title: Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay.
abstract: Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is currently available on the market and is suspected of causing congenital malformations in babies born to mothers who take the drug during the first trimester of pregnancy. We utilized organismal performance assays (OPAs), a novel toxicity assessment method, to assess the safety of paroxetine during pregnancy in a rodent model. OPAs utilize genetically diverse wild mice (Mus musculus) to evaluate competitive performance between experimental and control animals as they compete among each other for limited resources in semi-natural enclosures. Performance measures included reproductive success, male competitive ability and survivorship. Paroxetine-exposed males weighed 13% less, had 44% fewer offspring, dominated 53% fewer territories and experienced a 2.5-fold increased trend in mortality, when compared with controls. Paroxetine-exposed females had 65% fewer offspring early in the study, but rebounded at later time points, presumably, because they were no longer exposed to paroxetine. In cages, paroxetine-exposed breeders took 2.3 times longer to produce their first litter and pups of both sexes experienced reduced weight when compared with controls. Low-dose paroxetine-induced health declines detected in this study that were undetected in preclinical trials with doses 2.5-8 times higher than human therapeutic doses. These data indicate that OPAs detect phenotypic adversity and provide unique information that could be useful towards safety testing during pharmaceutical development.
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA. Electronic address: Shannon.Gaukler@gmail.com.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Gaukler
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Ruff
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Tessa
authors.initials: T
authors.lastname: Galland
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Kirstie A
authors.initials: KA
authors.lastname: Kandaris
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Tristan K
authors.initials: TK
authors.lastname: Underwood
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Liu
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Young
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Morrison
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, USA.
authors.forename: Garold S
authors.initials: GS
authors.lastname: Yost
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Wayne K
authors.initials: WK
authors.lastname: Potts
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects*; D003163:Competitive Behavior / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D017374:Paroxetine / Q000494:pharmacology*; D016016:Proportional Hazards Models; D012098:Reproduction / Q000187:drug effects*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D017374:Paroxetine
keywords: Intraspecific competition; Pharmacodynamics; Reproductive success; SSRI; Semi-natural enclosures; Toxicity assessment