title: Male contraception via simultaneous knockout of α1A-adrenoceptors and P2X1-purinoceptors in mice.
abstract: Therapeutic targets for male contraception are associated with numerous problems due to their focus on disrupting spermatogenesis or hormonal mechanisms to produce dysfunctional sperm. Here we describe the dual genetic deletion of α1A-adrenergic G protein-coupled receptors (adrenoceptors) and P2X1-purinoceptor ligand gated ion channels in male mice, thereby blocking sympathetically mediated sperm transport through the vas deferens during the emission phase of ejaculation. This modification produced 100% infertility without effects on sexual behavior or function. Sperm taken from the cauda epididymides of double knockout mice were microscopically normal and motile. Furthermore, double knockout sperm were capable of producing normal offspring following intracytoplasmic sperm injection into wild-type ova and implantation of the fertilized eggs into foster mothers. Blood pressure and baroreflex function was reduced in double knockout mice, but no more than single knockout of α1A-adrenoceptors alone. These results suggest that this autonomic method of male contraception appears free of major physiological and behavioral side effects. In addition, they provide conclusive proof of concept that pharmacological antagonism of the P2X1-purinoceptor and α1A-adrenoceptor provides a safe and effective therapeutic target for a nonhormonal, readily reversible male contraceptive.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Choong
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Short
authors.forename: Betty
authors.initials: B
authors.lastname: Exintaris
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Malone
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Allen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Evans
authors.forename: Sabatino
authors.initials: S
authors.lastname: Ventura
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D017704:Baroreflex; D003267:Contraception; D055785:Gene Knockdown Techniques; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1; D058474:Receptors, Purinergic P2X1; D013081:Sperm Motility / Q000502:physiology; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism*
chemical_list: C547714:Adra1a protein, mouse; D058668:Adrenergic alpha-1 Receptor Antagonists; D058920:Purinergic P2X Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D058474:Receptors, Purinergic P2X1
keywords: ATP; noradrenaline; sympathetic neurotransmission