Thyroid Hormone In Brain Research Articles

SAT-248 Maternal Iron Deficiency Alters Brain Glucose, Lactate and Thyroxine Transport in Developing Neonatal Rats

Thyroid hormone insufficiency and iron deficiency (FeD) during fetal and neonatal life are both similarly deleterious to mammalian development suggesting a possible linkage between iron and thyroid hormone insufficiencies. Published data from our laboratory demonstrate a reduction in circulating and brain thyroid hormone levels in neonatal rats when dams are fed an iron deficient diet. We have also previously reported an observed increase in brain vascular density in iron deficient neonatal rats as a possible compensatory mechanism for increasing oxygen delivery to the developing brain. We now report the effects of gestational and neonatal FeD on glucose, lactate, and thyroxine transport in the neonatal rat brain. Gestational day 2 (G2) Sprague-Dawley rat dams were assigned to two groups. The Control group was fed a standard chow diet with 84 ppm iron while the FeD group was fed an iron deficient diet (10 ppm Fe). All animals were maintained on the defined diets from G2 through weaning. Serum hemoglobin, glucose, lactate and thyroxine levels were measured at postnatal days 7 (P7), 14, and 21. Blood vessel density was assessed by immunohistochemistry. Finally, a brain perfusion method was developed to quantify total brain vascular volume and measure transport rates for substrates glucose, lactate, and thyroxine. Hemoglobin levels were significantly reduced by 40% in FeD P7 up to 60% by P21 indicating a marked reduction in iron stores was achieved at all ages in the FeD group. Consistent with our previously reported findings, we found significant 23% reductions in serum T4 in FeD pups at P14 and 36% increases in cortical blood vessel density. Brain vascular volume was similarly significantly increased at P14 (31%) and P21 (37%). Importantly, we found that glucose, lactate, and thyroxine blood-to-brain transport rates were all increased in the FeD neonates. Glucose transport rates significantly increased by 57% at P14 and 90% by P21. Lactic acid transport rates were significantly elevated by 44% at P14 and 36% at P21. Thyroxine transport rates were significantly increased by 23% at P14 only. Assessment of neonatal hypoxic hypoxia treatment on brain glucose transport is currently in progress. Together our data demonstrate a significant impact of gestational and neonatal iron deficiency on nutrient and thyroid hormone transport in the developing brain. Increased vascular density and vascular volume may explain the magnitude of increased lactate and thyroxine transport. However, the more substantially increased glucose transport rate suggests additional mechanisms of glucose transport regulation are altered during iron deficiency. Alterations in nutrient and hormone transport homeostasis may contribute to the developmental brain pathology associated with neonatal iron deficiency.

A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development

Cortical heterotopias are clusters of ectopic neurons in the brain and are associated with neurodevelopmental disorders like epilepsy and learning disabilities. We have previously characterized the robust penetrance of a heterotopia in a rat model, induced by thyroid hormone (TH) disruption during gestation. However, the specific mechanism by which maternal TH insufficiency results in this birth defect remains unknown. Here we first determined the developmental window susceptible to endocrine disruption and describe a cellular mechanism responsible for heterotopia formation. We show that five days of maternal goitrogen treatment (10 ppm propylthiouracil) during the perinatal period (GD19-PN2) induces a periventricular heterotopia in 100% of the offspring. Beginning in the early postnatal brain, neurons begin to aggregate near the ventricles of treated animals. In parallel, transcriptional and architectural changes of this region were observed including decreased Sonic hedgehog (Shh) expression, abnormal cell adhesion, and altered radial glia morphology. As the ventricular epithelium is juxtaposed to two sources of brain THs, the cerebrospinal fluid and vasculature, this progenitor niche may be especially susceptible to TH disruption. This work highlights the spatiotemporal vulnerabilities of the developing brain and demonstrates that a transient period of TH perturbation is sufficient to induce a congenital abnormality.

Prenatal Triclosan Exposure and Thyroid Hormones Measured at Birth

Triclosan (TCS) is an antibacterial compound introduced in 1972 and used in personal care products including soaps, cosmetics, and toothpastes. It has been shown to disrupt thyroid pathways; thus, exposure among pregnant women is concerning, given the role of thyroid hormones in early brain development.Although TCS was banned by the U.S. Food and Drug Administration in 2016 in soaps, it is still present in toothpastes, deodorants, and shave gels. The literature is inconsistent on the association between TCS exposure and thyroid hormones. We analyzed the association between prenatal TCS exposure and Thyroxine (T4), Free Thyroxine (FT4) and Thyroid Stimulating Hormone (TSH), in cord blood from participants in a prospective cohort study in New York City.Women were enrolled into the Columbia Center for Children’s Environmental Health (CCCEH) cohort from 1998-2006. TCS was measured in a spot urine sample collected in the third trimester. Relevant covariates were assessed by questionnaire or medical records. Umbilical cord thyroid hormones were measured for T4, FT4, and TSH. Among N=165 women with both TCS and thyroid hormone measures available, we used linear regression to assess the effects of TCS on thyroid hormones.TCS was detected in 80.5% of CCCEH urine samples with a median concentration of 8.4 ng/mL, after adjusting for urinary dilution. We found significant negative associations between prenatal TCS exposure and T4 (β= -2.69, p=0.01) and TSH (β= -0.08, p=0.03). The associations were strengthened after removing women with planned caesarian sections and restricting to women who went through labor (N=146), T4 (β= -3.47, p=0.003) and TSH (β= -0.104, p=0.014).confirmed, the continued use of TCS should be re-evaluated.We found detectable concentrations of TCS among women who were pregnant before the U.S. FDA ban and significant associations between prenatal TCS and thyroid hormones measured in cord blood. Additional research is needed to confirm the associations.

Thyroid Hormone Disruption in the Fetal and Neonatal Rat: Predictive Hormone Measures and Bioindicators of Hormone Action in the Developing Cortex.

Adverse neurodevelopmental consequences remain a primary concern when evaluating the effects of thyroid hormone (TH) disrupting chemicals. Though the developing brain is a known target of TH insufficiency, the relationship between THs in the serum and the central nervous system is not well characterized. To address this issue, dose response experiments were performed in pregnant rats using the goitrogen propylthiouracil (PTU) (dose range 0.1-10 ppm). THs were quantified in the serum and brain of offspring at gestational day 20 (GD20) and postnatal day 14 (PN14), two developmental stages included in OECD and EPA regulatory guideline/guidance studies. From the dose response data, the quantitative relationships between THs in the serum and brain were determined. Next, targeted gene expression analyses were performed in the fetal and neonatal cortex to test the hypothesis that TH action in the developing brain is linked to changes in TH concentrations within the tissue. Results show a significant reduction of T4/T3 in the serum and brain of the GD20 fetus in response to low doses of PTU; interestingly, very few genes were significantly different at any dose tested. In the PN14 pup significant reductions of T4/T3 in the serum and brain were also detected; however, twelve transcriptional targets were identified in the neonatal cortex that correlated well with reduced brain THs. These results show that serum T4 is a good predictor of brain THs, and offer several target genes that could serve as pragmatic readouts of T4/T3 dysfunction within the PN14 cortex.

Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels.

Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels.

The Type 3 Deiodinase: Epigenetic Control of Brain Thyroid Hormone Action and Neurological Function.

Thyroid hormones (THs) influence multiple processes in the developing and adult central nervous system, and their local availability needs to be maintained at levels that are tailored to the requirements of their biological targets. The local complement of TH transporters, deiodinase enzymes, and receptors is critical to ensure specific levels of TH action in neural cells. The type 3 iodothyronine deiodinase (DIO3) inactivates THs and is highly present in the developing and adult brain, where it limits their availability and action. DIO3 deficiency in mice results in a host of neurodevelopmental and behavioral abnormalities, demonstrating the deleterious effects of TH excess, and revealing the critical role of DIO3 in the regulation of TH action in the brain. The fact the Dio3 is an imprinted gene and that its allelic expression pattern varies across brain regions and during development introduces an additional level of control to deliver specific levels of hormone action in the central nervous system (CNS). The sensitive epigenetic nature of the mechanisms controlling the genomic imprinting of Dio3 renders brain TH action particularly susceptible to disruption due to exogenous treatments and environmental exposures, with potential implications for the etiology of human neurodevelopmental disorders.

Regulation of T3 Availability in the Developing Brain: The Mouse Genetics Contribution.

Alterations in maternal thyroid physiology may have deleterious consequences on the development of the fetal brain, but the underlying mechanisms remain elusive, hampering the development of appropriate therapeutic strategies. The present review sums up the contribution of genetically modified mouse models to this field. In particular, knocking out genes involved in thyroid hormone (TH) deiodination, transport, and storage has significantly improved the picture that we have of the economy of TH in the fetal brain and the underlying genetic program. These data pave the way for future studies to bridge the gap in knowledge between thyroid physiology and brain development.

Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework.

Adequate levels of thyroid hormone (TH) are needed for proper brain development, deficiencies may lead to adverse neurologic outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures and decline in serum TH resulting in neurodevelopmental impairment is poorly understood. The present study developed a quantitative adverse outcome pathway where serum thyroxin (T4) reduction following inhibition of thyroperoxidase in the thyroid gland are described and related to deficits in fetal brain TH and the development of a brain malformation, cortical heterotopia. Pregnant rats were exposed to 6-propylthiouracil (PTU 0, 0.1, 0.5, 1, 2, or 3 parts per million [ppm]) from gestational days 6-20, sequentially increasing PTU concentrations in maternal thyroid gland and serum as well as in fetal serum. Dams exposed to 0.5 ppm PTU and higher exhibited dose-dependent decreases in thyroidal T4. Serum T4 levels in the dam were significantly decreased with exposure to 2 and 3 ppm PTU. In the fetus, T4 decrements were first observed at a lower dose of 0.5 ppm PTU. Based on these data, fetal brain T4 levels were estimated from published literature sources, and quantitatively linked to increases in the size of the heterotopia present in the brains of offspring. These data show the potential of in vivo assessments and computational descriptions of biologic responses to predict the development of this structural brain malformation and use of quantitative adverse outcome pathway approach to evaluate brain deficits that may result from exposure to other TH disruptors.

Increased aggression and lack of maternal behavior in Dio3-deficient mice are associated with abnormalities in oxytocin and vasopressin systems.

Thyroid hormones regulate many aspects of brain development and function, and alterations in the levels of thyroid hormone action lead to abnormal anxiety- and depression-like behaviors. A complement of factors in the brain function independently of circulating levels of hormone to strictly controlled local thyroid hormone signaling. A critical factor is the type 3 deiodinase (DIO3), which is located in neurons and protects the brain from excessive thyroid hormone. Here, we examined whether a local increase in brain thyroid hormone action secondary to DIO3 deficiency is of consequence for social behaviors. Although we did not observe alterations in sociability, Dio3-/- mice of both sexes exhibited a significant increase in aggression-related behaviors and mild deficits in olfactory function. In addition, 85% of Dio3-/- dams manifested no pup-retrieval behavior and increased aggression toward the newborns. The abnormal social behaviors of Dio3-/- mice were associated with sexually dimorphic alterations in the physiology of oxytocin (OXT) and arginine vasopressin (AVP), 2 neuropeptides with important roles in determining social interactions. These alterations included low adult serum levels of OXT and AVP, and an abnormal expression of Oxt, Avp and their receptors in the neonatal and adult hypothalamus. Our results demonstrate that DIO3 is essential for normal aggression and maternal behaviors, and indicate that abnormal local regulation of thyroid hormone action in the brain may contribute to the social deficits associated with neurodevelopmental disorders.

Maternal photoperiod programs hypothalamic thyroid status via the fetal pituitary gland

In wild mammals, offspring development must anticipate forthcoming metabolic demands and opportunities. Within species, different developmental strategies may be used, dependent on when in the year conception takes place. This phenotypic flexibility is initiated before birth and is linked to the pattern of day length (photoperiod) exposure experienced by the mother during pregnancy. This programming depends on transplacental communication via the pineal hormone melatonin. Here, we show that, in the Siberian hamster (Phodopus sungorus), the programming effect of melatonin is mediated by the pars tuberalis (PT) of the fetal pituitary gland, before the fetal circadian system and autonomous melatonin production is established. Maternal melatonin acts on the fetal PT to control expression of thyroid hormone deiodinases in ependymal cells (tanycytes) of the fetal hypothalamus, and hence neuroendocrine output. This mechanism sets the trajectory of reproductive and metabolic development in pups and has a persistent effect on their subsequent sensitivity to the photoperiod. This programming effect depends on tanycyte sensitivity to thyroid stimulating hormone (TSH), which is dramatically and persistently increased by short photoperiod exposure in utero. Our results define the role of the fetal PT in developmental programming of brain function by maternal melatonin and establish TSH signal transduction as a key substrate for the encoding of internal calendar time from birth to puberty.

Sex Differences in Brain Thyroid Hormone Levels during Early Post-Hatching Development in Zebra Finch (Taeniopygia guttata).

Thyroid hormones are closely linked to the hatching process in precocial birds. Previously, we showed that thyroid hormones in brain had a strong impact on filial imprinting, an early learning behavior in newly hatched chicks; brain 3,5,3′-triiodothyronine (T3) peaks around hatching and imprinting training induces additional T3 release, thus, extending the sensitive period for imprinting and enabling subsequent other learning. On the other hand, blood thyroid hormone levels have been reported to increase gradually after hatching in altricial species, but it remains unknown how the brain thyroid hormone levels change during post-hatching development of altricial birds. Here, we determined the changes in serum and brain thyroid hormone levels of a passerine songbird species, the zebra finch using radioimmunoassay. In the serum, we found a gradual increase in thyroid hormone levels during post-hatching development, as well as differences between male and female finches. In the brain, there was clear surge in the hormone levels during development in males and females coinciding with the time of fledging, but the onset of the surge of thyroxine (T4) in males preceded that of females, whereas the onset of the surge of T3 in males succeeded that of females. These findings provide a basis for understanding the functions of thyroid hormones during early development and learning in altricial birds.

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer's neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer's Coordinating Center/Alzheimer's Disease Genetic Consortium data; n=2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer's Disease Neuroimaging Initiative data; n=1239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p<0.04 in two separately analyzed groups), but not in Alzheimer's disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.

Mct8 and trh co-expression throughout the hypothalamic paraventricular nucleus is modified by dehydration-induced anorexia in rats

Thyrotropin-releasing hormone (TRH) is a neuropeptide with endocrine and neuromodulatory effects. TRH from the paraventricular hypothalamic nucleus (PVN) participates in the control of energy homeostasis; as a neuromodulator TRH has anorexigenic effects. Negative energy balance decreases PVN TRH expression and TSH concentration; in contrast, a particular model of anorexia (dehydration) induces in rats a paradoxical increase in TRH expression in hypophysiotropic cells from caudal PVN and high TSH serum levels, despite their apparent hypothalamic hyperthyroidism and low body weight. We compared here the mRNA co-expression pattern of one of the brain thyroid hormones' transporters, the monocarboxylate transporter-8 (MCT8) with that of TRH in PVN subdivisions of dehydration-induced anorexic (DIA) and control rats. Our aim was to identify whether a low MCT8 expression in anorexic rats could contribute to their high TRH mRNA content. We registered daily food intake and body weight of 7-day DIA and control rats and analyzed TRH and MCT8 mRNA co-expression throughout the PVN by double in situ hybridization assays. We found that DIA rats showed increased number of TRHergic cells in caudal PVN, as well as a decreased percentage of TRH-expressing neurons that co-expressed MCT8 mRNA signal. Results suggest that the reduced proportion of double TRH/MCT8 expressing cells may be limiting the entry of hypothalamic triiodothyronine to the greater number of TRH-expressing neurons from caudal PVN and be in part responsible for the high TRH expression in anorexia rats and for the lack of adaptation of their hypothalamic-pituitary-thyroid axis to their low food intake.

Editorial: "Thyroid Hormone in Brain and Brain Cells".

Editorial: "Thyroid Hormone in Brain and Brain Cells".

Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/μ-Crystallin Under Physiological Conditions.

Mammalian ketimine reductase is identical to μ-crystallin (CRYM)-a protein that is also an important thyroid hormone binding protein. This dual functionality implies a role for thyroid hormones in ketimine reductase regulation and also a reciprocal role for enzyme catalysis in thyroid hormone bioavailability. In this research we demonstrate potent sub-nanomolar inhibition of enzyme catalysis at neutral pH by the thyroid hormones L-thyroxine and 3,5,3'-triiodothyronine, whereas other thyroid hormone analogues were shown to be far weaker inhibitors. We also investigated (a) enzyme inhibition by the substrate analogues pyrrole-2-carboxylate, 4,5-dibromopyrrole-2-carboxylate and picolinate, and (b) enzyme catalysis at neutral pH of the cyclic ketimines S-(2-aminoethyl)-L-cysteine ketimine (owing to the complex nomenclature trivial names are used for the sulfur-containing cyclic ketimines as per the original authors' descriptions) (AECK), Δ(1)-piperideine-2-carboxylate (P2C), Δ(1)-pyrroline-2-carboxylate (Pyr2C) and Δ(2)-thiazoline-2-carboxylate. Kinetic data obtained at neutral pH suggests that ketimine reductase/CRYM plays a major role as a P2C/Pyr2C reductase and that AECK is not a major substrate at this pH. Thus, ketimine reductase is a key enzyme in the pipecolate pathway, which is the main lysine degradation pathway in the brain. In silico docking of various ligands into the active site of the X-ray structure of the enzyme suggests an unusual catalytic mechanism involving an arginine residue as a proton donor. Given the critical importance of thyroid hormones in brain function this research further expands on our knowledge of the connection between amino acid metabolism and regulation of thyroid hormone levels.

Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents.

There is increasing evidence that local thyroid hormone (TH) availability changes profoundly in inflammatory conditions due to altered expression of deiodinases that metabolize TH. It is largely unknown, however, how inflammation affects TH availability via the expression of TH transporters. In this study we examined the effect of bacterial lipopolysaccharide (LPS) administration on two TH transporters that are critically important for brain TH homeostasis, organic anion-transporting polypeptide 1c1 (OATP1c1), and monocarboxylate transporter 8 (MCT8). MRNA levels were studied by in situ hybridization and qPCR as well as protein levels by immunofluorescence in both the rat and mouse forebrain. The mRNA of both transporters decreased robustly in the first 9 hours after LPS injection, specifically in brain blood vessels; OATP1c1 mRNA in astrocytes and MCT8 mRNA in neurons remained unchanged. At 24 and/or 48 hours after LPS administration, OATP1c1 and MCT8 mRNAs increased markedly above control levels in brain vessels. OATP1c1 protein decreased markedly in vessels by 24 hours whereas MCT8 protein levels did not decrease significantly. These changes were highly similar in mice and rats. The data demonstrate that OATP1c1 and MCT8 expression are regulated in a parallel manner during inflammation at the blood-brain barrier of rodents. Given the indispensable role of both transporters in allowing TH access to the brain, the results suggest reduced brain TH uptake during systemic inflammation.

Transport of thyroid hormone in brain.

Thyroid hormone (TH) transport into the brain is not only pivotal for development and differentiation, but also for maintenance and regulation of adult central nervous system (CNS) function. In this review, we highlight some key factors and structures regulating TH uptake and distribution. Serum TH binding proteins play a major role for the availability of TH since only free hormone concentrations may dictate cellular uptake. One of these proteins, transthyretin is also present in the cerebrospinal fluid (CSF) after being secreted by the choroid plexus. Entry routes into the brain like the blood–brain-barrier (BBB) and the blood–CSF-barrier will be explicated regarding fetal and adult status. Recently identified TH transmembrane transporters (THTT) like monocarboxylate transporter 8 (Mct8) play a major role in uptake of TH across the BBB but as well in transport between cells like astrocytes and neurons within the brain. Species differences in transporter expression will be presented and interference of TH transport by endogenous and exogenous compounds including endocrine disruptors and drugs will be discussed.

Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis

Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS.

Tissue-Specific Alterations in Thyroid Hormone Homeostasis in Combined Mct10 and Mct8 Deficiency

The monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the well-established TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific alterations in TH transport and metabolism, we speculated that Mct10 inactivation may compromise the tissue-specific TH homeostasis as well. However, analysis of Mct10 knockout (ko) mice revealed normal serum TH levels and tissue TH content in contrast to Mct8 ko mice that are characterized by high serum T3, low serum T4, decreased brain TH content, and increased tissue TH concentrations in the liver, kidneys, and thyroid gland. Surprisingly, mice deficient in both TH transporters (Mct10/Mct8 double knockout [dko] mice) showed normal serum T4 levels in the presence of elevated serum T3, indicating that the additional inactivation of Mct10 partially rescues the phenotype of Mct8 ko mice. As a consequence of the normal serum T4, brain T4 content and hypothalamic TRH expression were found to be normalized in the Mct10/Mct8 dko mice. In contrast, the hyperthyroid situation in liver, kidneys, and thyroid gland of Mct8 ko mice was even more severe in Mct10/Mct8 dko animals, suggesting that in these organs, both transporters contribute to the TH efflux. In summary, our data indicate that Mct10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for Mct8 deficiency.

Does thyroid disruption contribute to the developmental neurotoxicity of chlorpyrifos?

Although organophosphate pesticides are not usually characterized as “endocrine disruptors,” recent work points to potential, long-term reductions of circulating thyroid hormones after developmental exposures to chlorpyrifos that are devoid of observable toxicity. We administered chlorpyrifos to developing rats on gestational days 17–20 or postnatal days 1–4, regimens that produce distinctly different, sex-selective effects on neurobehavioral performance. The prenatal regimen produced a small, but statistically significant reduction in brain thyroxine levels from juvenile stages through adulthood; in contrast, postnatal exposure produced a transient elevation in young adulthood. However, in neither case did we observe the sex-selectivity noted earlier for neurobehavioral outcomes of these specific treatment regimens, or as reported earlier for effects on serum T4 in developing mice. Thus, although chlorpyrifos has the potential to disrupt thyroid status sufficiently to alter brain thyroid hormone levels, the effect is small, and any potential contribution to neurobehavioral abnormalities remains to be proven.