Maternal thyroid hormone: a strong repressor of neuronal nitric oxide synthase in rat embryonic neocortex.
Understanding of how maternal thyroid inadequacy during early gestation poses a risk for developmental outcomes is still a challenge for the neuroendocrine community. Early neocortical neurogenesis is accompanied by maternal thyroid hormone (TH) transfer to fetal brain, appearance of TH receptors, and absence of antineurogenesis signals, followed by optimization of neuronal numbers through apoptosis. However, the effects of TH deprivation on neurogenesis and neuronal cell death before the onset of fetal thyroid are still not clear. We show that maternal TH deficiency during early gestational period causes massive premature elevation in the expression of neuronal nitric oxide synthase (nNOS) with an associated neuronal death in embryonic rat neocortex. Maternal hypothyroidism was induced by feeding methimazole (0.025% wt/vol) in the drinking water to pregnant Sprague Dawley rats from embryonic d 6. Cerebral cortices from fetuses were harvested at different embryonic stages (embryonic d 14, 16, and 18) of hypothyroid and euthyroid groups. Immunoblotting and real-time PCR results showed that both protein and RNA levels of nNOS were prematurely increased under maternal hypothyroidism, and showed reversibility upon T4 administration. Immunohistochemistry revealed an increased nNOS immunoreactivity in both the cortical plate and proliferative zone of neocortex along with a corroborative decrease in the microtubule associated protein-2 positive neurons under maternal TH insufficiency. Results combined, put forth nNOS as a novel target of maternal TH action in embryonic neocortex, and underscore the importance of prenatal screening and timely rectification of maternal TH insufficiency, even of a moderate degree.
Sinha
Rohit Anthony
RA
Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India.
Pathak
Amrita
A
Mohan
Vishwa
V
Bandyopadhyay
Sanghamitra
S
Rastogi
Leena
L
Godbole
Madan M
MM
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003409:Congenital Hypothyroidism / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D033261:Maternal-Fetal Relations; D019579:Neocortex / Q000187:drug effects* / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013963:Thyroid Hormones / Q000097:blood / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D013963:Thyroid Hormones; D052248:Nitric Oxide Synthase Type I; C049301:microtubule-associated protein-2 phosphatase; D010749:Phosphoprotein Phosphatases