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.

Suppressive effects of neonatal bisphenol A on the neuroendocrine system

Thyroid hormones (THs) are essential for normal growth and development [1-30]. Hyperthyroidism causes a thyrotoxicosis [31], membrane lipid alterations [32], TSH reduction [4], neuropsychiatric and neurologic syndromes and myopathy [4,33]. In neonatal hyperthyroidism, cardiac symptoms, and abnormal neurological behaviors were observed by several authors [4,34-37]. Fetal thyrotoxicosis is the result of thyroidstimulating antibody transfer to the fetus in the setting of maternal Grave’s disease [6,38]. A fetal hydrops, demise, intrauterine growth restriction, and goiter were reported by Zimmerman et al. [39] and Ahmed et al. [4]. In maternal hyperthyroidism, the placenta lacks to optimize the maternaofetal transfer of THs [6].

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Hyperthyroidism and Developmental Dysfunction

Thyroid hormones (THs) are necessary for normal development particularly cytoskeletal system. Cytoskeletal system which consists of microtubules (Tubulin), microfilaments (Actin), and intermediate filaments, specific for neurons (Neurofilaments), glia (Glial Fibrillary Acidic Protein), or maturing cells (Vimentin, Nestin) can play important roles in neural cell shape and neuronal migration and outgrowth [1-40]. THs regulate and reorganize this system by nongenomic actions. Moreover, THs regulate the expression of extracellular matrix (ECM) and adhesion molecules that are important for neuronal migration and development, such as tenascin-C, neural cell adhesion molecule (N-CAM), reelin and dab1, laminin and fibronectin. Maternal THs controls the expression of neuronal migration and growth, branching of neurites, astrocytic cytoskeletal proteins, cell cycle regulators, neurotrophins and neurotrophin receptors and extracellular matrix proteins in the fetal brain [41-45].

Perinatal Hypothyroidism and Cytoskeleton Dysfunction

Thyroid hormones (THs) regulate the brain development(El-bakry et al., 2010; Ahmed, 2011, 2012a,b, 2013, 2014, 2015a-c, 2016a-d, 2017a-f; Ahmed et al., 2008, 2010, 2012, 2013a,b, 2014; 2015a,b; Ahmed and Ahmed,2012; Ahmed and Incerpi, 2013;Van Hercket al., 2013; Ahmed andElGareib, 2014;Incerpi et al., 2014; Candelotti et al., 2015; De Vito et al., 2015; El-Ghareeb et al., 2016; Ahmed and El-Gareib, 2017). The cholinergic system [acetylcholinesterase (AchE) and butyrylcholinesterase (BuchE)] (Carageorgiou et al., 2007; Tousson et al., 2012), and the neuronal development (Hadj-Sahraoui et al., 2000; Zhang et al., 2009) might disturb by neonatal thyroid deficiency (Ahmed andEl-Gareib, 2014; Ahmed et al., 2014).Also, these might diminish the development of cholinergic synapses and brain function. In contrast, hyperthyroidism can accelerate the development of the cholinergic neurons (Gould and Butcher, 1989; Ahmed et al., 2008). Thus, any thyroid disorders might be associated with neuro developmental defects through decreasing T3 level (Sawin et al., 1998) by recruitment of its transcriptional corepressors and/or dissociation of coactivators (Moriyama et al., 2007).

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Developmental Thyroid Diseases and Cholinergic Imbalance

The normal adequate of the maternal thyroid hormones (THs) (El-bakry et al., 2010; Ahmed, 2011, 2012a,b, 2013, 2014, 2015a-c, 2016a-d, 2017a-t; Ahmed et al., 2008, 2010, 2012, 2013a,b, 2014; 2015a,b; Ahmed and Ahmed, 2012; Ahmed and Incerpi, 2013;Van Hercket al., 2013; Ahmed and El-Gareib, 2014,Incerpi et al., 2014; Candelotti et al., 2015; De Vito et al., 2015; El-Ghareeb et al., 2016; Ahmed and ElGareib, 2017; Endendijk et al., 2017; Gigena et al., 2017) is necessary for the fetal/neonatal brain development (Henrichs et al., 2013). During the normal gestation, the level of thyrotropin (TSH) was increased and the level of free thyroxine (FT4) was correspondingly decreased (Stricker et al., 2007; Ahmed et al., 2008). These alterations are within the normal range and may be predictive of neonatal development (Pop et al., 1995, 1999 &2003; Ahmed et al., 2008). However, mothers with problems in the THs before and during pregnancy had neonates with the lowest mental and motor development scores (Pop et al., 1995, 1999 &2003; Endendijk et al., 2017). In addition, it seems that mild increases in TSH might delay the fetal brain development and consequent attention disorders or problems, specifically in boys (Glinoer et al., 1993; Endendijk et al., 2017).

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Maternal Thyroid Hormones Trajectories and Neonatal Behavioral Disorders

The aim of this study is to investigate the protective role of Zn on thyroid function and cerebellum impairments induced by carbimazole (CMI) in neonats at PND 28. Animals were divided into four groups: group I acts as control; group II received carbimazole (1.35mg/kg.b.w CMI) only; group III received Zn as zinc sulphate (3mg/kg.b.w) and group IV received Zn and CMI. The administration of maternal CMI caused significant decrease in serum T4, T3 and growth hormone (GH) levels and significant increase in serum TSH levels in both dams and their newborns relative to control group. While in Zinc-hypothyroid group, a reverse pattern was noticed for all previous parameters comparing with hypothyroid group. Maternal CMI administration caused significant decrease in GSH, SOD, GPX, CAT and t-SH of cerebellum and increased prooxidant levels including MDA, H 2 O 2 and NO while Zn administration to hypothyroid dams reversed this effect.  CMI administration caused some degeneration and deformation  in newborns cerebellum while zinc supplementation to CMI group enhanced structure, length, number and size of purkinje cells, also increase size of the granular layer. Our results indicated that zinc has an improvement role on THs levels and histoarchiture of cerebellum due to its antioxidant role. Key words: Carbimazole, zinc, thyroid hormones, antioxidant, prooxidant

A. M. El-Bakry

Papers

Effects of Zinc Supplementation in Neonatal Hypothyroidism and Cerebellar Distortion Induced by Maternal Carbimazole