Vitamin D, Gene Regulation, and the Thyroid
There is much ado about vitamin D these days and the fallout physically from being vitamin D deficient. Vitamin D deficiencies are high among the special needs kids’ population, as well as the hypothyroid population.
I am very thrilled to read the Vitamin D Council’s blog regarding a new study that finds that vitamin D helps regulate three genes involved in autism. These genes, as you will read in the blog, relate to regulation of the serotonin synthesis. This discovery is considered to be “groundbreaking.” I am deeply saddened that the equation that the thyroid hormone also plays into causing vitamin D deficiency, as well as these other “mysteries,” such as low oxytocin levels in children with autism, has been ignored. I have included various studies to show these physiological functions relating back to the thyroid hormone of these “groundbreaking” “mysteries.”
Here are a few excerpts from their blog.
“The authors also solved some of the mysteries surrounding autism. One mystery is why autistic individuals have low levels of serotonin in their brain but elevated serotonin levels in their peripheral blood. The authors discovered that there are two genes involved in turning tryptophan into serotonin, a central gene and a peripheral gene.
Vitamin D up-regulates the central serotonin gene and down-regulates the peripheral serotonin gene. That may explain why autistic kids have elevated blood serotonin but decreased brain serotonin when their vitamin D levels are low. To date, many studies of vitamin D levels in autism show autistic kids are vitamin D deficient.”
“Drs Patrick and Ames may have solved another mystery of autism: why autistic children have low levels of oxytocin. Oxytocin is a hormone that does a lot of things, such as promote socialization. The authors explain that oxytocin is also directly controlled by vitamin D. If children are deficient in vitamin D, they will also have low levels of oxytocin.”
You can read entirety of the New Study Finds Vitamin D Regulates Three Genes Involved in Autism, Vitamin D Council’s blog, yourself here.
Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.
Patrick RP1, Ames BN.
1Nutrition and Metabolism Center, Children’s Hospital Oakland Research Institute, Oakland, California, USA.
“Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder.-Patrick, R. P., Ames, B. N. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.”
Thyroid Hormone Regulates the Oxytocin Gene.
Adan RA, et al. Show all
Adan RA, Cox JJ, van Kats JP, Burbach JP.
J Biol Chem. 1992 Feb 25;267(6):3771-7.
“Endocrine factors involved in the transcriptional regulation of the oxytocin (OT) gene were investigated in heterologous expression systems. Plasmids having a 5′-flanking region of the rat OT gene (-363/+16) or the human OT gene (-382/+41) cloned in front of the firefly luciferase gene were co-transfected with an expression vector for the rat thyroid hormone receptor alpha in P19 embryonal carcinoma (EC) cells. Thyroid hormone (T3) stimulated the activity of the rat and human OT promoters about 10-fold. In MCF-7 breast tumor cells transfected with the human OT promoter-luciferase fusion gene, T3 stimulation through endogenous thyroid hormone receptors was about 5-fold. Co-transfection experiments in P19EC cells using 5′ deletion mutants of the rat OT gene showed that thyroid hormone responsiveness was located in two regions, one located between nucleotides -195 and -172, the other between nucleotides -172 and -148. Each region accounted for about 3-fold T3 stimulation. Gel retardation analysis using extracts from HeLa cells over-producing the c-erbA/TR alpha protein showed specific binding to the -172/-148 element, while no binding occurred on the -195/-172 element. The -172/-148 element which contains the imperfect estrogen response element, GGTGACCTTGACC, has inverted as well as direct repeats of the TGACC motif. Mutagenesis of TGACC motifs separately reduced thyroid hormone responsiveness by about 50%. However, simultaneous mutation of two TGACC motifs abolished the responsiveness to T3 completely. There was no cooperativity between the activated thyroid hormone and estrogen receptors in transfected MCF-7 cells nor in thyroid hormone receptor and estrogen receptor co-transfected P19EC cells. Negative interactions between these two receptors were observed and gel retardation assays showed interaction between the two receptors proteins. It was shown in an in vivo experiment that treatment of rats with thyroid hormone increased hypothalamic OT mRNA levels, the pituitary OT content, as well as OT levels in blood. The results reveal thyroid hormone as a physiological regulator of OT gene expression, which stimulates OT promoter activity directly through interaction with a thyroid hormone-response element in the OT gene.”
1371278 [PubMed – indexed for MEDLINE]
Free full text: HighWire”
Vitamin D and Autoimmune Thyroid Diseases.
Kivity S, et al. Show all
Kivity S, Agmon-Levin N, Zisappl M, Shapira Y, Nagy EV, Dankó K, Szekanecz Z, Langevitz P, Shoenfeld Y.
Cell Mol Immunol. 2011 May;8(3):243-7. doi: 10.1038/cmi.2010.73. Epub 2011 Jan 31.
“The role of vitamin D as an immune modulator has been emphasized in recent years, and low levels of the hormone were observed in several autoimmune diseases including multiple sclerosis and systemic lupus erythematosus. Vitamin D mediates its effect though binding to vitamin D receptor (VDR), and activation of VDR-responsive genes. While VDR gene polymorphism was found to associate with autoimmune thyroid diseases (AITDs), few studies examined levels of vitamin D in these patients and those that did yielded conflicting results. We therefore undertook to evaluate the levels of vitamin D in patients with AITDs compared to patients with non-AITDs and healthy controls. Serum vitamin D (25-OH) levels were measured in 50 patients with AITDs, 42 patients with non-AITDs and 98 healthy subjects, utilizing the LIAISON chemiluminescence immunoassay (DiaSorin, Saluggia, Italy). Vitamin D deficiency was designated at levels lower than 10 ng/ml. Antithyroid antibodies, thyroid functions and demographic parameters were evaluated in all patients. The prevalence of vitamin D deficiency was significantly higher in patients with AITDs compared with healthy individuals (72% versus 30.6%; P<0.001), as well as in patients with Hashimoto’s thyroiditis compared to patients with non-AITDs (79% versus 52%; P<0.05). Vitamin D deficiency also correlated to the presence of antithyroid antibodies (P=0.01) and abnormal thyroid function tests (P=0.059). Significantly low levels of vitamin D were documented in patients with AITDs that were related to the presence of anti thyroid antibodies and abnormal thyroid function tests, suggesting the involvement of vitamin D in the pathogenesis of AITDs and the advisability of supplementation.”
21278761 [PubMed – indexed for MEDLINE]
Full text: Nature Publishing Group
Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain.
Bauer M, et al. Show all
Bauer M, Heinz A, Whybrow PC.
Mol Psychiatry. 2002;7(2):140-56.
“The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been confirmed repeatedly. Interaction of the thyroid and monoamine neurotransmitter systems has been suggested as a potential underlying mechanism of action. While catecholamine and thyroid interrelationships have been reviewed in detail, the serotonin system has been relatively neglected. Thus, the goal of this article is to review the literature on the relationships between thyroid hormones and the brain serotonin (5-HT) system, limited to studies in adult humans and adult animals. In humans, neuroendocrine challenge studies in hypothyroid patients have shown a reduced 5-HT responsiveness that is reversible with thyroid replacement therapy. In adult animals with experimentally-induced hypothyroid states, increased 5-HT turnover in the brainstem is consistently reported while decreased cortical 5-HT concentrations and 5-HT2A receptor density are less frequently observed. In the majority of studies, the effects of thyroid hormone administration in animals with experimentally-induced hypothyroid states include an increase in cortical 5-HT concentrations and a desensitization of autoinhibitory 5-HT1A receptors in the raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. Furthermore, there is some indication that thyroid hormones may increase cortical 5-HT2 receptor sensitivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyroid economy has a modulating impact on the brain serotonin system. Thus it is postulated that one mechanism, among others, through which exogenous thyroid hormones may exert their modulatory effects in affective illness is via an increase in serotonergic neurotransmission, specifically by reducing the sensitivity of 5-HT1A autoreceptors in the raphe area, and by increasing 5-HT2 receptor sensitivity.”
11840307 [PubMed – indexed for MEDLINE]
Free full text: Nature Publishing Group