relate prenatal environmental influences to neuroanatomical abnormalities in the offspring, measured in utero and throughout life. We also assess the relationship between neuroanatomical abnormalities and cognitive and mental disorders. Timing- and gender-specific effects are considered, if reported. Our review provides evidence for adverse effects of an unfavorable prenatal environment on structural brain development that may contribute to the risk for cognitive, behavioral and mental health problems throughout life.

Metabolomic profiling on rat brain of prenatal malnutrition: implicated for oxidative stress and schizophrenia.

Schizophrenia is a kind of neurodevelopmental disease. Epidemiological data associates schizophrenia with prenatal exposure to famine. Relevant prenatal protein deprivation (PPD) rodent models support this result by observing decreasing prepulse inhibition, altered hippocampal morphology and impaired memory in offspring. All these abnormalities are highly consistent with the pathophysiology of schizophrenia. We developed a prenatal famine rat model by restricting daily diet of the pregnant rat to 50% of low protein diet. A metabolomics study of prefrontal cortex was performed to integrate GC-TOFMS and UPLC-QTOFMS. Thirteen controls and thirteen famine offspring were used to differentiate in PLS-DA (partial least squares-discriminate analysis) model. Furthermore, metabolic pathways and diseases were enriched via KEGG and HMDB databases, respectively. A total of 67 important metabolites were screened out according to the multivariate analysis. Schizophrenia was the most statistical significant disease (P = 0.0016) in our famine model. These metabolites were enriched in key metabolic pathways related to energy metabolism and glutamate metabolism. Based on these important metabolites, further discussion speculated famine group was characterized by higher level of oxidized damage compared to control group. We proposed that oxidative stress might be the pathogenesis of prenatal undernutrition which is induced schizophrenia.

Maternal stress, prenatal medical illnesses and obstetric complications: Risk factors for schizophrenia spectrum disorder, bipolar disorder and major depressive disorder.

Maternal stress and medical illnesses during early life are well-documented environmental indicators of an increased risk of schizophrenia. Few studies, conversely, have confirmed an association with major affective disorders. The present study examined the impact of maternal stress, medical illnesses and obstetric complications on the development of severe mental disorder in 240 patients with a diagnosis of schizophrenia spectrum disorder, bipolar disorder, or major depressive disorder and matched with 85 controls. Mothers of participants were asked about stressful events during pregnancy using the Social Readjustment Scale; information on prenatal/perinatal illnesses were acquired from medical records. Schizophrenia spectrum disorder was positively associated with maternal stress (OR = 2.16), infections (OR = 7.67), inadequate weight gain (OR = 9.52) during pregnancy, and peripartum asphyxia (OR = 4.00). An increased risk of bipolar disorder was associated with head circumference < 32 cm at birth (OR = 5.40) and inversely with inadequate weight gain (OR = 0.29). Major depressive disorder diagnosis was inversely related to inadequate weight gain (OR = 0.22). These results support a role for maternal stress, medical illnesses and obstetric complications as risk factors for subsequent severe mental illness in adulthood. Further research is needed, especially with regard to affective disorders.

Schizophrenia in mid-adulthood after prenatal exposure to the Chinese Famine of 1959-1961.

Analyzing data from a large-scale, nationally representative sample, this study examines the association between prenatal exposure to the Chinese Famine (1959-1961) and schizophrenia risk in mid-adulthood and its urban/rural-specific and gender-specific patterns. The results showed that the cohort conceived and born during the famine had a higher risk of schizophrenia in mid-adulthood than cohorts conceived and born before or after the famine. In addition, schizophrenia risk was higher for urban residents than for rural residents and higher for females than for males. Drawing on the psychiatric features of late-onset schizophrenia in mid-adulthood, we then offer some theoretical mechanisms to explain the cohort, urban/rural, and gender differences.

Prenatal malnutrition and lead intake produce increased brain lipid peroxidation levels in newborn rats.

OBJECTIVES: Prenatal malnutrition (M) and lead intoxication (Pb) have adverse effects on neuronal development; one of the cellular mechanisms involved is a disruption of the pro- and anti-oxidant balance. In the developing brain, the vulnerability of neuronal membrane phospholipids is variable across the different brain areas. This study assesses the susceptibility of different brain regions to damage by quitar tissue oxidative stress and lead quitar concentrations to determine whether the combined effect of prenatal malnutrition (M) and lead (Pb) intoxication is worse than the effect of either of them individually. METHODS: M was induced with an isocaloric and hypoproteinic (6% casein) diet 4 weeks before pregnancy. Intoxication was produced with lead acetate in drinking water, from the first gestational day. Both the M and Pb models were continued until the day of birth. Four brain regions (hippocampus, cortex, striatum, and cerebellum) were dissected out to analyze the lipid peroxidation (LP) levels in four groups: normally nourished (C); normally nourished but intoxicated with lead (CPb); malnourished (M); and M intoxicated with lead (MPb). RESULTS: Dam body and brain weights were significantly reduced in the fourth gestational week in the MPb group. Their pups had significantly lower body weights than those in the C and CPb groups. The PbM group exhibited significant increases of lead concentration and LP in all areas evaluated. A potentiation effect of Pb and M on LP was found in the cerebellum. DISCUSSION: This study provides information on how environmental conditions (intoxication and malnutrition) during the intrauterine period could differentially affect the development of neuronal plasticity and, in consequence, alter adult brain functions such as learning and memory.

Anatomy of corpus callosum in prenatally malnourished rats

The effect of prenatal malnutrition on the anatomy of the corpus callosum was assessed in adult rats (45-52 days old). In the prenatally malnourished animals we observed a significant reduction of the corpus callosum total area, partial areas, and perimeter, as compared with normal animals. In addition, the splenium of corpus callosum (posterior fifth) showed a significant decrease of fiber diameters in the myelinated fibers without changing density. There was also a significant decrease in diameter and a significant increase in density of unmyelinated fibers. Measurements of perimeter's fractal dimensions from sagittal sections of the brain and corpus callosum did not show significant differences between malnourished and control animals. These findings indicate that cortico-cortical connections are vulnerable to the prenatal malnutrition, and suggest this may affect interhemispheric conduction velocity, particulary in visual connections (splenium).