Catherine Elizabeth Aiken

Transgenerational developmental programming

BACKGROUND The concept of developmental programming suggests that the early life environment influences offspring characteristics in later life, including the propensity to develop diseases such as the metabolic syndrome. There is now growing evidence that the effects of developmental programming may also manifest in further generations without further suboptimal exposure. This review considers the evidence, primarily from rodent models, for effects persisting to subsequent generations, and evaluates the mechanisms by which developmental programming may be transmitted to further generations. In particular, we focus on the potential role of the intrauterine environment in contributing to a developmentally programmed phenotype in subsequent generations. METHODS The literature was systematically searched at http://pubmed.org and http://scholar.google.com to identify published findings regarding transgenerational (F2 and beyond) developmental programming effects in human populations and animal models. RESULTS Transmission of programming effects is often viewed as a form of epigenetic inheritance, either via the maternal or paternal line. Evidence exists for both germline and somatic inheritance of epigenetic modifications which may be responsible for phenotypic changes in further generations. However, there is increasing evidence for the role of both extra-genomic components of the zygote and the interaction of the developing conceptus with the intrauterine environment in propagating programming effects. CONCLUSIONS The contribution of a suboptimal reproductive tract environment or maternal adaptations to pregnancy may be critical to inheritance of programming effects via the maternal line. As the effects of age exacerbate the programmed metabolic phenotype, advancing maternal age may increase the likelihood of developmental programming effects being transmitted to further generations. We suggest that developmental programming effects could be propagated through the maternal line de novo in generations beyond F2 as a consequence of development in a suboptimally developed intrauterine tract and not necessarily though directly transmitted epigenetic mechanisms.

Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart

Low birth weight and accelerated postnatal growth lead to increased risk of cardiovascular disease. We reported previously that rats exposed to a low‐protein diet in utero and postnatal catch‐up growth (recuperated) develop metabolic dysfunction and have reduced life span. Here we explored the hypothesis that cardiac oxidative and nitrosative stress leading to DNA damage and accelerated cellular aging could contribute to these phenotypes. Recuperated animals had a low birth weight (P<0.001) but caught up in weight to controls during lactation. At weaning, recuperated cardiac tissue had increased (P<0.05) protein nitrotyrosination and DNA single‐stranded breaks. This condition was preceded by increased expression of DNA damage repair molecules 8‐oxoguanine‐DNA‐glycosylase‐1, nei‐endonuclease‐VIII‐like, X‐ray‐repair‐complementing‐defective‐repair‐1, and Nthl endonuclease III‐like‐1 on d 3. These differences were maintained on d 22 and became more pronounced in the case of 8‐oxoguanine‐DNA‐glycosylase‐1 and neiendonuclease‐VIII‐like. This was accompanied by increases in xanthine oxidase (P<0.001) and NADPH oxidase (P<0.05), major sources of reactive oxygen species (ROS). The detrimental effects of increased ROS in recuperated offspring may be exaggerated at 22 d by reductions (P<0.001) in the antioxidant enzymes perox‐iredoxin‐3 and CuZn‐superoxide‐dismutase. We conclude that poor fetal nutrition followed by accelerated postnatal growth results in increased cardiac nitrosative and oxidative‐stress and DNA damage, which could contribute to age‐associated disease risk.—TarryAdkins, J. L., Martin‐Gronert, M. S., Fernandez‐Twinn, D. S., Hargreaves, I., Alfaradhi, M. Z., Land, J. M., Aiken, C. E., Ozanne, S. E. Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress and oxidative defense capacity in rat heart. FASEB J. 27, 379–390 (2013). www.fasebj.org

Requests for Abortion in Latin America Related to Concern about Zika Virus Exposure

With the rapid emergence of Zika virus throughout Latin America and its association with microcephaly, requests for access to abortion medications through online telemedicine have increased in countries where access to safe abortion is not universally available.

Variations in mouse mitochondrial DNA copy number from fertilization to birth are associated with oxidative stress.

Mitochondria are inherited maternally via the oocyte, which in the mouse contains 150-250 x 10(3) copies of mitochondrial DNA (mtDNA). The number of mtDNA copies/embryo is thought to be stable during cleavage, being progressively diluted/cell with each round of cell division, until replication begins at an undefined time post-implantation. Post-natally, tissues differ in copy number of mtDNA/cell, but when and how these differences arise is unclear. A ratiometric quantitative real-time polymerase chain reaction assay of the levels of a single mitochondrial gene against a single copy nuclear gene was used to estimate the average copy value of mtDNA/per cell from zygote to birth. A novel Bayesian statistical model was used to identify day 5.15-6.15 as the time at which replication recommences, consistent with the viability patterns of embryos carrying mitochondrial mutations. Mitochondrial DNA copy number/cell in a range of post-day 9.5 fetal and placental tissues showed tissue-specific temporal expression patterns. Western blotting was used to quantify post-day 9.5 tissue markers for oxidative stress and manganese superoxide dismutase, and revealed correlations with the changes in mtDNA copy number. These findings have potential implications for fetal programming, in-vitro embryo culture, and the mechanism underlying the mitochondrial bottleneck.

Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth

Background: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. Objectives: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. Design: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed “recuperated”). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase–polymerase chain reaction. Results: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). Conclusions: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.

Suboptimal nutrition in utero causes DNA damage and accelerated aging of the female reproductive tract

Early life exposure to adverse environments can lead to a variety of metabolic and cardiovascular diseases in offspring. We hypothesize that female reproductive function may also be affected, with subsequent implications for fertility. We used an established maternal low‐protein model where animals are born small but undergo rapid postnatal catch‐up growth by suckling a control‐fed dam (recuperated offspring). Markers of oxidative stress and cellular aging in reproductive tract tissues were assessed at 3 and 6 mo of age. Recuperated offspring had lower birth weight than controls (P<0.01) but caught up during lactation. 4‐Hydroxynonenal (4HNE; an indicator of oxidative stress) was increased in recuperated animals compared with controls in both ovaries and oviducts at 6 mo. At 3 and 6 mo, ovaries and oviducts of recuperated offspring had increased mitochondrial (mt)DNA copy number (P<0.01). By contrast, germ‐line cells showed no difference in mtDNA copy number, suggesting they were protected from suboptimal maternal nutrition. Oviduct and somatic ovarian telomere length declined more rapidly with age in recuperated animals. This accelerated cellular aging was associated with a declined ovarian reserve in developmentally programmed animals. These findings have significant clinical implications in light of worldwide trends to delayed childbearing.—Aiken, C. E., Tarry‐Adkins, J. L., Ozanne, S. E., Suboptimal nutrition in utero causes DNA damage and accelerated aging of the female reproductive tract. FASEB J. 27, 3959–3965 (2013). www.fasebj.org

Transgenerational Developmental Programming of Ovarian Reserve.

Exposure to an adverse early-life environment leads to long-term health problems, many of which are recapitulated in subsequent generations. The female reproductive tract is particularly sensitive to early-life influences, and plays a pivotal role in programming the conceptus. We examine the influence of suboptimal grandmaternal diet on reproductive potential of granddaughters in the absence of any further dietary manipulations in the daughters in a rat low-protein diet model. Exposure to low-protein grand-maternal diet leads to decreased ovarian reserve and increased intra-abdominal fat mass in granddaughters, accompanied by accelerated accumulation of oxidative stress and mtDNA copy number instability in the ovaries. Ovarian telomere length declines more rapidly in the exposed granddaughters, indicating accelerated ageing in the reproductive tract. Thus, we demonstrate that suboptimal grandmaternal diet during pregnancy accelerates reproductive ageing across subsequent generations. These findings have important implications for understanding both individual rates of decline in fertility with age, and the clinical impact of current global trends towards delayed childbearing.

Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, and increased lipid peroxidation in female mouse offspring exposed to an obesogenic maternal diet

Maternal diet during pregnancy influences the later life reproductive potential of female offspring. We investigate the molecular mechanisms underlying the depletion of ovarian follicular reserve in young adult females following exposure to obesogenic diet in early life. Furthermore, we explore the interaction between adverse maternal diet and post‐weaning diet in generating reduced ovarian reserve. Female mice were exposed to either maternal obesogenic (high fat/high sugar) or maternal control diet in utero and during lactation, then weaned onto either obesogenic or control diet. At 12 wk of age, the offspring ovarian reserve was depleted following exposure to maternal obesogenic diet (P < 0.05), but not postweaning obesogenic diet. Maternal obesogenic diet was associated with increased mitochondrial DNA biogenesis (copy number P < 0.05; transcription factor A, mitochondrial expression P < 0.05), increased mitochondrial antioxidant defenses [manganese superoxide dismutase (MnSOD) P < 0.05; copper/zinc superoxide dismutase P < 0.05; glutathione peroxidase 4 P < 0.01] and increased lipoxygenase expression (arachidonate 12‐lipoxygenase P < 0.05; arachidonate 15‐lipoxygenase P < 0.05) in the ovary. There was also significantly increased expression of the transcriptional regulator NF‐kB (P < 0.05). There was no effect of postweaning diet on any measured ovarian parameters. Maternal diet thus plays a central role in determining follicular reserve in adult female offspring. Our observations suggest that lipid peroxidation and mitochondrial biogenesis are the key intracellular pathways involved in programming of ovarian reserve.—Aiken, C. E., Tarry‐Adkins, J. L., Penfold, N. C., Dearden, L., Ozanne, S. E. Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, and increased lipid peroxidation in female mouse offspring exposed to an obesogenic maternal diet. FASEB J. 30, 1548–1556 (2016). www.fasebj.org

Factors influencing the likelihood of instrumental delivery success

OBJECTIVE: To evaluate risk factors for unsuccessful instrumental delivery when variability between individual obstetricians is taken into account. METHODS: We conducted a retrospective cohort study of attempted instrumental deliveries over a 5-year period (2008–2012 inclusive) in a tertiary United Kingdom center. To account for interobstetrician variability, we matched unsuccessful deliveries (case group) with successful deliveries (control group) by the same operators. Multivariate logistic regression was used to compare successful and unsuccessful instrumental deliveries. RESULTS: Three thousand seven hundred ninety-eight instrumental deliveries of vertex-presenting, single, term newborns were attempted, of which 246 were unsuccessful (6.5%). Increased birth weight (odds ratio [OR] 1.11; P<.001), second-stage labor duration (OR 1.01; P<.001), rotational delivery (OR 1.52; P<.05), and use of ventouse compared with forceps (OR 1.33; P<.05) were associated with unsuccessful outcome. When interobstetrician variability was controlled for, instrument selection and decision to rotate were no longer associated with instrumental delivery success. More senior obstetricians had higher rates of unsuccessful deliveries (12% compared with 5%; P<.05) but were used to undertake more complicated cases. Cesarean delivery during the second stage of labor without previous attempt at instrumental delivery was associated with higher birth weight (OR 1.07; P<.001), increased maternal age (OR 1.03; P<.01), and epidural analgesia (OR 1.46; P<.001). CONCLUSION: Results suggest that birth weight and head position are the most important factors in successful instrumental delivery, whereas the influence of instrument selection and rotational delivery appear to be operator-dependent. Risk factors for lack of instrumental delivery success are distinct from risk factors for requiring instrumental delivery, and these should not be conflated in clinical practice. LEVEL OF EVIDENCE: II

Transgenerational effects of maternal diet on metabolic and reproductive ageing

The early-life environment, in particular maternal diet during pregnancy, influences a wide range of organs and systems in adult offspring. Mounting evidence suggests that developmental programming can also influence health and disease in grand-offspring. Transgenerational effects can be defined as those persisting into an F2 generation, where the F0 mother experiences suboptimal diet during her pregnancy. In this review, we critically examine evidence for transgenerational developmental programming effects in human populations, focusing on metabolic and reproductive outcomes. We discuss evidence from historical cohorts suggesting that grandchildren of women exposed to famine and other dietary alterations during pregnancy may experience increased rates of later health complications than their control counterparts. The methodological difficulties with transgenerational studies in human cohorts are explored. In particular, the problems with assessing reproductive outcomes in human populations are discussed. In light of the relative paucity of evidence available from human cohorts, we consider key insights from transgenerational experimental animal models of developmental programming by maternal diet; data are drawn from a range of rodent models, as well as the guinea-pig and the sheep. The evidence for different potential mechanisms of transgenerational inheritance or re-propagation of developmental programming effects is evaluated. Transgenerational effects could be transmitted through methylation of the gametes via the paternal and maternal lineage, as well as other possible mechanisms via the maternal lineage. Finally, future directions for exploring these underlying mechanisms further are proposed, including utilizing large, well-characterized, prospective pregnancy cohorts that include biobanks, which have been established in various populations during the last few decades.