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The transgenerational effects of oocyte mitochondrial supplementation.

ABSTRACT: Many women suffer from either failed fertilisation or their embryos arrest early during development. Autologous mitochondrial supplementation has been proposed as an assisted reproductive technology to overcome these problems. However, its safety remains to be tested in an animal model to determine if there are transgenerational effects. We have supplemented oocytes with autologous populations of mitochondria to generate founders. We mated the female founders and their offspring to produce three generations. We assessed litter size, the ovarian reserve, and weight gain and conducted a full histopathological analysis from each of the three generations. Across the generations, we observed significant increases in litter size and in the number of primordial follicles in the ovary matched by changes in global gene expression patterns for these early-stage oocytes. However, full histopathological analysis revealed that cardiac structure was compromised in first and second generation offspring, which could seriously affect the health of the offspring. Furthermore, the offspring were prone to increased weight gain during early life. Mitochondrial supplementation appears to perturb the regulation of the chromosomal genome resulting in transgenerational phenotypic gains and losses. These data highlight the need for caution when using autologous mitochondrial supplementation to treat female factor infertility.

SUBMITTER: St John JC

PROVIDER: S-EPMC6491721 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The transgenerational effects of oocyte mitochondrial supplementation.

St John Justin C JC Makanji Yogeshwar Y Johnson Jacqueline L JL Tsai Te-Sha TS Lagondar Simone S Rodda Fleur F Sun Xin X Pangestu Mulyoto M Chen Penny P Temple-Smith Peter P

Scientific reports 20190430 1

Many women suffer from either failed fertilisation or their embryos arrest early during development. Autologous mitochondrial supplementation has been proposed as an assisted reproductive technology to overcome these problems. However, its safety remains to be tested in an animal model to determine if there are transgenerational effects. We have supplemented oocytes with autologous populations of mitochondria to generate founders. We mated the female founders and their offspring to produce three ...[more]

PMID: 31040316

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Project description:BackgroundDietary fiber (DF) is often eschewed in swine diet due to its anti-nutritional effects, but DF is attracting growing attention for its reproductive benefits. The objective of this study was to investigate the effects of DF intake level on oocyte maturation and uterine development, to determine the optimal DF intake for gilts, and gain microbial and metabolomic insight into the underlying mechanisms involved.MethodsSeventy-six Landrace × Yorkshire (LY) crossbred replacement gilts of similar age (92.6 ± 0.6 d; mean ± standard deviation [SD]) and body weight (BW, 33.8 ± 3.9 kg; mean ± SD) were randomly allocated to 4 dietary treatment groups (n = 19); a basal diet without extra DF intake (DF 1.0), and 3 dietary groups ingesting an extra 50% (DF 1.5), 75% (DF 1.75), and 100% (DF 2.0) dietary fiber mixture consisting of inulin and cellulose (1:4). Oocyte maturation and uterine development were assessed on 19 d of the 2nd oestrous cycle. Microbial diversity of faecal samples was analysed by high-throughput pyrosequencing (16S rRNA) and blood samples were subjected to untargeted metabolomics.ResultsThe rates of oocytes showing first polar bodies after in vitro maturation for 44 h and uterine development increased linearly with increasing DF intake; DF 1.75 gilts had a 19.8% faster oocyte maturation rate and a 48.9 cm longer uterus than DF 1.0 gilts (P < 0.05). Among the top 10 microbiota components at the phylum level, 8 increased linearly with increasing DF level, and the relative abundance of 30 of 53 microbiota components at the genus level (> 0.1%) increased linearly or quadratically with increasing DF intake. Untargeted metabolic analysis revealed significant changes in serum metabolites that were closely associated with microbiota, including serotonin, a gut-derived signal that stimulates oocyte maturation.ConclusionsThe findings provide evidence of the benefits of increased DF intake by supplementing inulin and cellulose on oocyte maturation and uterine development in gilts, and new microbial and metabolomic insight into the mechanisms mediating the effects of DF on reproductive performance of replacement gilts.

Project description:Mating often bears large costs to females, especially in species with high levels of sexual conflict over mating rates. Given the direct costs to females associated with multiple mating, which include reductions in lifespan and lifetime reproductive success, past research focused on identifying potential indirect benefits (through increases in offspring fitness) that females may accrue. Far less attention has, however, been devoted to understanding how costs of sexual interactions to females may extend across generations. Hence, little is known about the transgenerational implications of variation in mating rates, or the net consequences of maternal sexual activities across generations. Using the seed beetle, Callosobruchus maculatus, a model system for the study of sexual conflict, we investigate the effects of mating with multiple males versus a single male, and tease apart effects due to sexual harassment and those due to mating per se, over three generations. A multigenerational analysis indicated that females that were exposed to ongoing sexual harassment and who also were permitted to mate with multiple males showed no difference in net fitness compared to females that mated just once without ongoing harassment. Intriguingly, however, females that were continually harassed, but permitted to mate just once, suffered a severe decline in net fitness compared to females that were singly (not harassed) or multiply mated (harassed, but potentially gaining benefits via mating with multiple males). Overall, the enhanced fitness in multiply mated compared to harassed females may indicate that multiple mating confers transgenerational benefits. These benefits may counteract, but do not exceed (i.e., we found no difference between singly and multiply mated females), the large transgenerational costs of harassment. Our study highlights the importance of examining transgenerational effects from an inclusive (looking at both indirect benefits but also costs) perspective, and the need to investigate transgenerational effects across several generations if we are to fully understand the consequences of sexual interactions, sexual conflict evolution, and the interplay of sexual conflict and multi-generational costs and benefits.

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The transgenerational effects of oocyte mitochondrial supplementation.

Publications

The transgenerational effects of oocyte mitochondrial supplementation.

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