Pseudoephedrine hydrochloride causes hyperactivity in zebrafish via modulation of the serotonin pathway.

This study aimed to explore behavioral changes of embryonic and larval zebrafish caused by pseudoephedrine hydrochloride (PSE) and its underlying mechanism. Zebrafish embryos were exposed to 0.5 µM, 2 µM, and 8 µM PSE at 4 h post-fertilization (4 hpf) or 22-23 hpf. Mortality, hatching rate, coiling frequency, heart rate, behavior changes, and related gene expression were observed at different developmental stages. PSE below 8 µM did not affect zebrafish mortality, hatching rate, and heart rate compared with the control group. For embryos, PSE caused an increase at 16-32 hpf in zebrafish coiling frequency which could be rescued by serotonin antagonist WAY100635. Similarly, PSE caused an increase in the swimming distance of zebrafish larvae at 120 hpf. PSE also elevated the expression of serotonin (5-HT)-related genes 5-htr1ab and tph2 and dopamine-related gene dbh. Behavioral changes in zebrafish embryos and larvae caused by PSE may be closely associated with increased expression of 5-HT and dopamine-related genes. This may be reflected that the behavioral changes in zebrafish are a possible PSE monitoring indicator.

Perinatal fluoxetine treatment promotes long-term behavioral changes in adult mice.

Serotonin exerts a significant role in the mammalian central nervous system embryogenesis and brain ontogeny. Therefore, we investigate the effect of perinatal fluoxetine (FLX), a selective serotonin reuptake inhibitor, administration on the behavioral expression of adult male Swiss mice. For this purpose, two groups (n = 6 each, and ~ 35 g) of pregnant female Swiss mice were mated. Their offspring were treated with FLX (10 mg/Kg, s.c.) from postnatal day (PND) 5 to 15. At PND 16, one male puppy of each litter was euthanized, and the hippocampus was dissected for RNA analysis. At 70 days of life, the male offspring underwent a behavioral assessment in the open field, object recognition task, light-dark box, tail suspension and rotarod test. According to our results, the programmed animals had a decrease in TPH2, 5HT1a, SERT, BDNF, and LMX1B expression. Also, it was observed less time of immobility in tail suspension test and higher grooming time in the open field test. In the light-dark box test, the FLX-treated offspring had less time in the light side than control. We also observed a low cognitive performance in the object recognition task and poor motor skill learning in the rotarod test. These findings suggest that programming with FLX during the neonatal period alters a hippocampal serotonergic system, promoting anxiety and antidepressant behavior in adults, as well as a low mnemonic capacity.

Suppressive effects of neonatal bisphenol A on the neuroendocrine system.

The aim of this study was to assess the effects of neonatal bisphenol A (BPA) administration on neuroendocrine features (the thyroid-brain axis). BPA (20 or 40 µg/kg) was orally administered to juvenile male albino rats ( Rattus norvegicus) from postnatal days (PNDs) 15 to 30. Both doses resulted in lower serum thyroxine (T4), triiodothyronine (T3), and growth hormone levels and higher thyrotropin level than the control levels at PND 30. In the neonatal cerebellum and cerebrum, vacuolation, pyknosis, edema, degenerative changes, and reductions in the size and number of the cells were observed in both treated groups. Alternatively, elevations in oxidative markers (lipid peroxidation, nitric oxide, and hydrogen peroxide [H2O2]) at both dose levels were recorded at PND 30, along with decreased activities of antioxidant markers (ascorbic acid, total thiol [t-SH], glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and catalase) with respect to control levels. Thus, the BPA-induced hypothyroid state may disturb the neonatal thyroid-brain axis via production of free radicals, and this could damage the plasma membrane and cellular components, delaying cerebrum and cerebellum development.

Thyroid hormone inhibition in L6 myoblasts of IGF-I-mediated glucose uptake and proliferation: new roles for integrin αvß3.

Thyroid hormones L-thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3) have been shown to initiate short- and long-term effects via a plasma membrane receptor site located on integrin αvß3. Also insulin-like growth factor type I (IGF-I) activity is known to be subject to regulation by this integrin. To investigate the possible cross-talk between T4 and IGF-I in rat L6 myoblasts, we have examined integrin αvß3-mediated modulatory actions of T4 on glucose uptake, measured through carrier-mediated 2-deoxy-[3H]-D-glucose uptake, and on cell proliferation stimulated by IGF-I, assessed by cell counting, [3H]-thymidine incorporation, and fluorescence-activated cell sorting analysis. IGF-I stimulated glucose transport and cell proliferation via the cell surface IGF-I receptor (IGFIR) and, downstream of the receptor, by the phosphatidylinositol 3-kinase signal transduction pathway. Addition of 0.1 nM free T4 caused little or no cell proliferation but prevented both glucose uptake and proliferative actions of IGF-I. These actions of T4 were mediated by an Arg-Gly-Asp (RGD)-sensitive pathway, suggesting the existence of crosstalk between IGFIR and the T4 receptor located near the RGD recognition site on the integrin. An RGD-sequence-containing integrin inhibitor, a monoclonal antibody to αvß3, and the T4 metabolite tetraiodothyroacetic acid all blocked the inhibition by T4 of IGF-I-stimulated glucose uptake and cell proliferation. Western blotting confirmed roles for activated phosphatidylinositol 3-kinase and extracellular regulated kinase 1/2 (ERK1/2) in the effects of IGF-I and also showed a role for ERK1/2 in the actions of T4 that modified the effects of IGF-I. We conclude that thyroid hormone inhibits IGF-I-stimulated glucose uptake and cell proliferation in L6 myoblasts.

Epigenetic signature in neural plasticity: the journey so far and journey ahead.

Neural plasticity is a remarkable characteristic of the brain which allows neurons to rewire their structure in response to internal and external stimuli. Many external stimuli collectively referred to as 'epigenetic factors' strongly influence structural and functional reorganization of the brain, thereby acting as a potential driver of neural plasticity. DNA methylation and demethylation, histone acetylation, and deacetylation are some of the frontline epigenetic mechanisms behind neural plasticity. Epigenetic signature molecules (mostly proteins) play a pivotal role in epigenetic reprogramming. Though neuro-epigenetics is an incredibly important field of emerging research, the critical role of signature proteins associated with epigenetic alteration and their involvement in neural plasticity needs further attention. This study gives an integrated and systematic overview of the current state of knowledge with a clear idea of types of neural plasticity and the context-dependent role of epigenetic signature molecules and their modulation by some natural bioactive compounds.

Novel Coronavirus SARS-CoV-2 (COVID-19) and Pregnancy: A Hypothetical View.

The complications of the SARS-CoV-2 infection and its COVID-19 disease on mothers and their offspring are less known. This review aimed to determine the transmission, severity, and complications of SARS- CoV-2 infection during pregnancy. This review showed the influence of COVID-19 disease on neonatal neurogenesis. Owing medicines that were reported for the treatment of COVID-19 disease, this review suggested some control strategies like treatments (medicinal plants, antiviral therapy, cellular therapy, and immunotherapy), nutrition uptake, prevention, and recommendations. This overview showed that severe infection of SARS-CoV-2 during the early stage of pregnancy might increase the risk of stress, panic, and anxiety. This disorder can disturb the maternal immune system, and thus causing a neurodevelopmental disturbance. This hypothesis may be depending on the severity and intensity of the SARS-CoV-2 infection during pregnancy. However, vertical transmission of SARS-CoV-2 from dams to their fetuses is absent until now. During this global pandemic disease, maintaining safety during pregnancy, vaginal delivery, and breastfeeding may play a vital role in a healthy life for the offspring. Thus, international, and national organizations should be continuing for perinatal management, particularly during the next pandemic or disaster time.

Maternal Sodium Valproate Exposure Alters Neuroendocrine-Cytokines and Oxido-inflammatory Axes in Neonatal Albino Rats.

OBJECTIVE: The aim of the study was to determine the influence of maternal sodium valproate (SVP) on neonatal neuroendocrine (hypothalamic-pituitary-adrenal; HPA)-cytokines and oxido-inflammatory axes. METHODS: Pregnant rats (Rattus norvegicus) were orally administered (by gavage) SVP (50 mg/kg) from gestation day (GD) 8 to lactation day (LD) 21. RESULTS: The elevation in serum corticotropin-releasing hormone (CRH), corticosterone, and adrenocorticotropic hormone (ACTH) levels was highly significant at postnatal days (PNDs) 14 and 21 in both dams and neonates of the maternal SVP-treated group relative to those in the control group. However, hypercortisolism (cortisolemia) was highly significant in neonates at both PNDs 14 and 21, while in dams, it was not significantly increased at LD 14 but was at LD 21. This disruption caused adverse effects on maternal food consumption and maternal/neonatal body weight. The maternal SVP treatment resulted in higher levels of neonatal serum adrenaline, noradrenaline, neuropeptide Y (NPY), tumor necrosis factor-alpha (TNF-α), leptin, interleukins (IL-1ß, IL-17, IL-4, IL-6 & IL-2), transforming growth factor-beta (TGF-ß), and prostaglandin E2 (PGE2), and lower levels of neonatal serum growth hormone (GH), insulin growth factor-1 (IGF-1) and adiponectin at both PNDs. This administration also induced the oxidative stress in neonatal cerebrum and cerebellum at both tested PNDs via the production of free radicals (malondialdehyde; MDA & nitric oxide; NO) and reduction of antioxidant parameters (glutathione; GSH, superoxide dismutase; SOD & catalase; CAT). CONCLUSION: Maternal SVP treatment stimulated the neonatal stress-brain (HPA) axis, resulted in an oxido-inflammatory state, and disrupted the neuroendocrine-cytokines axis, and generally neonatal health.

Maternal lithium chloride exposure alters the neuroendocrine-cytokine axis in neonatal albino rats.

The aim of this work was to clarify whether maternal lithium chloride (LiCl) exposure disrupts the neonatal neuroendocrine-cytokine axis. Pregnant Wistar rats were orally administrated 50 mg LiCl/kg b.wt. from gestational day (GD) 1 to postpartum day 28. Maternal administration of LiCl induced a hypothyroid state in both dams and their neonates compared to the control dams and neonates at lactation days (LDs) 14, 21 and 28, where the levels of serum free triiodothyronine (FT3) and free thyroxin (FT4) were decreased and the level of serum thyrotropin (TSH) level was increased. A noticeable depression in maternal body weight gain, neonatal body weight and neonatal serum growth hormone (GH) was observed on all examined postnatal days (PNDs; 14, 21 and 28). A single abortion case was recorded at GD 17, and three dead neonates were noted at birth in the LiCl-treated group. Maternal administration of LiCl disturbed the levels of neonatal serum tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-ß), interleukin-1 beta (IL-1ß), interferon-gamma (INF-γ), leptin, adiponectin and resistin at all tested PNDs compared to the control group. This administration produced a stimulatory action on the level of neonatal cerebral serotonin (5-HT) at PND 14 and on the level of neonatal cerebral norepinephrine (NE) at PNDs 21 and 28. However, this administration produced an inhibitory action on the level of neonatal cerebral dopamine (DA) at all examined PNDs and on the level of neonatal cerebral NE at PND 14 and the level of neonatal cerebral 5-HT at PNDs 21 and 28 compared to the corresponding control group. Thus, maternal LiCl exposure-induced hypothyroidism disrupts the neonatal neuroendocrine-cytokine system, which delay cerebral development.

Overdoses of Acetaminophen Disrupt the Thyroid-Liver Axis in Neonatal Rats.

OBJECTIVE: The aim of the study was to examine the impact of neonatal acetaminophen (APAP; paracetamol) administrations on the thyroid-liver axis in male Wistar rats. METHODS: APAP (100 or 350mg/kg) was orally administered to neonates from Postnatal Day (PND) 20 to 40. RESULTS: Both APAP doses elicited a substantial increase in serum TSH, albumin, AST, ALT, and ALP values, and a profound decrease in serum FT4 and FT3 values at PND 40 relative to those in the control group. Additionally, the hypothyroid state in both APAP-treated groups may increase the histopathological variations in the neonatal liver, such as destructive degeneration, fibrosis, fatty degeneration, fibroblast proliferation, haemorrhage, oedema, and vacuolar degeneration, at PND 40. Moreover, in the APAP groups, a marked depression was recorded in the t-SH and GSH levels and GPx and CAT activities at PND 40 in the neonatal liver compared to those in the control group. However, the levels of hepatic LPO, H2O2, and NO were increased in both APAP-treated groups at PND 40. All previous alterations were dose- dependent. CONCLUSION: Neonatal APAP caused a hypothyroidism and disturbed hepatic cellular components by increasing prooxidant markers and decreasing antioxidant markers, causing hepatotoxicity. Thus, neonatal administrations of APAP may act as a neonatal thyroid-liver disruptor.

Gestational Arsenic Trioxide Exposure Acts as a Developing Neuroendocrine-Disruptor by Downregulating Nrf2/PPARγ and Upregulating Caspase-3/NF-ĸB/Cox2/BAX/iNOS/ROS.

The goal of this investigation was to evaluate the effects of gestational administrations of arsenic trioxide (ATO; As2O3) on fetal neuroendocrine development (the thyroid-cerebrum axis). Pregnant Wistar rats were orally administered ATO (5 or 10 mg/kg) from gestation day (GD) 1 to 20. Both doses of ATO diminished free thyroxine and free triiodothyronine levels and augmented thyrotropin level in both dams and fetuses at GD 20. Also, the maternofetal hypothyroidism in both groups caused a dose-dependent reduction in the fetal serum growth hormone, insulin growth factor-I (IGF-I), and IGF-II levels at embryonic day (ED) 20. These disorders perturbed the maternofetal body weight, fetal brain weight, and survival of pregnant and their fetuses. In addition, destructive degeneration, vacuolation, hyperplasia, and edema were observed in the fetal thyroid and cerebrum of both ATO groups at ED 20. These disruptions appear to depend on intensification in the values of lipid peroxidation, nitric oxide, and H2O2, suppression of messenger RNA (mRNA) expression of nuclear factor erythroid 2-related factor 2 and peroxisome proliferator-activated receptor gamma, and activation of mRNA expression of caspase-3, nuclear factor kappa-light-chain-enhancer of activated B cells, cyclooxygenase-2, Bcl-2-associated X protein, and inducible nitric oxide synthase in the fetal cerebrum. These data suggest that gestational ATO may disturb thyroid-cerebrum axis generating fetal neurodevelopmental toxicity.

Thyroid hormones states and brain development interactions.

The action of thyroid hormones (THs) in the brain is strictly regulated, since these hormones play a crucial role in the development and physiological functioning of the central nervous system (CNS). Disorders of the thyroid gland are among the most common endocrine maladies. Therefore, the objective of this study was to identify in broad terms the interactions between thyroid hormone states or actions and brain development. THs regulate the neuronal cytoarchitecture, neuronal growth and synaptogenesis, and their receptors are widely distributed in the CNS. Any deficiency or increase of them (hypo- or hyperthyroidism) during these periods may result in an irreversible impairment, morphological and cytoarchitecture abnormalities, disorganization, maldevelopment and physical retardation. This includes abnormal neuronal proliferation, migration, decreased dendritic densities and dendritic arborizations. This drastic effect may be responsible for the loss of neurons vital functions and may lead, in turn, to the biochemical dysfunctions. This could explain the physiological and behavioral changes observed in the animals or human during thyroid dysfunction. It can be hypothesized that the sensitive to the thyroid hormones is not only remarked in the neonatal period but also prior to birth, and THs change during the development may lead to the brain damage if not corrected shortly after the birth. Thus, the hypothesis that neurodevelopmental abnormalities might be related to the thyroid hormones is plausible. Taken together, the alterations of neurotransmitters and disturbance in the GABA, adenosine and pro/antioxidant systems in CNS due to the thyroid dysfunction may retard the neurogenesis and CNS growth and the reverse is true. In general, THs disorder during early life may lead to distortions rather than synchronized shifts in the relative development of several central transmitter systems that leads to a multitude of irreversible morphological and biochemical abnormalities (pathophysiology). Thus, further studies need to be done to emphasize this concept.

Gestational 3,3',4,4',5-pentachlorobiphenyl (PCB 126) exposure disrupts fetoplacental unit: Fetal thyroid-cytokines dysfunction.

Exposure to polychlorinated biphenyls (PCBs) is related to several endocrine disorders. This study examined the effect of maternal exposure of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) on the fetoplacental unit and fetal thyroid-cytokine axis during the pregnancy. Pregnant albino rats received PCB 126 (20 or 40µg/kgb.wt.) by oral gavage from gestation day (GD) 1 to 20. Potential effects of PCB 126 were evaluated by following the histopathological changes in the placenta by Haematoxylin and Eosin (H&E) stain and measuring the maternofetal thyroid axis (ELIZA), maternofetal body weight, and fetal growth markers (ELIZA), and cytokines (ELIZA) at embryonic day (ED) 20. Placental tissues of both treated groups showed hyperemia, hemorrhage, degeneration and apoptosis in labyrinth layer and spiral artery at GD 20. Both administrations of PCB 126 elevated serum thyrotropin (TSH) concentration, and decreased free thyroxine (FT4) and free triiodothyronine (FT3) concentrations, resulting in a maternofetal hypothyroidism. The presence of hypothyroidism increased fetal serum concentration of transforming growth factor-ß (TGF-ß), leptin (LEP), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and decreased the fetal serum insulin growth factor-I (IGF-I), IGF-II, insulin, adiponectin (ADP), and growth hormone (GH) in both treated groups at ED 20. However, the increase in resistin (RETN) and interferon-γ (IFN-γ) was non-significant in low-dose group and highly significant in high-dose group. Simultaneously, the reduction in body weight of the dams and fetuses was observed in both PCB 126 groups of examined day with respect to the control group. The maternal PCB 126 distorted the fetoplacental unit might disrupt the fetal thyroid-cytokines axis and prenatal development.

Maternal carbamazepine alters fetal neuroendocrine-cytokines axis.

This study detected the impact of maternal carbamazepine (CBZ) on the fetal neuroendocrine-cytokines axis. 25 or 50mg/kg of CBZ was intraperitoneally administrated to pregnant albino rats from the gestation day (GD) 1 to 20. Both administrations of CBZ caused a hypothyroidism in dams and fetuses whereas the decreases in serum thyroxine (T4) and triiodothyronine (T3) and increases in serum thyrotropin (TSH) levels were highly significant (LSD; P <0.01) at GD 20 compared to untreated control dams. Also, both administrations had undesirable impacts on the maternofetal body weight, litter weight, survival of dams and fetuses, and their food consumption in comparison to the corresponding control. These administrations also elicited a reduction in fetal serum growth hormone (GH), interferon-γ (IFNγ), interleukins (IL-2 & 4) and prostaglandin E2 (PGE2) levels. Also, the elevation in fetal serum tumor necrosis factor-alpha (TNFα), transforming growth factor-beta (TGFß), and interleukins (IL-1ß & 17) levels was observed at embryonic day (ED) 20. Moreover, there were a cellular fragmentation, distortion, hyperemia, oedema and vacuolation in the fetal cerebellar cortex due to both maternal administrations. These developmental changes were dose-dependent. These novel results suggest that CBZ may act as a developmental immunoneuroendocrine disruptor.

Gestational dexamethasone alters fetal neuroendocrine axis.

This study tested whether the maternal transport of dexamethasone (DEXA) may affect the development of the neuroendocrine system. DEXA (0.2mg/kg b.w., subcutaneous injection) was administered to pregnant rats from gestation day (GD) 1-20. In the DEXA-treated group, a decrease in maternal serum thyroxine (T4), triiodothyronine (T3), and increase in thyrotropin (TSH) levels (hypothyroid status) were observed at GDs 15 & 20 with respect to control group. The reverse pattern (hyperthyroid status) was observed in their fetuses at embryonic days (EDs) 15 & 20. Although the maternal body weight was diminished, the weight of the thyroid gland was increased at studied GDs as compared to the control group. The fetal growth retardation, hyperleptinemia, hyperinsulinism, and cytokines distortions (transforming growth factor-beta; TGF-ß, tumor necrosis factor-alpha; TNF-α, and interferon-γ; IFN-γ) were noticed at examined EDs if compared to the control group. Alternatively, the maternofetal thyroid dysfunctions due to the maternal DEXA administration attenuated the levels of fetal cerebral norepinephrine (NE) and epinephrine (E), and elevated the levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) at considered days. These alterations were age-dependent and might damage the nerve transmission. Finally, maternal DEXA might act as neuroendocrine disruptor causing dyshormonogenesis and fetal cerebral dysfunction.

Maternal bisphenol A alters fetal endocrine system: Thyroid adipokine dysfunction.

Because bisphenol A (BPA) has been detected in animals, the aim of this study was to investigate the possible effects of maternal BPA exposure on the fetal endocrine system (thyroid-adipokine axis). BPA (20 or 40 µg/kg body weight) was orally administered to pregnant rats from gestation day (GD) 1-20. In both treated groups, the dams and their fetuses had lower serum thyroxine (T4) and triiodothyronine (T3) levels, and higher thyrotropin (TSH) level than control dams and fetuses at GD 20. Some histopathological changes in fetal thyroid glands were observed in both maternal BPA groups at embryonic day (ED) 20, including fibroblast proliferation, hyperplasia, luminal obliteration, oedema, and degeneration. These disorders resulted in the suppression of fetal serum growth hormone (GH), insulin growth factor-1 (IGF1) and adiponectin (ADP) levels, and the elevation of fetal serum leptin, insulin and tumor necrosis factor-alpha (TNFα) levels in both treated groups with respect to control. The depraved effects of both treated groups were associated with reduced maternal and fetal body weight compared to the control group. These alterations were dose dependent. Thus, BPA might penetrate the placental barrier and perturb the fetal thyroid adipokine axis to influence fat metabolism and the endocrine system.

Heat stress induced histopathology and pathophysiology of the central nervous system.

The number of reports on the effects of heat stress is still increasing on account of the temperature is one of the most encountered stressful factors on the different biological systems. Because the heat stress (HS) considered a model of thermal injury to the central nervous system (CNS), the purpose of this review was to assess the histopathological changes of HS on CNS. Also, this review emphasized that the heat stress may retard partially the degree of the postnatal neurogenesis and growth of CNS. Taken together, owing to one of the most important functions of heat shock protein is to protect the organisms from the deleterious effects of temperature, thus, it can be hypothesized that the formation of heat shock proteins may be related to the deleterious effect of HS. On the other hands, the alterations of neurotransmitters in the central nervous system might be involved in the physiological and biochemical responses that occur during heat stress. The hypothalamic monoaminergic systems play an important role in the thermoregulation through regulate the heat production and heat dissipation. In addition, the disturbance in the biochemical variables due to the high temperature may be the cause of the histopathological changes and the partial retardation in CNS and the reverse is true. Thus, further studies need to be done to emphasize this concept.

Hypothyroidism and brain developmental players.

Most of our knowledge on the mechanisms of thyroid hormone (TH) dependent brain development is based on clinical observations and animal studies of maternal/fetal hypothyroidism. THs play an essential role in brain development and hormone deficiency during critical phases in fetal life may lead to severe and permanent brain damage. Maternal hypothyroidism is considered the most common cause of fetal TH deficiency, but the problem may also arise in the fetus. In the case of congenital hypothyroidism due to defects in fetal thyroid gland development or hormone synthesis, clinical symptoms at birth are often mild as a result of compensatory maternal TH supply. TH transporters (THTs) and deiodinases (Ds) are important regulators of intracellular triiodothyronine (T3) availability and therefore contribute to the control of thyroid receptors (TRs)-dependent CNS development and early embryonic life. Defects in fetal THTs or Ds may have more impact on fetal brain since they can result in intracellular T3 deficiency despite sufficient maternal TH supply. One clear example is the recent discovery of mutations in the TH transporter (monocarboxylate transporter 8; MCT8) that could be linked to a syndrome of severe and non reversible psychomotor retardation. Even mild and transient changes in maternal TH levels can directly affect and alter the gene expression profile, and thus disturb fetal brain development. Animal studies are needed to increase our understanding of the exact role of THTs and Ds in prenatal brain development.

Protective effects of GM-CSF in experimental neonatal hypothyroidism.

Hypothyroidism induced by methimazole (MMI), has a negative impact on the postnatal development. Neonatal Granulocyte Macrophage-Colony Stimulating Factor [GM-CSF; 50µg/kg, intramuscular injection at postnatal day (PND) 17] had been tested to ameliorate the effects of MMI [0.05%, (weight per volume; w/v), intraperitoneal injection at PND 15]-induced hypothyroidism in Wistar rats. The hypothyroid conditions due to the administration of MMI produced inhibitory effects on neonatal serum thyroxine (T4), 3,5,3'-triiodothyronine (T3), neutrophil count in bone marrow and blood, cerebellar glutathione (GSH) and acetylcholinesterase (AchE), although it induced stimulatory actions on serum thyrotropin (TSH), growth hormone (GH), insulin growth factor-II (IGF-II), tumor necrosis factor alpha (TNF-α), and cerebellar malondialdehyde (MDA) at PND 19. The treatment with GM-CSF could reverse the depressing and stimulating effects of MMI on these markers except for cerebellar AchE where its enhancement was non-significant (P>0.05) at tested PND. Thus, neonatal GM-CSF may be responsible for suppressing autoimmune responses and preventing hypothyroidism.

Immune stimulation improves endocrine and neural fetal outcomes in a model of maternofetal thyrotoxicosis.

The potentiation of the immune system in pregnant rats was performed with Complete Freund's Adjuvant [CFA; 20µl, subcutaneous at gestation day (GD) 18] in experimentally-induced hyperthyroidism by Levo-thyroxine (L-T4; 10µg/100g of b.w., intraperitoneal from GD 2 to 17). The potential effects on the fetal neuroendocrine function were evaluated by observing some histopathological investigations in pregnant rats and measuring some biochemical parameters in dams and their fetuses at GD 20. In hyperthyroid group, an increase in maternofetal serum thyroxine (T4), triiodothyronine (T3) and a decrease in thyrotropin (TSH) levels were noticed, while the concentrations of fetal serum growth hormone (GH) and insulin-like growth factor-1 (IGF1) levels were increased at tested GD with respect to control and CFA groups. Moreover, the activity of uterine and placental myeloperoxidase (MPO) was increased (P<0.001) in CFA and CFA-treated hyperthyroid groups in respect to control or hyperthyroid groups, respectively. The gestational thyrotoxicosis led to some histopathological lesions in uterine and placental tissues characterized by severe degeneration in trophoblast spongioblast cell layer with congestion, mild congested blood vessels in the endometrium and deficient in spiral artery remodeling. Although, the elevation in fetal serum transforming growth factor-beta (TGFß) and cerebellar monoamines [norepineprine (NE), epinephrine (E), dopamine (DA) and 5-hydroxytryptamine (5-HT)] was observed, the reduction in fetal serum tumor necrosis factor-alpha (TNFα) and adipokines (Leptin and adiponectin) was detected. Treatment of dams with CFA showed an obviously reversing and protecting effect against hyperthyroid perturbations. Thus, the maternal CFA can be used in treatment of the fetal neuroendocrine dysfunctions.

Early weaning PCB 95 exposure alters the neonatal endocrine system: thyroid adipokine dysfunction.

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that can severely disrupt the endocrine system. In the present study, early-weaned male rats were administered a single dose of 2,3,6-2',5'-pentachlorinated biphenyl (PCB 95; 32 mg/kg per day, by i.p. injection) for two consecutive days (postnatal days (PNDs) 15 and 16) and killed 24 and 48 h after the administration of the last dose. Compared with the control group, administration of PCB 95 induced a reduction (P<0.01) in serum concentrations of thyroxine, triiodothyronine, and GH and an increase (P<0.01) in the serum concentration of TSH at PNDs 17 and 18. These conspicuous perturbations led to some histopathological deterioration in the thyroid gland characterized by follicular degeneration, edema, fibrosis, hemorrhage, luminal obliteration, and hypertrophy with reduced colloidal contents at PND 18. The dyshormonogenesis and thyroid dysgenesis may be attributed to the elevation of DNA fragmentation at PNDs 17 and 18. Furthermore, this hypothyroid state revealed higher (P<0.01) serum concentrations of leptin, adiponectin, and tumor necrosis factor and lower (P<0.01) serum concentrations of IGF1 and insulin at both PNDs compared with the control group. Interestingly, the body weight of the neonates in the PCB 95 group exhibited severe decreases throughout the experimental period in relation to that of the control group. These results imply that PCB 95 may act as a disruptor of the developmental hypothalamic-pituitary-thyroid axis. Hypothyroidism caused by PCB 95 may impair the adipokine axis, fat metabolism, and in general postnatal development. Thus, further studies need to be carried out to understand this concept.