Morphological evidence indicates a role for microglia in shaping the PCOS-like brain.

Although polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility worldwide, the aetiology of the disorder remains poorly defined. Animal-based evidence highlights the brain as a prime suspect in both the development and maintenance of PCOS. Prenatally androgenised (PNA) models of PCOS exhibit excessive GABAergic wiring associated with PCOS-like reproductive deficits in adulthood, with aberrant brain wiring detected as early as postnatal day (P) 25, prior to disease onset, in the PNA mouse. The mechanisms underlying this aberrant brain wiring remain unknown. Microglia, the immune cells of the brain, are regulators of neuronal wiring across development, mediating both the formation and removal of neuronal inputs. Here, we tested the hypothesis that microglia play a role in the excessive GABAergic wiring that leads to PCOS-like features in the PNA brain. Using specific immunolabelling, microglia number and morphology associated with activation states were analysed in PNA and vehicle-treated controls across developmental timepoints, including embryonic day 17.5, P0, P25 and P60 (n = 7-14 per group), and in two regions of the hypothalamus implicated in fertility regulation. At P0, fewer amoeboid microglia were observed in the rostral preoptic area (rPOA) of PNA mice. However, the greatest changes were observed at P25, with PNA mice exhibiting fewer total microglia, and specifically fewer "sculpting" microglia, in the rPOA. Based on these findings, we assessed microglia-mediated refinement of GABAergic synaptic terminals at two developmental stages of peak synaptic refinement: P7 and P15 (n = 7 per group). PNA mice showed a reduction in the uptake of GABAergic synaptic material at P15. These findings reveal time-specific changes in the microglia population and refinement of GABAergic inputs in a mouse model of PCOS driven by prenatal androgen excess and suggest a role for microglia in shaping the atypical brain wiring associated with the development of PCOS features.

Neonatal Brain Response to Deviant Auditory Stimuli and Relation to Maternal Trait Anxiety.

OBJECTIVE: Excessive response to unexpected or "deviant" stimuli during infancy and early childhood represents an early risk marker for anxiety disorders. However, research has yet to delineate the specific brain regions underlying the neonatal response to deviant stimuli near birth and the relation to risk for anxiety disorders. The authors used task-based functional MRI (fMRI) to delineate the neonatal response to deviant stimuli and its relationship to maternal trait anxiety. METHODS: The authors used fMRI to measure brain activity evoked by deviant auditory stimuli in 45 sleeping neonates (mean age, 27.8 days; 60% female; 64% African American). In 41 of the infants, neural response to deviant stimuli was examined in relation to maternal trait anxiety on the State-Trait Anxiety Inventory, a familial risk factor for offspring anxiety. RESULTS: Neonates manifested a robust and widespread neural response to deviant stimuli that resembles patterns found previously in adults. Higher maternal trait anxiety was related to higher responses within multiple brain regions, including the left and right anterior insula, the ventrolateral prefrontal cortex, and multiple areas within the anterior cingulate cortex. These areas overlap with brain regions previously linked to anxiety disorders and other psychiatric illnesses in adults. CONCLUSIONS: The neural architecture sensitive to deviant stimuli robustly functions in newborns. Excessive responsiveness of some circuitry components at birth may signal risk for anxiety and other psychiatric disorders.

Effects of psychological or physical prenatal stress on attention and locomotion in juvenile rats.

Background: Prenatal stress has been shown to affect the cognition of offspring, including memory and learning abilities.Methods: In the current study, the long-term effects of chronic prenatal exposure to the physical or psychological stress on locomotion and attention were evaluated by using open field test (OFT) and prepulse inhibition (PPI) of the acoustic startle reflex (ASR). In addition, the level of corticosterone was measured after the ASR trial.Results: Male and female rodents that underwent prenatal physical and psychological stress had an augmented velocity in OFT, and only male animals showed an increased ASR. Neither male nor female offsprings had an alteration in the level of corticosterone and PPI values regardless of the stress type.Conclusion: Our results revealed that exposure to stress during the development of fetus increases ASR in a sex-dependent manner. This finding might implicate the effect of prenatal stress on attention in male offspring regardless of the stress type.

Vertical exposition to Luffa operculata extract deregulates behavior and hypothalamus neurotransmitters in juvenile rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Luffa operculata (L.) Cogn (Cucurbitaceae) is a traditional plant popularly used in the abortion induction, against sinusitis and is toxic. AIM OF THE STUDY: To verify the influence of the aqueous extract obtained from the dry fruit of L. operculata (BNE) on the male rats vertically exposed to a subabortive dose of BNE, by evaluating alterations in behavior and neurochemical features in hypothalamus, striatum and frontal cortex, at a juvenile age, after receiving a stress challenge given by the use of the "New York subway stress" technique (NYS). MATERIALS AND METHODS: Pregnant female rats (F0 generation) received 1.0 mg/kg BNE, or distilled water (100 mL/kg), by gavage, between gestation days GD17 and GD21. The pups were weaned at PND21 and were kept up to PND60 (juvenile age) in controlled environmental conditions. Four groups were obtained: control (CG), experimental (EG), stress control (SCG) and stress experimental (SEG) After being stressed, the animals were behavioral screened for in the open field (OF) and in light-dark box (LDB) apparatuses. They were euthanized, and the liver, kidneys and brain were removed for both macroscopic and microscopic analyses, and for quantification of vanillylmandelic acid (VMA), norepinephrine (NE), dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the serotonin (5-HT) and its metabolite 5-hydroxyindolylacetic acid (5-HIAA) were accessed in the hypothalamus, frontal cortex and striatum. RESULTS AND DISCUSSION: although most of the behavior changes were due to the stress challenge, the rats spent more time in the dark side of the LDB and were less likely to explore the light side, indicating that the treatment with BNE induced to fear. Interferences of BNE over behavior were due to impairment of VMA, NE, 5-HT and DA and increasing of DOPAC in the hypothalamus, and an increase of 5-HIAA in the frontal cortex, indicating alterations in the hypothalamic-hypophysis-adrenal axis (HHAA). No macroscopic or histopathological changes were observed in the liver, kidneys, or brain, although GFAP was diminished in the SCG, as expected for stressed rats. CONCLUSION: the vertical exposition of juvenile rats to BNE led to the manifestation of fear and to a down regulation of the hypothalamic-hypophysis-adrenal axis.

GC-TOF-MS-Based Metabolomic Analysis and Evaluation of the Effects of HX106, a Nutraceutical, on ADHD-Like Symptoms in Prenatal Alcohol Exposed Mice.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that occurs in children characterized by inattention and hyperactivity. Prenatal alcohol exposure (PAE) can disrupt fetal neuronal development and cause an ADHD-like hyperactive behavior in the offspring. In this study, we hypothesized that metabolic disturbance would involve in ADHD neuropathology and aimed to investigate the changes in metabolite profile in PAE-induced ADHD-like model and the effects of HX106, a nutraceutical, on ADHD-like pathophysiology and metabolite changes. To this end, we administered HX106 to the mouse offspring affected by PAE (OPAE) and assessed the hyperactivity using the open field test. We observed that HX106-treated OPAE showed less hyperactive behavior than vehicle-treated OPAE. The effects of HX106 were found to be related to the regulation of dopamine transporter and D2 dopamine receptor expression. Furthermore, using gas chromatography time-of-flight mass spectrometry-based metabolomics, we explored the metabolite changes among the experimental groups. The metabolite profile, particularly related with the amino acids, linoleic acid and amino sugar pathways, was altered by PAE and reversed by HX106 treatment partially similar to that observed in the control group. Overall, this study suggest that metabolite alteration would be involved in ADHD pathology and that HX106 can be an efficient supplement to overcome ADHD by regulating dopamine signaling-related protein expression and metabolite changes.

Molecular mechanisms underlying altered neurobehavioural development of female offspring of mothers with polycystic ovary syndrome: FOS-mediated regulation of neurotrophins in placenta.

BACKGROUND: This study explored the mechanisms underlying altered neurobehavioural development of female offspring born to mothers with polycystic ovary syndrome (PCOS). METHODS: In total, 20 women with PCOS and 32 healthy women who underwent caesarean deliveries with a single female foetus were recruited. Infants were assessed with Dubowitz scoring. Swan71 cell line with stable FOS overexpression was used to verify the regulatory effects of FOS on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) expression. Learning and memory in female first-generation (F1) and second-generation (F2) offspring in a rat model of PCOS was tested using the Morris water maze at puberty and adulthood. Transcriptome analysis of pubertal hippocampi and hypothalami of female F1 offspring was conducted. FINDINGS: Total score and behaviour subscales of Dubowitz scoring were significantly lower in female infants of women with PCOS. FOS and NGF protein levels were downregulated in placental villi of the PCOS group. FOS played a key role in BDNF inhibition and enhancing NGF in Swan71 cells. PCOS female F1 rats exhibited lower target crossing times during puberty when compared to controls. Transcriptome analysis revealed significant changes in hippocampal and hypothalamic neuronal pathways in female F1 rats at puberty. INTERPRETATION: FOS regulation of neurotrophins in the placenta negatively affects neurobehavioural development of female offspring of PCOS mothers. FUNDING: This study was funded by the National Key R&D Program of China (2018YFC1004900 to F.Q. and F.W.) and the National Natural Science Foundation of China (81874480 to F.Q.; 81873837 to F.W.).

Silymarin administration during pregnancy and breastfeeding: evaluation of initial development and adult behavior of mice.

Silymarin is a phytotherapeutic agent derived from the species Silybum marianum (Asteraceae), commonly is known as milk thistle, and traditionally used as a hepatoprotective; however, recent studies have proposed its use in order to promote lactogenesis, but there are few reports of its effects on the development of offspring. Thus, the objective of this study was to evaluate the effect of silymarin treatment during pregnancy and breastfeeding on the sensory-somatic-motor development and adult behavior of F1-generation Swiss mice. The pregnant females of the parental generation were distributed in four experimental groups and treated orally with doses of 100, 200 or 300 mg/kg of silymarin, with a control group receiving vehicle - vegetable oil (VEH), to obtain the F1-generation. At the end of lactation, the parental generation were submitted to euthanasia. Body mass evolution was determined in both generations. The sensory-motor development of the offspring (F1-generation) was evaluated, and one male pup from each litter was followed up for an analysis of adult behavior. In the F1 analysis, no differences between the groups were observed in initial development from the sensory-somatic-motor analysis performed during the 1st to 21st postnatal days. In the behavioral evaluation of adults from the F1 generation, all the groups from dams treated with silymarin in open field (OF) analysis showed a decrease in the time spent in the periphery and an increase in the time spent in the center, but the ambulation observed by the number of quadrant crossed showed no difference. In addition, during OF, the 100 and 200 mg/kg groups presented an increase in fecal bolus compared with the VEH group. There was a decrease in immobility time in the forced swimming test in the 300 mg/kg group compared to the VEH group. Regarding the memory and learning test, the groups did not differ in their recognition scores. The results of this study using an animal model indicate that treatment with silymarin during pregnancy and breastfeeding does not promote significant morpho-functional changes in the offspring in their initial development and adult behavior, indicating the safety of its use during gestation and lactation.

Role of astaxanthin in the modulation of brain-derived neurotrophic factor and spatial learning behavior in perinatally undernourished Wistar rats.

Objective: Maternal health and nutrition during the perinatal period is the predominant factor influencing the functional development of the brain. Maternal malnutrition during the perinatal period causes retardation of brain development. The current study investigates the role of Astaxanthin (AsX) in spatial learning and memory and BDNF in perinatally undernourished Wistar rats.Methods: The albino wistar rats were perinatally undernourished and administered with different dosages of AsX. The spatial learning and memory performance and BDNF level were assessed. Data were collected and analysed.Results: The % Correct choice during the acquisition phase, performance at the end of the acquisition phase and the mean BDNF level at the Hippocampus, Cerebellum, and Cerebral cortex showed significant decline (P<0.001) in the PUN group and significantly high (P<0.001) in the PUNA2 group compared to the control. However, the mean RME and mean WME during different days of the acquisition phase were significantly high (P<0.001) in the PUN group and insignificant (P>0.05) in PUNA2 compared to the control.Discussion: The results showed that AsX effectively modulated the cognitive deficit that occurred in perinatally undernourished rats. This can be attributed to BDNF upregulation as evidenced by the significant increase of the BDNF level.

Maternal B vitamin intake during pregnancy and childhood behavioral problems in Japan: The Kyushu Okinawa Maternal and Child Health Study.

Objectives: The current prebirth cohort study investigated the relationship between maternal B vitamin intake during pregnancy and behavioral problems in Japanese children aged 5 years. Methods: Subjects were 1199 mother-child pairs. Dietary intake was assessed using a diet history questionnaire. Emotional problems, conduct problems, hyperactivity problems, peer problems, and low prosocial behavior were examined using the Japanese parent-report version of the Strengths and Difficulties Questionnaire. Adjustment was made for maternal age, gestation at baseline, region of residence, number of children, maternal and paternal education, household income, maternal depressive symptoms, alcohol intake, vitamin B complex supplement use, smoking during pregnancy, child's birth weight, child's sex, breastfeeding duration, and smoking in the household during the first year of life. Results: Maternal folate intake during pregnancy was independently inversely associated with childhood low prosocial behavior: the adjusted odds ratio (OR) (95% confidence interval [CI], P for trend) between extreme quartiles was 0.55 (0.37-0.80, 0.0002). Maternal vitamin B6 intake during pregnancy was independently inversely related to childhood hyperactivity problems and low prosocial behavior: the adjusted ORs (95% CIs, P for trend) between extreme quartiles were 0.57 (0.34-0.94, 0.01) and 0.58 (0.40-0.85, 0.0009), respectively. Maternal vitamin B2 intake during pregnancy was independently inversely associated with childhood emotional problems: the adjusted OR (95% CI, P for trend) between extreme quartiles was 0.58 (0.33-0.99, 0.11). Conclusions: Maternal intake of folate, vitamin B6, and vitamin B2 during pregnancy may be protective against childhood low prosocial behavior, hyperactivity problems and low prosocial behavior, and emotional problems, respectively.

Effects of Perinatal Cardamom Exposure on Social Behavior, Anxiety, Locomotor Activity, Blood Biochemical Parameters and Brain Acetylcholinesterase of Mice Offspring.

BACKGROUND: Cardamom is the flavouring spices mainly cultivated all over the world. Apart from being used as the spice, it has many medicinal values. Therefore, the present study aimed to investigate the potential use of cardamom and its effects on the ability of learning, developmental, and various biochemical factors of Swiss-Webster mice offspring at different stages. METHODS: In this method, Swiss-Webster mice offspring at different stages were used for the analysis of biochemical factors. After the administration of cardamom orally, the pups were subjected to various tests for determining social and defense behaviors of males and females, anxiety behavior; locomotor and neuromuscular activities, haemotological parameters, and hormonal factors of males and females. RESULTS: The present findings indicate that the cardamom induced reduction in the social and defense behaviors of males and females, respectively, and also anxiety behavior. Interestingly, locomotor and neuromuscular activities decreased significantly. DISCUSSION: In addition, the packed cell volume, red blood count, hemoglobin content, AChE in forebrain, the testosterone in males and progesterone in females were observed to increase significantly, whereas the blood platelets and total white blood count decreased non-significantly. Through perinatal exposure, cardamom can pass through the placenta or/and lactation and reaches the fetus. Care must be taken when using cardamom and especially during pregnancy and lactation. CONCLUSION: The administration of cardamom enhances the ability of social, developmental, and various biochemical factors of Swiss-Webster mice offspring at different stages.

The effects of developmental alcohol exposure on the neurobiology of spatial processing.

The consumption of alcohol during gestation is detrimental to the developing central nervous system. One functional outcome of this exposure is impaired spatial processing, defined as sensing and integrating information pertaining to spatial navigation and spatial memory. The hippocampus, entorhinal cortex, and anterior thalamus are brain regions implicated in spatial processing and are highly susceptible to the effects of developmental alcohol exposure. Some of the observed effects of alcohol on spatial processing may be attributed to changes at the synaptic to circuit level. In this review, we first describe the impact of developmental alcohol exposure on spatial behavior followed by a summary of the development of brain areas involved in spatial processing. We then provide an examination of the consequences of prenatal and early postnatal alcohol exposure in rodents on hippocampal, anterior thalamus, and entorhinal cortex-dependent spatial processing from the cellular to behavioral level. We conclude by highlighting several unanswered questions which may provide a framework for future investigation.

The association of maternal polyunsaturated fatty acids during pregnancy with social competence and problem behaviours at 7 years of age: The MEFAB cohort.

BACKGROUND: The prenatal exposure to maternal n-6 and n-3 polyunsaturated fatty acids (PUFAs) might influence the development of social competence and internalizing and externalizing behaviours of the child, because of the numerous functions of PUFAs within the nervous system. METHODS: To analyse the association of selected maternal PUFAs (i.e., AA, EPA, DHA, total n-6, total n-3, and the n-6:n-3 ratio) measured during gestation with childhood social competence and problem behaviours, we examined 311 mother-child pairs from the Maastricht Essential Fatty Acid Birth (MEFAB) cohort. For each woman, PUFA-specific changes in relative concentrations were calculated by identifying the best-fitting curve of PUFA concentration by linear splines of gestational age. The associations of changes in maternal PUFAs in early and late pregnancy with childhood social competence, total problems, internalizing and externalizing behaviours, measured with the Child Behaviour Checklist 4/18 at age 7, were investigated with linear regression analyses adjusted for maternal and children's socio-demographic characteristics. RESULTS: In late gestation (i.e., from gestational week 30), an increase in AA was associated with higher social competence, while a decrease in total n-6 was associated with lower externalizing behaviours. No other significant associations were found. DISCUSSION: In this prospective study, increasing maternal AA and decreasing total n-6 were associated with improved social competence and externalizing behaviours, respectively, in 7-year old children. Nonetheless, the clinical significance of the identified associations is modest and further investigations are warranted to clarify the relationship between maternal AA and total n-6 during pregnancy and childhood social and behavioural development.

Children who face development risks due to maternal addiction during pregnancy require extra medical and psychosocial resources.

AIM: This study examined medical and psychosocial risk factors in children born to women with addiction problems during pregnancy and the children's needs for extra medical and psychosocial resources. METHODS: Swedish midwives routinely screen pregnant women for drugs and alcohol and refer women with addictions to the Maternity and Child Healthcare Resource Team. We investigated the medical records of 127 children (51% girls) whose mothers were referred to the Resource Team from 2009 to 2015. Additional data were obtained from local child healthcare services (CHS), which provide routine paediatric care. RESULTS: More than three-quarters (76%) of the children had prenatal exposure to alcohol and drugs, and 17% were born with withdrawal symptoms. The mothers had a high rate of psychiatric diagnoses (38%) and were more likely to smoke after delivery and less likely to breastfeed than the general population. However, adherence to the CHS programme was generally high. Additional visits to the nurse, referrals to specialists, collaboration meetings and reports of concerns to social services decreased when the children began attending ordinary CHS centres. CONCLUSION: Children born to women with addictions during pregnancy faced a high risk of developmental problems and should be offered additional CHS resources to minimise negative long-term consequences.

Chronic dietary changes in n-6/n-3 polyunsaturated fatty acid ratios cause developmental delay and reduce social interest in mice.

Polyunsaturated fatty acids (PUFAs) are one of the main cellular building blocks, and dietary changes in PUFA composition are proposed as a potential route to influence brain development. For example, initial studies indicated that there is a relation between blood omega-6(n-6)/omega-3(n-3) PUFA ratios and neurodevelopmental disease diagnosis. To study the consequences of dietary n-6/n-3 PUFA ratio changes, we investigated the impact of a n-3 supplemented and n-3 deficient diet in developing BTBR T + Itpr3tf/J (BTBR) - a mouse inbred strain displaying Autism Spectrum Disorder (ASD)-like symptomatology - and control C57BL/6J mice. This study showed that pre- and postnatal changed dietary n-6/n-3 ratio intake has a major impact on blood and brain PUFA composition, and led to delayed physical development and puberty onset in both strains. The PUFA induced developmental delay did not impact adult cognitive performance, but resulted in reduced social interest, a main ASD behavioral feature. Thus, both chronic dietary n-3 PUFA supplementation and depletion may not be beneficial.

Prenatal undernutrition decreases the anorectic response to septic doses of lipopolysaccharides in adulthood in male rats.

Prenatal undernutrition affects some physiological functions after birth, and such changes are associated with the pathogenesis of various diseases. Recently, we have reported that prenatally undernourished male rats exhibited stronger febrile and anorectic responses to immune stress induced by moderate-dose lipopolysaccharide (LPS) treatment in adulthood. In the present study, we evaluated the effects of prenatal undernutrition on stress responses to the administration of a septic dose (3 mg/kg) of LPS in later life, mainly focusing on changes in hypothalamic proinflammatory cytokine expression. We also evaluated the expression of hypothalamic and peripheral reproductive factors because it has been suggested that the stress responses of reproductive functions are affected by prenatal and neonatal stress and nutritional conditions. As a result, we found that prenatal undernutrition attenuated the anorectic response to septic-dose LPS treatment in adulthood in male rats. In addition, it attenuated the LPS-induced suppression of serum testosterone levels and the changes in hypothalamic proinflammatory cytokine (interleukin (IL)-1ß, tumor necrosis factor-α, and IL-6) expression induced by septic-dose LPS treatment in adulthood. These results suggest that prenatal undernutrition attenuates stress and reproductive responses under severe immune stress conditions. The downregulation of hypothalamic stress-related factor expression might be involved in such attenuated stress responses, which could be one of the protective mechanisms used to prevent excessive immune responses and aid survival.

Effect of Choline Supplementation on Neurological, Cognitive, and Behavioral Outcomes in Offspring Arising from Alcohol Exposure During Development: A Quantitative Systematic Review of Clinical and Preclinical Studies.

Prenatal alcohol exposure results in cognitive, behavioral, and neurological deficits in offspring. There is an urgent need for safe and effective treatments to overcome these effects. Maternal choline supplementation has been identified as a potential intervention. Our objective was to review preclinical and clinical studies using choline supplementation in known cases of fetal alcohol exposure to determine its effectiveness in ameliorating deficits in offspring. A systematic search of 6 electronic databases was conducted and studies selected by reviewing titles/abstracts against specific inclusion/exclusion criteria. Study characteristics, population demographics, alcohol exposure, and intervention methods were tabulated, and quality of reporting was assessed. Data on cognitive, behavioral, and neurological outcomes were extracted and tabulated. Quantitative analysis was performed to determine treatment effects for individual study outcomes. A total of 189 studies were retrieved following duplicate removal. Of these, 22 studies (2 randomized controlled trials, 2 prospective cohort studies, and 18 preclinical studies) met the full inclusion/exclusion criteria. Choline interventions were administered at different times relative to alcohol exposure, impacting on their success to prevent deficits for specific outcomes. Only 1 clinical study showed significant improvements in information processing in 6-month-old infants from mothers treated with choline during pregnancy. Preclinical studies showed significant amelioration of deficits due to prenatal alcohol exposure across a wide variety of outcomes, including epigenetic/molecular changes, gross motor, memory, and executive function. This review suggests that choline supplementation has the potential to ameliorate specific behavioral, neurological, and cognitive deficits in offspring caused by fetal alcohol exposure, at least in preclinical studies. As only 1 clinical study has shown benefit, we recommend more clinical trials be undertaken to assess the effectiveness of choline in preventing deficits across a wider range of cognitive domains in children.

Increased intake of vitamin B12, folate, and omega-3 fatty acids to improve cognitive performance in offspring born to rats with induced hypertension during pregnancy.

Vitamin B12, folic acid, and docosahexaenoic acid levels are reported to be altered in women with preeclampsia. This study examined the effect of the above nutrients on brain neurotrophins and on the cognitive performance in adult offspring in a pregnancy-induced hypertension rat model. Pregnant dams were assigned to control, PIH-induced, and PIH-induced supplemented with vitamin B12, folate, omega-3 fatty acids, and the combined supplementation of vitamin B12, folate, and omega-3 fatty acids groups. In the PIH group, brain-derived neurotrophic factor levels (BDNF) were lower in the offspring at birth, while the adult offspring showed lower levels of docosahexaenoic acid (DHA) in the hippocampus and BDNF (p < 0.05 for both) in the cortex as compared to in the control group. They also demonstrated higher (p < 0.05) escape latency in the Morris water maze test and performed a greater (p < 0.01 for all) number of errors in the Radial eight-arm maze test. A combined supplementation of vitamin B12, folic acid, and omega-3 fatty acids improved the levels of LCPUFA, neurotrophins, and cognition. A maternal diet consisting of high levels of folate, vitamin B12, and DHA reduced the risk for cognitive disorders in the adult offspring in an animal model of pregnancy-induced hypertension.

Mice exposed to bisphenol A exhibit depressive-like behavior with neurotransmitter and neuroactive steroid dysfunction.

Fetal exposure to endocrine disrupting chemicals (EDCs) has been associated with adverse neurobehavioral outcomes across the lifespan and can persist across multiple generations of offspring. However, the underlying mechanisms driving these changes are not well understood. We investigated the molecular perturbations associated with EDC-induced behavioral changes in first (F1) and second (F2) filial generations, using the model EDC bisphenol A (BPA). C57BL/6J dams were exposed to BPA from preconception until lactation through the diet at doses (10 µg/kg bw/d-lower dose or 10 mg/kg bw/d-upper dose) representative of human exposure levels. As adults, F1 male offspring exhibited increased depressive-like behavior, measured by the forced swim test, while females were unaffected. These behavioral changes were limited to the F1 generation and were not associated with altered maternal care. Transcriptome analysis by RNA-sequencing in F1 control and upper dose BPA-exposed adult male hippocampus revealed neurotransmitter systems as major pathways disrupted by developmental BPA exposure. High performance liquid chromatography demonstrated a male-specific reduction in hippocampal serotonin. Administration of the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg bw) rescued the depressive-like phenotype in males exposed to lower, but not upper, dose BPA, suggesting distinct mechanisms of action for each exposure dose. Finally, high resolution mass spectrometry revealed reduced circulating levels of the neuroactive steroid dehydroepiandrosterone in BPA-exposed males, suggesting another potential mechanism underlying the depressive-like phenotype. Thus, behavioral changes associated with early life BPA exposure may be mediated by sex-specific disruptions in the serotonergic system and/or sex steroid biogenesis in male offspring.

Feasibility and Acceptability of Maternal Choline Supplementation in Heavy Drinking Pregnant Women: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Choline, an essential nutrient, serves as a methyl-group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. Findings from animal studies suggest that choline supplementation during pregnancy can mitigate adverse effects of prenatal alcohol exposure on growth and neurocognitive function. We conducted a randomized, double-blind exploratory trial to examine feasibility and acceptability of a choline supplementation intervention during pregnancy. METHODS: Seventy heavy drinkers, recruited in mid-pregnancy, were randomly assigned to receive a daily oral dose of 2 g of choline or a placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape-flavored drink. Adherence was assessed by collecting used and unused drink packets on a monthly basis and tabulating the number used. Side effects were assessed in monthly interviews. Blood samples obtained at enrollment and at 4 and 12 weeks after randomization were assayed for plasma choline concentration. RESULTS: Adherence was good-to-excellent (median doses taken = 74.0%; interquartile range = 53.9 to 88.7%) and was not related to a range of sociodemographic characteristics or to alcohol consumption ascertained using a timeline follow-back interview. By 4 weeks, plasma choline concentrations were significantly higher in the choline supplementation than the placebo arm, and this group difference continued to be evident at 12 weeks. The only side effect was a small increase in nausea/dyspepsia. No effects were seen for diarrhea, vomiting, muscle stiffness, blood pressure, or body odor changes. CONCLUSIONS: This study demonstrated that a choline supplementation program with very heavy drinkers during pregnancy is feasible even among highly disadvantaged, poorly educated women. The broad acceptability of this intervention is indicated by our finding that adherence was not related to maternal education, intellectual function, depression, nutritional status, or alcohol use.

Maternal fat intake during pregnancy and behavioral problems in 5-y-old Japanese children.

OBJECTIVE: The aim of this cohort study was to investigate the relationship between maternal fat consumption during pregnancy and behavioral problems in 1199 Japanese children at age 5 y. METHODS: Dietary intake of mothers during pregnancy was assessed using a diet history questionnaire. Emotional, conduct, hyperactivity, and peer problems in children were assessed using the Strengths and Difficulties Questionnaire; the four scale scores were dichotomized, comparing children with borderline and abnormal scores to children with normal scores. Logistic regression analysis was applied to estimate adjusted odds ratios and 95% confidence intervals for each behavioral problem according to the quartile of dietary factors under study, adjusting for potential confounding factors. RESULTS: Higher maternal intake of monounsaturated fatty acids, α-linolenic acid, ω-6 polyunsaturated fatty acids, and linoleic acid during pregnancy was independently associated with an increased risk for childhood emotional problems. The adjusted odds ratios between extreme quartiles (95% confidence intervals, Ptrend) were 1.85 (1.11 - 3.17, 0.04), 1.60 (0.99 - 2.60, 0.03), 2.06 (1.24 - 3.46, 0.002), and 2.09 (1.26 - 3.51, 0.002), respectively. No such positive associations were observed for the other outcomes. No relationships were found between maternal intake of total fat, saturated fatty acids, ω-3 polyunsaturated fatty acids, eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid, or cholesterol, or the ratio of ω-3 to ω-6 polyunsaturated fatty acid intake during pregnancy and any of the outcomes. CONCLUSIONS: Maternal consumption of monounsaturated fatty acids, α-linolenic acid, ω-6 polyunsaturated fatty acids, and linoleic acid during pregnancy may increase the risk for childhood emotional problems.