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Sex differences in the intergenerational inheritance of metabolic traits

Abstract

Strong evidence suggests that early-life exposures to suboptimal environmental factors, including those in utero, influence our long-term metabolic health. This has been termed developmental programming. Mounting evidence suggests that the growth and metabolism of male and female fetuses differ. Therefore, sexual dimorphism in response to pre-conception or early-life exposures could contribute to known sex differences in susceptibility to poor metabolic health in adulthood. However, until recently, many studies, especially those in animal models, focused on a single sex, or, often in the case of studies performed during intrauterine development, did not report the sex of the animal at all. In this review, we (a) summarize the evidence that male and females respond differently to a suboptimal pre-conceptional or in utero environment, (b) explore the potential biological mechanisms that underlie these differences and (c) review the consequences of these differences for long-term metabolic health, including that of subsequent generations.

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Fig. 1: Factors that influence the intergenerational inheritance of metabolic traits at each stage of organismal development.
Fig. 2: Sexual dimorphic effects related to sex chromosomes and sex hormones.
Fig. 3: Developmental epigenetic reprogramming leading to sex-related effects on gene expression patterns.
Fig. 4: Sexual dimorphic effects related to mitochondria.
Fig. 5: Sex differences in placental and maternal adaptations to pregnancy.
Fig. 6: Pathways leading to sex differences in the intergenerational inheritance of metabolic disease.

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Acknowledgements

This work was supported by funding from the Medical Research Council (MRC_MC_UU_00014/4 to M.C. and S.E.O.) and the British Heart Foundation (RG/17/12/33167 to S.E.O.). A.H. was supported by a Wellcome Trust studentship (108926/B/15/Z).

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S.E.O. and D.S.F.-T. conceived the outline and wrote the synopsis of the review. S.E.O. and M.C. elaborated the concepts, wrote the introductory and concluding sections, gave feedback on all other sections, and had oversight of this review. A.H. wrote the section on sexual dimorphism vulnerabilities during pre-conception and intrauterine development, including Table 1, and drew Fig. 1. I.S. wrote the section on biological mechanisms leading to sex differences in intergenerational programming of metabolic traits and drew Figs. 26. D.S.F.-T. wrote the section on consequences for long-term and intergenerational inheritance of metabolic traits. All authors read and gave feedback on all sections, and approved the final version of the paper.

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Correspondence to Miguel Constância or Susan E. Ozanne.

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Nature Metabolism thanks Kelle Moley and Michael Golding for their contribution to the peer review of this work.

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Sandovici, I., Fernandez-Twinn, D.S., Hufnagel, A. et al. Sex differences in the intergenerational inheritance of metabolic traits. Nat Metab 4, 507–523 (2022). https://doi.org/10.1038/s42255-022-00570-4

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