Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042755 (masculinization)
 2,562 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During normal development there is a perinatal sensitive period during which the male brain is exposed to high levels of gonadal steroids, resulting in permanent differentiation of neural substrates. The cellular mechanisms mediating hormonally induced sexual differentiation remain largely unknown. In the adult brain, steroids exert profound influences on the amino acid transmitters, GABA, and glutamate. We have found steroid regulation of amino acid neurotransmission during the perinatal sensitive period and propose this may be functionally related to sexual differentiation of the brain. Specifically, the mRNA coding for the rate-limiting enzyme in GABA synthesis, glutamic acid decarboxylase (GAD), is up to twice as high in some steroid-concentrating regions of the neonatal male brain compared to females, including the arcuate nucleus, dorsomedial nucleus, and the CA1 region of hippocampus. Sex differences in GABA tissue concentrations positively correlate with GAD mRNA differences in several brain regions. There are also sex differences in protein levels of GABA(A) receptor subunits. In parallel with these findings are significantly higher levels of binding to the non-NMDA glutamate receptor in steroid-concentrating regions of male brain. Given that GABA is an inhibitory transmitter and glutamate is an excitatory amino acid, these results initially appear paradoxical. However, in contrast to its inhibitory action in the adult brain, early in development GABA is actually excitatory and acts in a manner analogous to glutamate. Therefore, the combination of increased excitatory GABAergic and glutamatergic activity should result in substantially higher levels of neuronal excitation in the male brain. We speculate that an increased level of neuronal excitation is a potential mechanism mediating the permanent masculinization of the brain.
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PMID:Excitatory neurotransmission and sexual differentiation of the brain. 937 Feb 15

During development, exposure to gonadal steroids results in brain sexual differentiation. Postnatally, hypothalamic gamma-aminobutyric acid (GABA) levels are almost double in males versus females. We hypothesized that increased GABA neonatally results in masculinization. Males, females, and androgenized females were infused intrahypothalamically with antisense oligonucleotides against glutamic acid decarboxylase (GAD) mRNA at birth to reduce GABA synthesis. GAD protein and GABA levels were reduced 24 hr later without obvious toxic effects, as determined by histological examination. As adults, neonatally antisense-treated, androgenized females showed reduced intromission-like behavior and lordosis quotients compared with vehicle and scrambled controls. Lordosis quotients were reduced about 50% in nonandrogenized females versus vehicle and scrambled controls. These data suggest that GABA is involved in mediating brain sex differentiation and may act in both males and females.
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PMID:Decreasing GAD neonatally attenuates steroid-induced sexual differentiation of the rat brain. 1108 6

Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) interferes with masculinization and defeminization of male sexual behaviors and gonadotropin release patterns. We previously demonstrated that the mRNA encoding the arylhydrocarbon receptor (AhR), a protein that mediates TCDD effects, is found in brain regions that control reproductive functions, most notably in the preoptic area (POA). The pattern of distribution of the AhR gene closely overlaps that of an enzyme necessary for Gamma-aminobutyric acid (GABA) synthesis, glutamic acid decarboxylase (GAD) 67. To test the hypothesis that GABAergic neurons in the POA are targets of TCDD during development, we used dual-label in situ hybridization histochemistry (ISHH) to co-localize GAD and AhR mRNAs in the region. In addition, we used ISHH to determine the effects of TCDD (1 microg/kg body weight, gestational day 15) on GAD 67 gene expression in POA regions in pups examined on postnatal day 3. We found that virtually all GABAergic neurons in the POA expressed the AhR gene. Furthermore, GAD 67 mRNA levels were higher in females than in males in the rostral POA/anteroventral periventricular nucleus (rPOA/AVPV) and in the rostral portion of the medial preoptic nucleus (MPN). TCDD abolished sex differences in the rPOA/AVPV but had no effect in the rostral MPN. In the caudal MPN, there were no sex differences in GAD 67 gene expression, but TCDD depressed expression specifically in males. Our findings demonstrate that GABAergic neurons in the brain are targets of TCDD and may mediate developmental effects of this contaminant on reproductive function.
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PMID:Evidence that GABAergic neurons in the preoptic area of the rat brain are targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin during development. 1206 Aug 31