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D Sampson, MR Pickard, AK Sinha, IM Evans, AJ Leonard and RP Ekins

Maternal thyroid hormone (TH) crosses the placenta and is postulated to regulate fetal brain development. However, TH-dependent stages of fetal brain development remain to be characterised. We have therefore compared the levels of several neuronal and glial cytoskeletal proteins in fetal brains from normal (N) and partially thyroidectomised (TX) rat dams by immunoblotting. Pregnancies were studied both before and after the onset of fetal TH secretion, which occurs at 17.5 days gestation (dg) in the rat. Maternal hypothyroidism disrupted fetal growth, so that fetal body and brain weights were reduced near term. Vimentin expression was unaffected, however, indicating normal acquisition of neuronal and glial precursor cells. Fetal brain levels of glial fibrillary acidic protein (GFAP) were reduced at 21 dg, suggesting delayed astrocytic differentiation, although regression analysis demonstrated appropriate GFAP levels for brain weight. Levels of alpha-internexin, the earliest neurofilament protein expressed in fetal brain were reduced at 16 dg in TX dams, but increased at 21 dg. The ontogeny of neurofilament-L was also perturbed in these pregnancies, with deficient levels apparent at both 16 and 21 dg. These effects on neuronal cytoskeletal proteins were unrelated to fetal brain growth retardation. These findings confirm that maternal hypothyroidism disrupts early fetal brain development. Early disturbances in neuronal differentiation are not corrected by the onset of fetal TH secretion. Such disturbances may contribute to the neurological damage observed in children born to hypothyroxinaemic mothers.

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IM Evans, AK Sinha, MR Pickard, PR Edwards, AJ Leonard and RP Ekins

Maternal thyroid status influences early brain development and, consequently, cognitive and motor function in humans and rats. The biochemical targets of maternal thyroid hormone (TH) action in fetal brain remain poorly defined. A partially thyroidectomized rat dam model was therefore used to investigate the influence of maternal hypothyroxinemia on the specific activities of cholinergic and monoaminergic neurotransmitter metabolic enzymes in the developing brain. Maternal hypothyroxinemia was associated with reduced monoamine oxidase (MAO) activity in fetal whole brain at 16 and 19 days gestation (dg). A similar trend was observed for choline acetyltransferase (ChAT) activity. In contrast, DOPA decarboxylase (DDC) activity was markedly elevated at 21 dg. Further study of these enzymes at 14 dg showed no differences between normal and experimental progeny - suggesting they become TH sensitive after this age. Tyrosine hydroxylase (TyrH) and acetylcholinesterase (AChE) activities were unaffected prenatally. During postnatal development, the activities of TyrH, MAO, DDC and, to a lesser extent, AChE were increased in a brain region- and age-specific manner in experimental progeny. The prenatal disturbances noted in this study may have wide-ranging consequences since they occur when neurotransmitters have putative neurotropic roles in brain development. Furthermore, the chronic disturbances in enzyme activity observed during postnatal life may affect neurotransmission, thereby contributing to the behavioural dysfunction seen in adult progeny of hypothyroxinemic dams.

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MR Pickard, AK Sinha, LM Ogilvie, AJ Leonard, PR Edwards and RP Ekins

The influence of maternal hypothyroxinemia on the expression of the glucose transporters, GLUT1 and GLUT3, in rat fetal brain and placenta was investigated. Fetal growth was retarded in hypothyroxinemic pregnancies, but only before the onset of fetal thyroid hormone synthesis. Placental weights were normal, but placental total protein concentration was reduced at 19 days gestation (dg). Immunoblotting revealed a decreased abundance of GLUT1 in placental microsomes at 16 dg, whereas GLUT3 was increased. Fetal serum glucose levels were reduced at 16 dg. In fetal brain, the concentration of microsomal protein was deficient at 16 dg and the abundance of parenchymal forms of GLUT1 was further depressed, whereas GLUT3 was unaffected. Northern hybridization analysis demonstrated normal GLUT1 mRNA levels in placenta and fetal brain. In conclusion, maternal hypothyroxinemia results in fetal growth retardation and impaired brain development before the onset of fetal thyroid function. Glucose uptake in fetal brain parenchyma may be compromised directly, due to deficient GLUT1 expression in this tissue, and indirectly, as a result of reduced placental GLUT1 expression. Though corrected by the onset of fetal thyroid hormone synthesis, these deficits are present during the critical period of neuroblast proliferation and may contribute to long term changes in brain development and function seen in this model and in the progeny of hypothyroxinemic women.

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Tracey A Quinn, Udani Ratnayake, Margie Castillo-Melendez, Karen M Moritz, Hayley Dickinson and David W Walker

Antenatal stress disturbs the development of the fetal hypothalamic–pituitary–adrenal axis and adrenal steroidogenesis. We investigated the effect of brief maternal exposure to high glucocorticoids (dexamethasone (DEX)) at mid- and late-pregnancy on adrenal structure and production of steroids in spiny mouse. Pregnant spiny mice were treated for 60 h with 125 μg/kg DEX or saline s.c. by osmotic minipump at day 20 (0.5) or 30 (0.75) of gestation. Immunohistochemical expression of steroidogenic acute regulatory-protein (StAR), 3β-hydroxysteroid dehydrogenase (3βHSD), 17-hydroxylase,17-20lyase (P450C17), and cytochromeb5 (CYTB5) was determined in adrenals on postnatal (P) day 170±20. DHEA, testosterone, and cortisol were measured by RIA. Maternal DEX at 20 days significantly reduced the expression of STAR, P450C17 (CYP17A1), and CYTB5 in the adrenal zona reticularis (ZR) of adult offspring, with greater change in male vs female offspring (P<0.05). Plasma DHEA was decreased in male offspring from DEX-treated (6.84±1.24 ng/ml) vs saline-treated (13±0.06 ng/ml; P=0.01) dams, and the DHEA:cortisol ratio was lower in males (P<0.05). Testosterone levels increased in male offspring from DEX (266.03±50.75 pg/ml) vs saline (83.47±32.3 pg/ml, P<0.05)-treated dams. DEX treatment at 0.75 gestation had no significant effect on any parameters measured. This study shows that brief exposure to excess glucocorticoid has long-term impacts on the ZR and adrenal steroidogenesis, affecting the secretion of DHEA and testosterone in male offspring, an effect produced at 0.5 but not at 0.75 gestation. DHEA is important for brain development, and its suppression in adult life might contribute to the neurobehavioral pathologies that can arise after illness and stress during pregnancy.

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Hongyu Su, Xueyi Chen, Yueming Zhang, Linglu Qi, Yun He, Juanxiu Lv, Yingying Zhang, Xiang Li, Jiaqi Tang and Zhice Xu

Cerebral circulation is important in fetal brain development, and angiotensin II (Ang II) plays vital roles in regulation of adult cerebral circulation. However, functions of Ang II in fetal cerebral vasculature and influences of in utero hypoxia on Ang II-mediated fetal cerebral vascular responses are largely unknown. This study investigated the effects and mechanisms of in utero hypoxia on fetal middle cerebral arteries (MCA) via Ang II. Near-term ovine fetuses were exposed to in utero hypoxia, and fetal MCA responses to Ang II were tested for vascular tension, calcium transient, and molecular analysis. Ang II caused significant dose-dependent contraction in control fetal MCA. Ang II-induced MCA constriction was decreased significantly in hypoxic fetuses. Neither losartan (AT1R antagonist, 10−5 mol/L) nor PD123,319 (AT2R antagonist, 10−5 mol/L) altered Ang II-mediated contraction in fetal MCA. Phenylephrine-mediated constriction was also significantly weaker in hypoxic fetuses. Bay K8644 caused similar contractions between the two groups. Protein expression of L-type voltage-dependent calcium channels was unchanged. There were no differences in caffeine-mediated vascular tension or calcium transients. Contraction induced by PDBu (PKC agonist) was obviously weaker in hypoxic MCA. Protein expression of PKCβ was reduced in the hypoxic compared with the control, along with no differences in phosphorylation levels. The results showed that fetal MCA was functionally responsive to Ang II near term. Intrauterine hypoxia reduced the vascular agonist-mediated contraction in fetal MCA, probably via decreasing PKCβ and its phosphorylation, which might play protective effects on fetal cerebral circulation against transient hypoxia.

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J Patel, K Landers, H Li, R H Mortimer and K Richard

hormones and brain development has been derived from rodent experiments. As in humans, normal neurological development depends on thyroid hormone. TRs and deiodinase enzymes are expressed in the early brain before the thyroid gland develops ( Obregon et

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Andréa Gonçalves Trentin

& Robitaille 2003 , Nedergaard et al. 2003 , Bachoo et al. 2004 ). Astrocytes are mediators of thyroid hormone metabolism in the brain The importance of thyroid hormone for normal brain development is well documented

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Nathanael J Yates, Dijana Tesic, Kirk W Feindel, Jeremy T Smith, Michael W Clarke, Celeste Wale, Rachael C Crew, Michaela D Wharfe, Andrew J O Whitehouse and Caitlin S Wyrwoll

suggestive of features of ASD, including communication differences, lack of interest in social interaction, restricted and repetitive behaviour and changes in brain development. Variation in maternal care has a profound influence on offspring

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S Benvenuti, P Luciani, I Cellai, C Deledda, S Baglioni, R Saccardi, S Urbani, F Francini, R Squecco, C Giuliani, G B Vannelli, M Serio, A Pinchera and A Peri

Introduction Thyroid hormones (TH) play a fundamental role in fetal life, particularly in promoting brain development. TH affect the expression of several genes, which are related to cell migration (i.e. reelin, laminin, tenascin C), myelination (i

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E Nieves-Martinez, W E Sonntag, A Wilson, A Donahue, D P Molina, J Brunso-Bechtold and M M Nicolle

, which begins around PD28. Brain development continues through adolescence to young adulthood (PD63–70) ( McCutcheon & Marinelli 2009 ). Because of the high density of GH and IGF1 receptors in the hippocampus ( Adem et al . 1989 , Lai et al . 1993