ABSTRACT
Posttraumatic stress disorder (PTSD) affects 5-10% percent of the US adult population with a higher prevalence among women compared with men. Although it remains unclear how biological sex associates with susceptibility to PTSD, one mechanism may involve a role for estrogen in a gene by environment interaction. We previously demonstrated a sex-dependent association between the pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) and PTSD, where carriers of a C allele at single-nucleotide polymorphism (SNP) rs2267735 within the PAC1 receptor gene (ADCYAP1R1) have increased symptoms of PTSD. This SNP is located within a predicted estrogen response element (ERE), which regulates gene transcription when bound to estradiol (E2) activated estrogen receptor alpha (ERα). In the current study, we examined E2 regulation of ADCYAP1R1 in vitro, in cell culture, and in vivo in mice and humans. We find in mice that fear conditioning and E2 additively increase ADCYAP1R1 expression. In vitro, we show that E2/ERα binds to the ADCYAP1R1 ERE, with less efficient binding to an ERE containing the C allele of rs2267735. In women with low serum E2, the CC genotype associates with lower ADCYAP1R1 expression, which further associates with higher PTSD symptoms. These findings lead to a model in which E2 induces the expression of ADCYAP1R1 through binding of ERα at the ERE as an adaptive response to stress. Inhibition of E2/ERα binding to the ERE containing the rs2267735 risk allele results in reduced expression of ADCYAP1R1, diminishing estrogen regulation as an adaptive stress response and increasing risk for PTSD.
Subject(s)
Estradiol/physiology , Genetic Variation/genetics , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Stress Disorders, Post-Traumatic/genetics , Adult , Alleles , Animals , Brain/metabolism , Cell Line , Conditioning, Classical/physiology , Fear/physiology , Female , Gene Expression/genetics , Genetic Carrier Screening , Genotype , Humans , Mice , Phenotype , Polymorphism, Single Nucleotide/genetics , Sex Factors , Stress Disorders, Post-Traumatic/physiopathologySubject(s)
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Reflex, Startle/genetics , Adolescent , Adult , Adult Survivors of Child Abuse/psychology , Child , Darkness , Depression/genetics , Female , Genotype , Humans , Male , Polymorphism, Single Nucleotide/genetics , Sex Characteristics , Stress Disorders, Post-Traumatic/geneticsABSTRACT
In the nematode worm C. elegans, individuals with mutations in the spe-9 gene produce spermatozoa with wild-type morphology and motility that cannot fertilize oocytes even after contact between gametes. Therefore, disruption of spe-9 function affects either gamete recognition, adhesion, signaling, and/or fusion. The spe-9 gene encodes a sperm transmembrane protein with an extracellular domain that contains ten epidermal growth factor-like repeats. A common feature of proteins that include epidermal growth factor-like motifs is their involvement in extracellular functions such as adhesive and ligand-receptor interactions. Additionally, the overall structure of the predicted SPE-9 protein is similar to that of ligands for the Notch/LIN-12/GLP-1 family of transmembrane receptors. These results suggest that SPE-9 functions in the specialized cell-cell interactions required for fertilization.
Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans/physiology , Fertilization/physiology , Membrane Proteins/biosynthesis , Spermatozoa/physiology , Amino Acid Sequence , Animals , Caenorhabditis elegans/genetics , Cloning, Molecular , Disorders of Sex Development , Epidermal Growth Factor/chemistry , Female , Genes, Helminth , Germ Cells/physiology , Male , Membrane Proteins/chemistry , Membrane Proteins/genetics , Molecular Sequence Data , Ovulation , Polymerase Chain Reaction , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Sperm Motility , Sperm-Ovum Interactions/physiologyABSTRACT
We have obtained comparative data for the intraocular absorption of topically administered clindamycin hydrochloride hydrate and clindamycin phosphate, made feasible with a new gas chromatographic method of analysis. Results indicated that clindamycin phosphate underwent hydrolysis in the eye, liberating the biologically active clindamycin. However, topical clindamycin hydrochloride produced higher levels (two to six times more) of the antibiotic than those achievable with the phosphates ester in the uvea, aqueous humor, and cornea, presumably due to clindamycin hydrochloride's higher lipid solubility. Based on this data, clindamycin hydrochloride appears to be the preferred form of the antibiotic for topical ocular applications.
Subject(s)
Clindamycin/administration & dosage , Eye/metabolism , Administration, Topical , Animals , Aqueous Humor/analysis , Chemical Phenomena , Chemistry , Chromatography, Gas , Clindamycin/metabolism , Cornea/metabolism , Esters , Female , Phosphates/metabolism , RabbitsABSTRACT
Clindamycin is a recently developed, semisynthetic antibiotic whose spectrum of activity suggests a potential for the treatment of common ocular infections. The upake by various ocular tissues and serum in albino rabbits after topical administration of 0.2% clindamycin hydrochloride was studied. Therapeutic levels were achieved in the cornea, aqueous humor, and iris-ciliary body and persisted for two hours. Peak concentration occurred in the cornea within 15 minutes and in the aqueous humor and the iris-ciliary body at 30 minutes. Freezing of the tissue reduced active clindamycin levels in the cornea by a factor of 2 to 2 1/2 of those determined by fresh tissue analysis but had no apparent effect on aqueous humor and iris-ciliary body. There were, however, no detectable levels in the serum or vitreous humor.
