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

ABSTRACT: While conducting a toxicity assessment of the antidepressant paroxetine (Paxil®), in wild-derived mice (Mus musculus), we observed that exposed dams (P0) produced female biased litters (32:68 M:F). Though numerous experimental manipulations have induced sex ratio bias in mice, none have assessed the fitness of the offspring from these litters relative to controls. Here, we retrospectively analyze experimentally derived fitness data gathered for the purpose of toxicological assessment in light of 2 leading hypothesis (Trivers-Willard hypothesis [TWH] and cost of reproduction hypothesis [CRH]), seeking to test if this facultative sex ratio adjustment fits into an adaptive framework. Control F1 males were heavier than F1 females, but no differences in mass were detected between exposed F1 males and females, suggesting that exposed dams did not save energy by producing fewer males, despite producing 29.2% lighter litters relative to controls. F1 offspring of both treatments were released into seminatural enclosures where fitness was quantified. In enclosures, the relative reproductive success of F1-exposed males (compared with controls) was reduced by ~20% compared with the relative reproductive success of F1-exposed females. Thus, exposed dams increased their fitness by adjusting litters toward females who were less negatively affected by the exposure than males. Collectively, these data provide less support that the observed sex ratio bias results in energetic savings (CRH), and more support for the TWH because fitness was increased by biasing litters toward female offspring. These mammalian data are unique in their ability to support the TWH through the use of relevant fitness data.

SUBMITTER: Gaukler SM

PROVIDER: S-EPMC4943110 | biostudies-literature | 2016 Jul-Aug

REPOSITORIES: biostudies-literature

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

Gaukler Shannon Marie SM Ruff James Steven JS Potts Wayne K WK

Behavioral ecology : official journal of the International Society for Behavioral Ecology 20160227 4

While conducting a toxicity assessment of the antidepressant paroxetine (Paxil®), in wild-derived mice (<i>Mus musculus</i>), we observed that exposed dams (P<sub>0</sub>) produced female biased litters (32:68 M:F). Though numerous experimental manipulations have induced sex ratio bias in mice, none have assessed the fitness of the offspring from these litters relative to controls. Here, we retrospectively analyze experimentally derived fitness data gathered for the purpose of toxicological asse ...[more]

PMID: 27418753

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Project description:The Trivers-Willard hypothesis (TWH) states that parents in good condition tend to bias their offspring sex ratio toward the sex with a higher variation in reproductive value, whereas parents in bad condition favor the opposite sex. Although the TWH has been generalized to predict various Trivers-Willard effects (TWE) depending on the life cycle of a species, existing work does not sufficiently acknowledge that sex-specific reproductive values depend on the relative abundances of males and females in the population. If parents adjust their offspring sex ratio according to the TWE, offspring reproductive values will also change. This should affect the long-term evolutionary dynamics and might lead to considerable deviations from the original predictions. In this paper, I model the full evolutionary dynamics of the TWE, using a published two-sex integral projection model for the Columbian ground squirrel (Urocitellus columbianus). Offspring sex ratio is treated as a nonparametric continuous function of maternal condition. Evolutionary change is treated as the successive invasion of mutant strategies. The simulation is performed with varying starting conditions until an evolutionarily stable strategy (ESS) is reached. The results show that the magnitude of the evolving TWE can be far greater than previously predicted. Furthermore, evolutionary dynamics show considerable nonlinearities before settling at an ESS. The nonlinear effects depend on the starting conditions and indicate that evolutionary change is fastest when starting at an extremely biased sex ratio and that evolutionary change is weaker for parents of high condition. The results show neither a tendency to maximize average population fitness nor to minimize the deviation between offspring sex ratio and offspring reproductive value ratio. The study highlights the importance of dynamic feedback in models of natural selection and provides a new methodological framework for analyzing the evolution of continuous strategies in structured populations.

Project description:Study questionIs there a negative relationship, as predicted in the Trivers-Willard hypothesis (TWH), between the intensity of maternal stress and sex ratio at birth (SRB)?Summary answerUsing a comprehensive data set with multiple indicators of maternal stress, most measures of stress show no statistically significant association with SRB over a period spanning 243 years, indicating no support for the TWH.What is known alreadyEvolutionary biologists have proposed a widely discussed hypothesis that women in poor and stressful conditions during pregnancy are more likely to give birth to girls, and exposure to stressful events may therefore lead to a reduction in sex (male-to-female) ratio at birth. The empirical evidence so far is mixed.Study design, size, durationAnnual time series data, spanning 243 years between 1749 and 1991 for Sweden at the national level, were drawn from multiple sources. The outcome is defined as the percentage of male births relative to all births in Sweden in a given year. The covariates include a set of economic and climatic variables as proxies for maternal stress.Participants/materials, setting, methodsWe conduct a series of ARIMA (autoregressive integrated moving average) models to examine the relationship between maternal stress and SRB during three periods: 1749-1991, 1749-1861 and 1862-1991.Main results and the role of chanceIn 1749-1991, economic proxies for maternal stress showed no statistically significant association with SRB. In 1749-1861, two indicators were significantly associated with SRB, but the coefficients were opposite in direction to the TWH. In 1862-1991, five out of six covariates showed no significant association with SRB. An additional analysis found no significant correlation between sex ratio of stillbirths and all covariates in 1862-1991. Our results are incompatible with the TWH and suggest that previous findings in support of the TWH are not robust.Limitations, reasons for cautionThis study provides population-level evidence that may not necessarily reflect the nature of all individuals due to the ecological fallacy. The time series analysed in this study are annual data, and we cannot examine the potential seasonality due to the lack of disaggregated monthly data. Our findings may not be generalised to the contexts of extreme maternal stress conditions such as famine and war.Wider implications of the findingsThe results from existing studies in this topic may be speculative, and additional research with more comprehensive design, data and covariates is needed to reconsider the robustness of previous findings.Study funding/competing interest(s)The author receives no external funding and has no conflict of interest to declare.Trial registration numberN/A.

Project description:Background and objectivesThe thrifty phenotype hypothesis proposes that at resource limitation, the growth of some organs/tissues is selectively spared to preserve more critical ones, such as the brain or lungs. The Trivers-Willard hypothesis (TWH) predicts that boys are more vulnerable in the case of resource limitation than girls. Both hypotheses were tested in children from disrupted families, differing in the extent of deprivation/adversities imposed on them.MethodologyIn a retrospective cohort study in the mid-20th century Estonia (Juhan Aul's database), different types of orphans and children of divorced parents (treatment groups; n = 106-1401) were compared with children from bi-parental families (control groups; n = 2548-8648) so that children from treatment groups were matched with control children on the basis of sex, age, year of birth, urban versus rural origin and socioeconomic position.ResultsChildren in orphanages suffered strong growth suppression, best explained by psychosocial deprivation. Their feet were on average 0.5 SD shorter than the feet of the controls, followed by height, leg/torso ratio and cranial volume that differed from controls by ca 0.4 SD. Weight difference was 0.2 SD units, while body mass index did not differ from controls. The growth of boys and girls in orphanages was suppressed to the same extent. Boys whose mothers were dead were relatively smaller and less masculine than girls from such families. Fathers' absence was unrelated to growth suppression. Sons of divorced parents had broader shoulders than boys whose fathers were dead.Conclusions and implicationsPrediction of TWH about the greater vulnerability of male growth may hold under some conditions but not universally. Predictions of the thrifty phenotype hypothesis were partly supported: trunk growth was spared at the expense of leg growth; however, no evidence for brain sparing was found. Comparison of children of divorced versus dead fathers may appear useful for indirect assessment of sexual selection on offspring quality.Lay Summary: Boys and girls in orphanages suffered similarly strong growth suppression, best explained by psychosocial deprivation. Boys whose mothers were dead were relatively smaller and less masculine than girls from such families. The occurrence of sex-specific associations between family structure and children's growth depends on the type of family disruption.

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

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

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