Vitamin D and the Central Nervous System: Causative and Preventative Mechanisms in Brain Disorders.

Twenty of the last one hundred years of vitamin D research have involved investigations of the brain as a target organ for this hormone. Our group was one of the first to investigate brain outcomes resulting from primarily restricting dietary vitamin D during brain development. With the advent of new molecular and neurochemical techniques in neuroscience, there has been increasing interest in the potential neuroprotective actions of vitamin D in response to a variety of adverse exposures and how this hormone could affect brain development and function. Rather than provide an exhaustive summary of this data and a listing of neurological or psychiatric conditions that vitamin D deficiency has been associated with, here, we provide an update on the actions of this vitamin in the brain and cellular processes vitamin D may be targeting in psychiatry and neurology.

Association between circulating 25-hydroxyvitamin D concentrations and hip replacement for osteoarthritis: a prospective cohort study.

BACKGROUND: To examine the association between circulating 25(OH)D concentrations and incidence of total hip replacement for osteoarthritis in a prospective cohort study. METHODS: This study examined a random sample of 2651 participants in the Melbourne Collaborative Cohort Study who had 25(OH)D concentrations measured from dried blood spots collected in 1990-1994. Participants who underwent total hip replacement for osteoarthritis between January 2001 and December 2018 were identified by linking the cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of total hip replacement for osteoarthritis in relation to 25(OH)D concentrations, adjusted for confounders. RESULTS: Eighty-six men and eighty-seven women had a total hip replacement for osteoarthritis. Compared with men in the lowest (1st) quartile of 25(OH)D concentration, the HR for total hip replacement was 2.32 (95% CI 1.05, 5.13) for those in the 2nd quartile, 2.77 (95% CI 1.28, 6.00) for those in the 3rd quartile, and 1.73 (95% CI 0.75, 4.02) for those in the highest quartile of 25(OH)D concentrations (p for trend 0.02). There was little evidence of an association in women. CONCLUSIONS: Higher circulating 25(OH)D concentrations were associated with an increased risk of total hip replacement for osteoarthritis in men but not in women. Although the underlying mechanism warrants further investigation, our findings highlight the need to determine the optimal levels of circulating 25(OH)D to reduce the risk of hip osteoarthritis.

Developmental Inhibition of Long Intergenic Non-Coding RNA, HOTAIRM1, Impairs Dopamine Neuron Differentiation and Maturation.

The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is controlled by a complex web of transcriptional factors that dictate DA neuron specification, differentiation, and maturation. A growing body of evidence suggests that these transcriptional factors are under the regulation of newly discovered non-coding RNAs. However, with regard to DA neuron development, little is known of the roles of non-coding RNAs. The long non-coding RNA (lncRNA) HOX-antisense intergenic RNA myeloid 1 (HOTAIRM1) is present in adult DA neurons, suggesting it may have a modulatory role in DA systems. Moreover, HOTAIRM1 is involved in the neuronal differentiation in human stem cells suggesting it may also play a role in early DA neuron development. To determine its role in early DA neuron development, we knocked down HOTAIRM1 using RNAi in vitro in a human neuroblastoma cell line, and in vivo in mouse DA progenitors using a novel in utero electroporation technique. HOTAIRM1 inhibition decreased the expression of a range of key DA neuron specification factors and impaired DA neuron differentiation and maturation. These results provide evidence of a functional role for HOTAIRM1 in DA neuron development and differentiation. Understanding of the role of lncRNAs in the development of DA systems may have broader implications for brain development and neurodevelopmental disorders such as schizophrenia.

How do established developmental risk-factors for schizophrenia change the way the brain develops?

The recognition that schizophrenia is a disorder of neurodevelopment is widely accepted. The original hypothesis was coined more than 30 years ago and the wealth of supportive epidemiologically data continues to grow. A number of proposals have been put forward to suggest how adverse early exposures in utero alter the way the adult brain functions, eventually producing the symptoms of schizophrenia. This of course is extremely difficult to study in developing human brains, so the bulk of what we know comes from animal models of such exposures. In this review, I will summarise the more salient features of how the major epidemiologically validated exposures change the way the brain is formed leading to abnormal function in ways that are informative for schizophrenia symptomology. Surprisingly few studies have examined brain ontogeny from embryo to adult in such models. However, where there is longitudinal data, various convergent mechanisms are beginning to emerge involving stress and immune pathways. There is also a surprisingly consistent alteration in how very early dopamine neurons develop in these models. Understanding how disparate epidemiologically-validated exposures may produce similar developmental brain abnormalities may unlock convergent early disease-related pathways/processes.

Vitamin D and schizophrenia: 20 years on.

Many epidemiological studies have highlighted the link between vitamin D deficiency and schizophrenia. In particular, two prominent studies report an association between neonatal vitamin D deficiency and an increased risk of schizophrenia. In parallel, much has been learnt about the role of vitamin D in the developing central nervous system over the last two decades. Studies in rodent models of developmental vitamin D (DVD)-deficiency describe how brain development is altered leading to a range of neurobiological and behavioral phenotypes of interest to schizophrenia. While glutamate and gamma aminobutyric acid (GABA) systems have been little investigated in these models, alterations in developing dopamine systems are frequently reported. There have been far more studies reporting patients with schizophrenia have an increased risk of vitamin D deficiency compared to well controls. Here we have conducted a systematic review and meta-analysis that basically confirms this association and extends this to first-episode psychosis. However, patients with schizophrenia also have poorer general health, poorer diets, are frequently less active and also have an increased risk of other medical conditions, all factors which reduce circulating vitamin D levels. Therefore, we would urge caution in any causal interpretation of this association. We also summarize the inconsistent results from existing vitamin D supplementation trials in patients with schizophrenia. In respect to animal models of adult vitamin D deficiency, such exposures produce subtle neurochemical alterations and effects on cognition but do not appear to produce behavioral phenotypes of relevance to schizophrenia. We conclude, the hypothesis that vitamin D deficiency during early life may increase the risk of schizophrenia remains plausible and warrants ongoing research.

Developmental vitamin D and autism spectrum disorders: findings from the Stockholm Youth Cohort.

Animal studies indicate that early life vitamin D is crucial for proper neurodevelopment. Few studies have examined whether maternal and neonatal vitamin D concentrations influence risk of autism spectrum disorders (ASD). Participants were sampled from the Stockholm Youth Cohort, a register-based cohort in Sweden. Concentrations of total 25-hydroxyvitamin D (25OHD) were assessed from maternal and neonatal biosamples using a highly sensitive liquid chromatography tandem mass spectrometry method. The maternal sample consisted of 449 ASD cases and 574 controls, the neonatal sample: 1399 ASD cases and 1607 controls; and the paired maternal-neonatal sample: 340 ASD cases and 426 controls. Maternal 25OHD was not associated with child ASD in the overall sample. However, in Nordic-born mothers, maternal 25OHD insufficiency (25 - <50 nmol/L) at ~11 weeks gestation was associated with 1.58 times higher odds of ASD (95% CI: 1.00, 2.49) as compared with 25OHD sufficiency (≥50 nmol/L). Neonatal 25OHD < 25 nmol/L was associated with 1.33 times higher odds of ASD (95% CI: 1.02, 1.75) as compared with 25OHD ≥ 50 nmol/L. Sibling-matched control analyses indicated these associations were not likely due to familial confounding. Children with both maternal 25OHD and neonatal 25OHD below the median had 1.75 (95% CI: 1.08, 2.86) times the odds of ASD compared with children with maternal and neonatal 25OHD both below the median. Our results are consistent with an increasing body of evidence suggesting that vitamin D concentrations in early life may be associated with increased risk of neurodevelopmental disorders including ASD.

Circulating 25-hydroxyvitamin D concentration and cause-specific mortality in the Melbourne Collaborative Cohort Study.

Vitamin D deficiency is associated with higher all-cause mortality, but associations with specific causes of death are unclear. We investigated the association between circulating 25-hydroxyvitamin D (25(OH)D) concentration and cause-specific mortality using a case-cohort study within the Melbourne Collaborative Cohort Study (MCCS). Eligibility for the case-cohort study was restricted to participants with baseline dried blood spot samples and no pre-baseline diagnosis of cancer. These analyses included participants who died (n = 2307) during a mean follow-up of 14 years and a sex-stratified random sample of eligible cohort participants ('subcohort', n = 2923). Concentration of 25(OH)D was measured using liquid chromatography-tandem mass spectrometry. Cox regression, with Barlow weights and robust standard errors to account for the case-cohort design, was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cause-specific mortality in relation to 25(OH)D concentration with adjustment for confounders. Circulating 25(OH)D concentration was inversely associated with risk of death due to cancer (HR per 25 nmol/L increment = 0.88, 95 % CI 0.78-0.99), particularly colorectal cancer (HR = 0.75, 95 % CI 0.57-0.99). Higher 25(OH)D concentrations were also associated with a lower risk of death due to diseases of the respiratory system (HR = 0.62, 95 % CI 0.43-0.88), particularly chronic obstructive pulmonary disease (HR = 0.53, 95 % CI 0.30-0.94), and diseases of the digestive system (HR = 0.44, 95 % CI 0.26-0.76). Estimates for diabetes mortality (HR = 0.64, 95 % CI 0.33-1.26) and cardiovascular disease mortality (HR = 0.90, 95 % CI 0.76-1.07) lacked precision. The findings suggest that vitamin D might be important for preventing death due to some cancers, respiratory diseases, and digestive diseases.

Developmental Vitamin D Deficiency in the Rat Impairs Recognition Memory, but Has No Effect on Social Approach or Hedonia.

Developmental vitamin D (DVD) deficiency is a risk factor for schizophrenia. In rodents we show that DVD-deficiency alters brain development and produces behavioral phenotypes in the offspring of relevance to the positive symptoms of schizophrenia. The aims of this study are to examine behavioral phenotypes specific to the cognitive and negative symptoms of schizophrenia in this model, and to vary the duration of vitamin D deficiency during gestation and beyond birth. We hypothesize that a longer duration of DVD-deficiency would result in greater behavioral impairments. Female vitamin D-deficient Sprague Dawley dams were mated at 10 weeks of age. Dietary vitamin D was reintroduced to dams and/or pups at different developmental time-points: Conception, Birth, Post-natal day (PND) 6 and PND21. Adult male and female offspring were assessed on a battery of behavioral tests, including sucrose preference, open field, novel object recognition (NOR), social approach and social novelty. We find that all windows of DVD-deficiency impaired NOR a cognitive measure that requires intact recognition memory. Sucrose consumption, social approach and social memory negative symptom-like phenotypes were unaffected by any maternal dietary manipulation. In addition, contrary to our hypothesis, we find that rats in the Conception group, that is the shortest duration of vitamin D deficiency, demonstrate increased locomotor activity, and decreased interaction time with novel objects. These findings have implications for the increasing number of studies examining the preclinical consequences of maternal vitamin D deficiency, and continue to suggest that adequate levels of maternal vitamin D are required for normal brain development.

1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex.

Schizophrenia has been associated with a range of genetic and environmental risk factors. Here we explored a link between two risk factors that converge on a shared neurobiological pathway. Recent genome-wide association studies (GWAS) have identified risk variants in genes that code for L-type voltage-gated calcium channels (L-VGCCs), while epidemiological studies have found an increased risk of schizophrenia in those with neonatal vitamin D deficiency. The active form of vitamin D (1,25(OH)2D) is a secosteroid that rapidly modulates L-VGCCs via non-genomic mechanisms in a range of peripheral tissues, though its non-genomic effects within the brain remain largely unexplored. Here we used calcium imaging, electrophysiology and molecular biology to determine whether 1,25(OH)2D non-genomically modulated L-VGCCs in the developing prefrontal cortex, a region widely implicated in schizophrenia pathophysiology. Wide-field Ca2+ imaging revealed that physiological concentrations of 1,25(OH)2D rapidly enhanced activity-dependent somatic Ca2+ levels in a small subset of neurons in the developing PFC, termed vitamin D-responsive neurons (VDRNs). Somatic nucleated patch recordings revealed a rapid, 1,25(OH)2D-evoked increase in high-voltage-activated (HVA) Ca2+ currents. Enhanced activity-dependent Ca2+ levels were mediated by L-VGCC but not associated with any changes to Cacna1c (L-VGCC pore-forming subunit) mRNA expression. Since L-VGCC activity is critical to healthy neurodevelopment, these data suggest that suboptimal concentrations of 1,25(OH)2D could alter brain maturation through modulation of L-VGCC signalling and as such may provide a parsimonious link between epidemiologic and genetic risk factors for schizophrenia.

Neonatal vitamin D status in relation to autism spectrum disorder and developmental delay in the CHARGE case-control study.

Vitamin D appears essential for normal neurodevelopment and cognitive and behavioral function. We examined neonatal vitamin D in relation to the child's later diagnosis of autism spectrum disorder (ASD) or developmental delay (DD). Children aged 24-60 months enrolled in the population-based CHARGE case-control study were evaluated clinically for ASD (n = 357), DD (n = 134), or typical development (TD, n = 234) at the MIND Institute (Sacramento, CA) using standardized assessments. Total 25-hydroxyvitamin D (25[OH]D) was measured using sensitive isotope dilution liquid chromatography-tandem mass spectrometry in archived dried blood spots collected for the California Department of Public Health's Newborn Screening Program. Multinomial logistic regression was used to calculate ORs as measures of the associations between 25 nmol/L change in 25(OH)D and ASD and DD. Associations between 25(OH)D and scores on Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales were assessed using robust linear regression. Effect modification was examined using stratified models and interaction product terms. Unadjusted mean (SD) 25(OH)D was lower for DD (73.2 [37.6]) than for TD (82.7 [39.3]) and ASD (80.1 [37.4]). After adjustment for maternal prepregnancy body mass index and education, a 25 nmol/L increase in total 25(OH)D was not associated with ASD (OR = 0.97; CI: 0.87-1.08) or DD (OR = 0.91; 95% CI: 0.78-1.06). Neonatal 25(OH)D was associated with significantly reduced ASD only in females (adjusted OR = 0.74; 95% CI: 0.55-0.99, Pinteraction = 0.03), and significantly reduced DD only in non-Hispanic white children (adjusted OR = 0.79; 95% CI: 0.63-0.98, Pinteraction = 0.11 for Hispanic, Pinteraction = 0.31 for other), driven by DD children with trisomy 21. This study provides evidence that neonatal vitamin D could be associated with ASD in females and with DD in non-Hispanic white children. Autism Res 2019, 12: 976-988. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Vitamin D appears essential for brain development and function. We examined neonatal total 25-hydroxyvitamin D (25[OH]D) measured in dried blood spots in relation to later diagnoses of autism spectrum disorder (ASD) or developmental delay (DD) and related assessment scores. Higher neonatal 25(OH)D was associated with a 26% reduction in the odds for ASD only in females. After taking into account factors that could contribute to vitamin D status, a significant association with 21% reduced odds for DD was found only in non-Hispanic white children. Though results were nonsignificant overall, certain subgroups might benefit from higher neonatal vitamin D.

Circulating 25-Hydroxyvitamin D Concentration and Risk of Breast, Prostate, and Colorectal Cancers: The Melbourne Collaborative Cohort Study.

BACKGROUND: The role of vitamin D in cancer risk remains controversial, and limited data exist on associations between vitamin D and subtypes of specific cancers. We investigated associations between circulating 25-hydroxyvitamin D (25(OH)D) and risk of colorectal, breast, and prostate cancers, including subtypes. METHODS: A case-cohort study within the Melbourne Collaborative Cohort Study included 547 colorectal, 634 breast, and 824 prostate cancers, and a sex-stratified random sample of participants (n = 2,996). Concentration of 25(OH)D in baseline-dried blood spots was measured using LC-MS/MS. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for each cancer in relation to plasma-equivalent 25(OH)D concentration. Associations by stage and BRAF/KRAS status for colorectal cancer, estrogen receptor status for breast cancer, and aggressiveness for prostate cancer were examined in competing risks models. RESULTS: 25(OH)D concentrations were inversely associated with risk of colorectal cancer [highest vs. lowest 25(OH)D quintile: HR, 0.71; 95% confidence interval (CI), 0.51-0.98], which was limited to women (HR, 0.52; 95% CI, 0.33-0.82). Circulating 25(OH)D was also inversely associated with BRAF V600E-positive colorectal cancer (per 25 nmol/L increment: HR, 0.71; 95% CI, 0.50-1.01). There were no inverse associations with breast cancer (HR, 0.98; 95% CI, 0.70-1.36) or prostate cancer (HR, 1.11; 95% CI, 0.82-1.48). CONCLUSIONS: Circulating 25(OH)D concentration was inversely associated with colorectal cancer risk for women, but not with risk of breast cancer or prostate cancer. IMPACT: Vitamin D might play a role in preventing colorectal cancer. Further studies are required to confirm whether vitamin D is associated with specific tumor subtypes.

Half the Genetic Variance in Vitamin D Concentration is Shared with Skin Colour and Sun Exposure Genes.

This study assessed the heritability of 25 hydroxyvitamin D3 (25(OH)D3) in a large twin cohort and the shared effect of sun exposure and skin colour on 25(OH)D3 variance. Study participants included 1604 twin pairs and their siblings (n = 4020). Twin correlations for 25(OH)D3 concentration were rMZ=0.79 (584 pairs) and rDZ = 0.52 (1020 pairs) consistent with an average h2 = 0.50 throughout the year. Significant phenotypic and genetic seasonal fluctuation was observed in 25(OH)D3 concentrations with heritability decreasing during the winter (h2 = 0.37) compared to summer (h2 = 0.62). Skin colour (measured both ordinally and quantitatively) and self-reported sun exposure were found to significantly affect 25(OH)D3 concentration. Twins with olive/dark skin had significantly lower 25(OH)D3 concentrations than those with fair/pale skin and multivariate genetic analysis showed that approximately half of the total additive genetic variation in 25(OH)D3 results from genes whose primary influence is on skin colour and sun exposure. Additionally, 37% of the total variance was attributed to shared environmental effects on vitamin D, skin colour and sun exposure measures. These results support a moderate estimate of vitamin D heritability and suggest significant influence of season, skin colour and sun exposure on the genetic variance.

Vitamin D status and the risk of type 2 diabetes: The Melbourne Collaborative Cohort Study.

AIMS: Inverse associations between vitamin D status and risk of type 2 diabetes observed in epidemiological studies could be biased by confounding and reverse causality. We investigated the prospective association between vitamin D status and type 2 diabetes and the possible role of reverse causality. METHODS: We conducted a case-cohort study within the Melbourne Collaborative Cohort Study (MCCS), including a random sample of 628 participants who developed diabetes and a sex-stratified random sample of the cohort (n = 1884). Concentration of 25-hydroxyvitamin D (25(OH)D) was measured using liquid chromatography-tandem mass spectrometry in samples collected at recruitment. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of type 2 diabetes for quartiles of 25(OH)D relative to the lowest quartile and per 25 nmol/L increase in 25(OH)D, adjusting for confounding variables. RESULTS: The ORs for the highest versus lowest 25(OH)D quartile and per 25 nmol/L increase in 25(OH)D were 0.60 (95% CI: 0.44, 0.81) and 0.76 (95% CI: 0.63, 0.92; p = 0.004), respectively. In participants who reported being in good/very good/excellent health approximately four years after recruitment, ORs for the highest versus lowest 25(OH)D quartile and per 25 nmol/L increase in 25(OH)D were 0.46 (95% CI: 0.29, 0.72) and 0.71 (95% CI: 0.56, 0.89; p = 0.003), respectively. CONCLUSIONS: In this sample of middle-aged Australians, vitamin D status was inversely associated with the risk of type 2 diabetes, and this association did not appear to be explained by reverse causality.

Increasing paternal age alters anxiety-related behaviour in adult mice.

Advanced paternal age (APA) is associated with an increased risk of adverse health outcomes in offspring, including autism and schizophrenia. In the present study, we investigated the behaviour of young (3-month-old; Control), middle aged (12 to 15-month-old; APA1) and old (24-month-old; APA2) C57BL/6J sires and their adult offspring. Male and female mice were tested at 10 weeks of age on a behavioural test battery including the elevated plus-maze, hole board, light/dark emergence, forced swim test, novelty-suppressed feeding and for prepulse inhibition of the acoustic startle response. Increasing the APA sire age to 24 months was shown to be associated with increased anxiety-related behaviour in the offspring, and indicated that increasing APA sire age produced a more robust hypoexplorative phenotype. Thus, increasing paternal age was associated with an increase in severity of an anxiogenic phenotype in their adult offspring. Ultimately, the results of these studies show that mouse models of APA are valuable for elucidating the mechanisms by which APA influences brain-related outcomes.

Associations of maternal and fetal vitamin D status with childhood body composition and cardiovascular risk factors.

Maternal vitamin D deficiency during pregnancy may have persistent adverse effects on childhood growth and development. We examined whether 25-hydroxyvitamin D (25(OH)D) concentrations during pregnancy and at cord blood were associated with childhood body composition and cardiovascular outcomes. This study was embedded in a population-based prospective cohort in Rotterdam, The Netherlands, among 4,903 mothers and their offspring. We measured 25(OH)D concentrations at a median gestational age of 20.4 weeks (95% range 18.5-23.4 weeks) and at birth (40.1 weeks [95% range 35.8-42.3 weeks]). 25(OH)D concentrations were categorized into severely deficient (<25.0 nmol/L); deficient (25.0 to 49.9 nmol/L); sufficient (50.0 to 74.9 nmol/L) and optimal (≥75.0 nmol/L). At 6 years, we measured childhood body mass index; fat and lean mass by Dual-energy X-ray Absorptiometry; blood pressure; and serum cholesterol, triglycerides, and insulin concentrations. Compared with children from mothers with optimal 25(OH)D concentrations (≥75.0 nmol/L), those of severely deficient vitamin D (<25.0 nmol/L) mothers had a 0.12 standard deviation score (SDS); (95% Confidence Interval (CI) [0.03, 0.21]) higher fat mass percentage and a 0.13 SDS (95% CI [-0.22, -0.04]) lower lean mass percentage. These associations remained after adjustment for current child vitamin D status. Maternal and cord blood 25(OH)D concentrations were not associated with cardiovascular risk factors in childhood. In conclusion, severe maternal 25(OH)D deficiency (<25.0 nmol/L) during pregnancy is associated with an adverse childhood body composition profile, but we did not observe evidence for an association with childhood cardiovascular risk factors. Further studies are needed to replicate our findings, to examine the underlying mechanisms, the causality of the associations, and the potential for public health interventions.

Functional and molecular changes in the nucleus accumbens of MK-801-sensitized rats.

Behavioural sensitization is a putative mechanism in the pathophysiology of drug addiction and neuropsychiatric disorders such as schizophrenia. In rodents, drug-induced behavioural sensitization has been described for several different drug classes. The N-methyl-D-aspartate receptor antagonist MK-801 can inhibit sensitization to other drugs of abuse. However, MK-801 also produces behavioural sensitization to its own hyperlocomotor inducing effects, suggesting that MK-801 sensitization has a distinctive mechanism of action. The aim of this study was to carry out a functional and molecular analysis of the nucleus accumbens (NAc) of adult male Sprague-Dawley rats sensitized to MK-801 (seven daily injections of 0.25 mg/kg, 5 days of withdrawal and subsequent 0.25 mg/kg challenge), or following acute MK-801 (0.25 mg/kg), or naive rats as controls. Locomotor activity was the primary measure of sensitization. Ex-vivo slice electrophysiology showed a decrease in the excitatory synaptic strength in the NAc of rats sensitized to MK-801 compared with acute MK-801 treatment or naive controls. An LC-MS/MS SWATH proteomics approach showed that proteins altered by MK-801 sensitization were predominantly related to functions including calcium and glutamate signalling, and mitochondrial dysfunction. These results shed some light on neural changes in the NAc after sensitization to MK-801. This model could prove useful for studying the role of N-methyl-D-aspartate receptors in the pathophysiology of drug addiction and schizophrenia.

A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk.

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13-1.31; P trend < 0.001). However, this association varied by disease aggressiveness (P heterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias. SIGNIFICANCE: This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.

The association between neonatal vitamin D status and risk of schizophrenia.

Clues from the epidemiology of schizophrenia, such as the increased risk in those born in winter/spring, have led to the hypothesis that prenatal vitamin D deficiency may increase the risk of later schizophrenia. We wish to explore this hypothesis in a large Danish case-control study (n = 2602). The concentration of 25 hydroxyvitamin D (25OHD) was assessed from neonatal dried blood samples. Incidence rate ratios (IRR) were calculated when examined for quintiles of 25OHD concentration. In addition, we examined statistical models that combined 25OHD concentration and the schizophrenia polygenic risk score (PRS) in a sample that combined the new sample with a previous study (total n = 3464; samples assayed and genotyped between 2008-2013). Compared to the reference (fourth) quintile, those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12-1.85). None of the other quintile comparisons were significantly different. There was no significant interaction between 25OHD and the PRS. Neonatal vitamin D deficiency was associated with an increased risk for schizophrenia in later life. These findings could have important public health implications related to the primary prevention of schizophrenia.

The vitamin D receptor (VDR) binds to the nuclear matrix via its hinge domain: A potential mechanism for the reduction in VDR mediated transcription in mitotic cells.

Vitamin D is best known for its regulation of calcium homeostasis. Vitamin D exerts its genomic actions via the vitamin D receptor (VDR). As a member of the superfamily of nuclear receptors (NR), the VDR is primarily located within the nucleus of non-dividing cells. We show here that the VDR relocates from the nucleus into the cytoplasm across all stages of cell division in CHO cells. Furthermore, we show that the VDR is transcriptionally inert during cell division. In addition, 1α, 25 dihydroxyvitamin D (1,25(OH)2D3) promotes VDR binding to the nuclear matrix. Finally, we assessed the structural nature of VDR binding to the nuclear matrix. Mutation of the hinge domain reduced VDR's ability to bind to the nuclear matrix and to initiate transcription in response to 1,25(OH)2D3. Taken together, our data suggest that the association between the VDR and the nuclear matrix accounts for the apparent cytosolic distribution as the matrix disperses within the cytoplasm when cells divide. This may also explain the dramatic reduction in VDR mediated transcription during cell division. Our data also confirm that similar to other NRs, the hinge domain of the VDR is responsible for this association.

Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons.

1,25(OH)2D3 (vitamin D) appears essential for the normal development of dopaminergic neurons. Vitamin D affects dopamine synthesis and metabolism as well as expression of glial cell line-derived neurotrophic factor (GDNF), which is crucial for the survival of dopaminergic neurons. We investigated the role of vitamin D on GDNF and its receptors protooncogene tyrosine-protein kinase receptor Ret (C-Ret) and GDNF family receptor alpha 1 (GFRα1) signaling. To this end, we used a developmental vitamin D-deficient rat model and SH-SY5Y cells transfected with vitamin D receptor (VDR). The absence of vitamin D ligand in gestation reduces C-Ret expression, but not GDNF and GFRα1, in embryo forebrains. Overexpression of VDR in SH-SY5Y in the absence of ligand (mimicking in vivo developmental vitamin D deficiency) also suppressed C-Ret mRNA levels. In the presence of vitamin D, C-Ret mRNA and protein expression were increased. The chromatin immunoprecipitation results suggested that C-Ret is directly regulated by vitamin D via VDR. GDNF was also increased by vitamin D in these cells. Our small interfering RNA studies showed that knocking down VDR leads to an increase in C-Ret in the absence of ligand. Finally, we confirmed the inverse relationship between GFRα1 and C-Ret, as knocking down C-Ret led to increases in GFRα1 expression. These data extend our knowledge of the diverse and important roles played by vitamin D in dopamine physiology.-Pertile, R. A. N., Cui, X., Hammond, L., Eyles, D. W. Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons.