Bisphenol-A analogs induce lower urinary tract dysfunction in male mice.

Bisphenol-A (BPA), an estrogenic endocrine disrupting chemical, significantly impacts numerous diseases and abnormalities in mammals. Estrogens are known to play an important role in the biology of the prostate; however, little is known about the role of bisphenols in the etiology of prostate pathologies, including benign prostate hyperplasia (BPH) and associated lower urinary tract dysfunction (LUTD). Bisphenol-F (BPF) and bisphenol-S (BPS) are analogs often used as substitutes for BPA; they are both reported to have in vitro and in vivo estrogenic effects similar to or more potent than BPA. The objective of this study was to assess the role of these bisphenols in the development of LUTD in adult male mice. In adult mice exposed to BPA, BPS or BPF, we examined urinary tract histopathology and physiological events associated with urinary dysfunction. Mice treated with bisphenols displayed increased bladder (p < 0.005) and prostate (p < 0.0001) mass, and there was an increased number of prostatic ducts in the prostatic urethra (p < 0.05) and decreased size of the urethra lumen (p < 0.05) compared to negative controls. After two months of bisphenol exposure, mice displayed notable differences in cystometric tracings compared to controls, consistent with LUTD. Treatment of male mice with all bisphenols also induced voiding dysfunction manifested by detrusor instability and histologic changes in the prostatic urethra of male rodents, consistent with LUTD. Our results implicate BPA and its replacements in the development and progression LUTD in mice and provide insights into the development and progression of BPH/LUTS in men.

Inhibition of the serotonin transporter induces microglial activation and downregulation of dopaminergic neurons in the substantia nigra.

Drugs that selectively inhibit the serotonin transporter (SERT) are widely used in the treatment of depression and anxiety disorders. These agents are associated with a range of extrapyramidal syndromes such as akathisia, dystonia, dyskinesia and parkinsonism, suggesting an effect on dopaminergic transmission. We studied the time course of changes in dopaminergic neurons in the substantia nigra (SN) after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (N = 9) or mixed with citalopram 5 mg/kg/day (N = 27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of SN were processed for tyrosine hydroxylase (TH) immunohistochemistry. Citalopram induced a significant decrease in TH-positive cell counts at 24 h (44%), 7 days (38%) and 28 days (33%). No significant differences among the citalopram treatment groups were observed in the SN. To determine whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28 day course of fluoxetine. As was observed with citalopram, fluoxetine induced a significant 21% reduction of TH cell counts in the SN. Immunoblot analysis showed that fluoxetine also induced a 45% reduction of striatal TH. To investigate a possible role for the innate immune system in mediating these changes, we also studied the microglial marker OX42 after administration of fluoxetine and noted a significant 63% increase in the SN of fluoxtine-treated animals. These results indicate that SERT inhibition can activate microglia and alter the regulation of TH, the rate limiting enzyme for dopamine biosynthesis. These changes may play a role in mediating the extrapyramidal side effects associated with SERT inhibitors.

Role of the dopamine transporter in mediating the neuroleptic-induced reduction of tyrosine hydroxylase-immunoreactive midbrain neurons.

We have previously reported a long-term downregulation of midbrain dopaminergic neurons following treatment with neuroleptic medications. The mechanism of this effect is not clear. The dopamine transporter (DAT) has been shown to play a role in the behavioural and biochemical action of neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We postulated a role for the DAT in mediating the changes induced by neuroleptic (i.e., antipsychotic) drugs. In the first experiment, Sprague-Dawley rats simultaneously received twice daily sub-cutaneous injections of either saline or the DAT inhibitor GBR 12909 (GBR; 5 mg/kg/day) and haloperidol (HAL; 2 mg/kg/day) or vehicle. In the second experiment, the animals were treated with daily sub-cutaneous injections of saline or the DAT inhibitor GBR 129091 plus oral risperidone (RISP; 1.5 mg/kg/day) or vehicle. In a third experiment, animals were given normal drinking water or water with clozapine (CLZ, 20 mg/kg/day). Animals were sacrificed immediately after the last treatment. Sections of the substantia nigra (SN) and ventral tegmental area (VTA) were processed for tyrosine hydroxylase (TH) immunoreactivity. Cell counts were analyzed by one-way analysis of variance followed by post-hoc Tukey tests, with significance set at p<0.05. Treatment with HAL or RISP resulted in a significant reduction (HAL 27%; RISP 25%) in the number of TH-immunoreactive cells present in the medial SN pars compacta. This effect was in both cases completely blocked by administration of the DAT inhibitor. In the VTA, TH-positive cell counts were significantly decreased with RISP, but not with HAL. Once again, the RISP-induced changes were blocked by co-administration of the DAT inhibitor. CLZ treatment did not significantly affect TH-positive cell counts in the SN. These results indicate a role for the active dopamine transporter in mediating the suppression of TH expression in midbrain dopaminergic neurons by antipsychotic drugs. DAT inhibitors may prove useful in ameliorating the neurological side effects of antipsychotic medication.

Role of serotonin transporter inhibition in the regulation of tryptophan hydroxylase in brainstem raphe nuclei: time course and regional specificity.

Drugs that selectively inhibit the serotonin transporter (SERT) are widely prescribed for treatment of depression and a range of anxiety disorders. We studied the time course of changes in tryptophan hydroxylase (TPH) in four raphe nuclei after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (n=9) or mixed with citalopram 5 mg/kg/day (n=27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of dorsal raphe nucleus (DRN), median raphe nucleus (MRN), raphe magnus nucleus (RMN) and caudal linear nucleus (CLN) were processed for TPH immunohistochemistry. Citalopram induced a significant reduction in DRN TPH-positive cell counts at 24 h (41%), 7 days (38%) and 28 days (52%). Similar reductions in TPH-positive cell counts were also observed at each timepoint in the MRN and in the RMN. In the MRN, citalopram resulted in significant reductions at 24 h (26%), 7 days (16%) and 28 days (23%). In the RMN, citalopram induced significant reductions of TPH-positive cell counts at 24 h (45%), 7 days (34%) and 28 days (43%). By contrast, no significant differences between control and treatment groups were observed in the CLN at any of the time points that we studied. To investigate whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28-day course of fluoxetine. As was observed with citalopram, fluoxetine induced significant reductions of TPH cell counts in the DRN (39%), MRN (38%) and RMN (41%), with no significant differences in the CLN. These results indicate that SERT inhibition can alter the regulation of TPH, the rate limiting enzyme for serotonin biosynthesis. This persistent and regionally specific downregulation of serotonin biosynthesis may account for some of the clinical withdrawal symptoms associated with drugs that inhibit SERT.

Discrete versus infinite molecular self-assembly: control in crystalline hydrogen-bonded assemblies based on resorcinol.

Cocrystallization of 1,2-bis(4-pyridyl)ethane (4,4'-bipyeth) with resorcinol (res), 4-chlororesorcinol (4-Cl-res), and 4,6-dichlororesorcinol (4,6-di-Cl-res) yields molecular solids (4,4'-bipyeth).(res) 1a, 2(4,4'-bipyeth).2(4-Cl-res) 1b, and 2(4,4'-bipyeth).2(4,6-di-Cl-res) 1c with components held together by O-H...N hydrogen bonds. In 1a the components form an infinite 1D polar array, whereas in 1b and 1c the components form 0D four-component complexes. Formation of the discrete assemblies is attributed to peripheral steric effects, which block the solid-state polymerization. [reaction: see text]

Coplanar recognition by a Rebek cleft is provided by cooperative structural effects involving a combination of O-H...O, O-H...N, and C-H...O forces.

Reaction of 2,7-di-tert-butyl-9,9-dimethyl-4,5-xanthenedicarboxylic acid (1), a Rebek cleft, with 1,2-trans-bis(2-pyridyl)ethylene (2) yields a three-component organic assembly, 2(1).2 (3), of nanoscale dimensions that is held together by 10 cooperative O-H.N, O-H.O, and C-H.O hydrogen bonds. The cleft adopts a planar conformation, by forming an intramolecular O-H.O hydrogen bond, which enables the host to recognize the guest in a coplanar orientation that facilitates the cooperativity displayed by the multiple forces.

Exploiting modularity in template-controlled synthesis: a new linear template to direct reactivity within discrete hydrogen-bonded molecular assemblies in the solid state.

Co-crystallization of 1,8-naphthalenedicarboxylic acid (1,8-nap) with trans-1,2-bis(n-pyridyl)ethylene (n,n'-bpe) (n = 2 or 4) yields a discrete four-component molecular assembly, 2(n,n'-bpe).2(1,8-nap) 1, that is held together by four O-H...N hydrogen bonds where the dicarboxylic acid, serving as a linear template, directs alignment of olefins in the solid state for [2 + 2] photoreaction.

Structural classification and general principles for the design of spherical molecular hosts.

Cryptands, carcerands, polyoxometalates, and molecular capsules are cagelike hosts that complex guests through encapsulation. Following the discovery of a nanometer scale supramolecular shell-like spheroid, these and other shell-like hosts were structurally classified. Their frameworks may be catalogued according to principles of solid geometry. This has led to the identification of hosts that have not yet been synthesized or discovered (such as the cuboctahedron shown; X=O, S) and should lead to the design of additional container assemblies.

1-(p-carbamoylphenyl)-3,3-dimethyl-triazene, an antitumour agent.

In the crystal structure of the title compound, 4-(3,3-dimethyl-1-triazeno)benzamide, C9H12N4O, (2), the N = N double bond [1.282 (8) A] is 0.030 A shorter than the N--N single bond [1.312 (8) A], but both bonds are shorter than an isolated N--N single bond suggesting that there is double-bond character in each N--N bond, although it is unequally distributed. The molecule adopts a trans geometry around the N = N bond, but there is a significant deviation from planarity between the benzene ring and the plane of the triazene moiety. Compound (2) forms chains in the solid state in which the molecules are linked by C = O...H--N hydrogen bonds between carbamoyl groups. These chains are cross-linked into sheets by hydrogen bonding between the second N--H moiety and triazene units in adjacent chains.