title: Time Course for Onset and Recovery from Effects of a Novel Male Reproductive Toxicant: Implications for Apical Preclinical Study Designs.
abstract: In the pharmaceutic ICH S5(R2) guidelines for reproductive toxicity testing, a premating dose duration of 14 days is considered sufficient for assessment of male fertility for compounds that are not testicular toxicants. A novel α7 subtype of nicotinic acetylcholine receptor (α7nAChR) agonist, originally intended for treatment of Alzheimer's disease, did not cause changes in sperm counts, motility, or testicular histopathology in rat toxicity studies of up to 6 months duration. However, profound decrements in male fertility (reduced pregnancy rates and litter sizes) occurred after 11 weeks of dosing in male rats. In two time-course investigations, dosed male rats were paired with undosed females after 5, 14, and 28 daily doses and again after 2 and 4 weeks off-dose. Effects on male fertility were undetectable after 5 days. After 14 days, there was no effect on pregnancy rate, but preimplantation losses were increased. Effects on both pregnancy rates and preimplantation losses were clearly detectable after 28 days, but were of lesser magnitude than after 11 weeks of dosing. Fertility recovered rapidly after dose cessation. These studies illustrate the sensitivity of a long premating dose period at revealing hazard and determining the magnitude of effect on male fertility for compounds that are intended for chronic administration and do not affect testicular histopathology.
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Alderley Edge, Macclesfield, Cheshire SK10 4TG.
authors.forename: Nicola
authors.initials: N
authors.lastname: Powles-Glover
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Alderley Edge, Macclesfield, Cheshire SK10 4TG.
authors.forename: Terri
authors.initials: T
authors.lastname: Mitchard
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Alderley Edge, Macclesfield, Cheshire SK10 4TG.
authors.forename: Jane
authors.initials: J
authors.lastname: Stewart
mesh_terms: D000177:Acrosome / Q000502:physiology; D000818:Animals; D018679:Cholinergic Agonists / Q000633:toxicity*; D010064:Embryo Implantation / Q000187:drug effects; D023381:Endpoint Determination; D005260:Female; D005298:Fertility / Q000187:drug effects; D008297:Male; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D013997:Time Factors; D018675:Toxicity Tests
chemical_list: D018679:Cholinergic Agonists
keywords: Han Wistar rat; ICH S5(R2); ICH S6(R1); OECD443; male fertility; sperm