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 amongst 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. 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 were undetected in preclinical trials with dose 2.5-8 times higher than human therapeutic doses. These data indicate that OPAs detect phenotypic adversity and provide unique information that could useful towards safety testing during pharmaceutical development.

Sexual selection constrains the body mass of male but not female mice

“…Subsections have food and water provided ad libitum associated with nest‐boxes in either “optimal” territories (with enclosed nest‐boxes) or “suboptimal” territories (with exposed boxes). Photographs and diagrams of enclosures may be found in the initial studies (Gaukler et al., 2015, 2016; Meagher et al., 2000). Offspring born within S1 populations were removed at ~6.4 weeks of age, while in S2 and S3 all offspring were collected at eight weeks into the study and then again at five‐week intervals; after removal, offspring were euthanized and tissues were harvested.…”

“…Gels were imaged on a FluorImager. Additional details on parentage analysis, including loci used, can be found in original reports (Carroll et al., 2004; Gaukler et al., 2015, 2016). …”

Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice

“…Mouse fitness is largely based upon intraspecific competition and can be measured directly in terms of reproductive success or indirectly through key fitness components such as survival and competitive ability. OPAs have previously been used to detect and quantify fitness costs of both cousin-and sibling-level inbreeding, the cost of bearing a selfish genetic element (t complex), and health consequences of added sugar consumption and pharmaceutical exposure (Meagher et al 2000;Carroll et al 2004;Ilmonen et al 2008;Ruff et al 2013Ruff et al , 2015Gaukler et al 2015). In all cases, OPAs revealed major fitness deficiencies that analyses with conventional, laboratory-based methods failed to detect.…”

“…Subsections have food and water sources provided ad libitum that are associated with a set of nest boxes in either one of the four "optimal" territories (with enclosed nest boxes) or two "suboptimal" territories (with exposed nest boxes). Photographs of OPA enclosures and detailed descriptions may be found elsewhere (Ruff et al 2013Gaukler et al 2015). OPAs are designed to promote natural mouse mating behavior wherein males compete for territories, a limited resource, which attracts high-quality females; these competitive interactions structure the base unit of house mouse biology-demes (for reviews see Sage 1981; Berdoy and Drickamer 2007).…”

Paroxetine exposure skews litter sex ratios in mice suggesting a Trivers–Willard process

“…To briefly summarize the published experiment (Gaukler et al 2015), paroxetine-exposed breeders (P 0 ) experienced delayed reproduction and F 1 offspring weighed less than their control counterparts. Paroxetine-exposed offspring (F 1 ) were then released into seminatural enclosures where they competed against control animals for mates, resources, and territories over a 28-week period, which represents approximately half of the estimated maximal lifespan for mice in wild populations (Sage 1981).…”