Palomar College Intergenerational Transmission of The Effects of Maternal Exposure to Childhood Maltreatment on Offspring Obesity Risk Summary

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A fetal programming perspective.

  • Read and Summarize [using APA format] the posted Journal Article ‘Intergenerational transmission of the effects of maternal exposure to childhood maltreatment on offspring obesity risk: A fetal programming perspective’  located immediately below the link to this assignment
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  • In lecture we discussed the epigenetics and how it has been shown that mothers who are morbidly obese during pregnancy risk genetically predisposing their offspring to obesity.  The article proposes that ‘maternal conditions and states experienced prior to conception, such as stress, obesity and metabolic dysfunction, may program offspring obesity risk’If you had to guess, what could be the possible long-term impact of this ‘perspective’ onWomen’s ‘fear’ of having childrenSociety’s perception of the seriousness of child maltreatmentThe perception of mother’s whose children are obese Psychoneuroendocrinology 116 (2020) 104659
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    Intergenerational transmission of the effects of maternal exposure to
    childhood maltreatment on offspring obesity risk: A fetal programming
    Karen L. Lindsaya,e, Sonja Entringera,e,f, Claudia Bussa,e,f, Pathik D. Wadhwaa,b,c,d,e,*
    Department of Pediatrics, University of California, Irvine, School of Medicine, CA 92697, USA
    Department of Psychiatry and Human Behavior, University of California, Irvine, School of Medicine, CA 92697, USA
    Department of Obstetrics and Gynecology, University of California, Irvine, School of Medicine, CA 92697, USA
    Department of Epidemiology, University of California, Irvine, School of Medicine, CA 92697, USA
    UCI Development, Health and Disease Research Program, University of California, Irvine, School of Medicine, CA 92697, USA
    Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health (BIH), Institute of Medical Psychology, Germany
    A R T I C LE I N FO
    A B S T R A C T
    Childhood obesity
    Childhood maltreatment
    Intergenerational transmission
    Fetal programming
    Gestational biology
    Childhood obesity constitutes a major global public health challenge. A substantial body of evidence suggests
    that conditions and states experienced by the embryo/fetus in utero can result in structural and functional
    changes in cells, tissues, organ systems and homeostatic set points related to obesity. Furthermore, growing
    evidence suggests that maternal conditions and states experienced prior to conception, such as stress, obesity and
    metabolic dysfunction, may spill over into pregnancy and influence those key aspects of gestational biology that
    program offspring obesity risk. In this narrative review, we advance a novel hypothesis and life-span framework
    to propose that maternal exposure to childhood maltreatment may constitute an important and as-yet-underappreciated risk factor implicated in developmental programming of offspring obesity risk via the long-term
    psychological, biological and behavioral sequelae of childhood maltreatment exposure. In this context, our
    framework considers the key role of maternal-placental-fetal endocrine, immune and metabolic pathways and
    also other processes including epigenetics, oocyte mitochondrial biology, and the maternal and infant microbiomes. Finally, our paper discusses future research directions required to elucidate the nature and mechanisms
    of the intergenerational transmission of the effects of maternal childhood maltreatment on offspring obesity risk.
    1. Introduction
    Childhood obesity represents a major, global public health challenge. Its etiology is multi-factorial, and currently identified risk factors
    account for only a moderate proportion of its prevalence (Robinson
    et al., 2017; van der Klaauw and Farooqi, 2015; Willyard, 2014). Furthermore, once established, obesity is extremely difficult to reverse
    (Schwartz et al., 2017), underscoring the critical importance of primary
    prevention (Ghoorah et al., 2014). Thus, the elucidation of additional
    risk factors remains a key priority. In this perspectives paper, we advance the concept that an additional determinant of an individual’s risk
    for childhood obesity may arise from her or his mother’s physiological
    and emotional states prior to conception. Specifically, we hypothesize
    that maternal exposure to maltreatment during the period of her own
    childhood may constitute an important and novel risk factor for
    increased susceptibility in her offspring for the development of obesity
    and metabolic dysfunction.
    The extent of an individual’s exposure to obesogenic factors clearly
    is an important determinant of her or his likelihood of developing
    obesity. However, it also is evident that individuals vary widely in
    terms of the effects of obesogenic exposures on obesity risk (i.e., exhibit
    considerable variation in their susceptibility) (Albuquerque et al.,
    2017). Thus, primary prevention of obesity necessitates not only addressing the obesogenic exposure part of the equation, but also and
    critically importantly a better understanding of the determinants of
    individual differences in susceptibility to the effects of obesogenic factors
    (Bluher, 2019).
    In this regard, growing evidence suggests developmental processes
    during intrauterine life play a key role in determining susceptibility to
    childhood obesity (i.e., the concept of fetal programming) (Entringer

    Corresponding author at: UC Irvine Development, Health and Disease Research Program, University of California, Irvine, School of Medicine, 3117 Gillespie,
    Neuroscience Research Facility (GNRF), 837 Health Sciences Road, Irvine, CA 92697, USA.
    E-mail address: (P.D. Wadhwa).
    Received 14 October 2019; Received in revised form 12 March 2020; Accepted 19 March 2020
    0306-4530/ © 2020 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 116 (2020) 104659
    K.L. Lindsay, et al.
    obesogenic factors.
    What, then, determines individual differences in susceptibility? The
    conventional paradigm proposes that an individual’s genetic makeup
    (reflected in DNA sequence variation) is the primary determinant of her
    or his susceptibility. However, based on findings from genome wide
    association and other studies, it is increasingly apparent that genetic
    makeup alone (i.e., independently) accounts for only a modest proportion of the observed variance in obesity risk (Robinson et al., 2017;
    Sluyter et al., 2013; van der Klaauw and Farooqi, 2015; Willyard,
    2014). Even among carriers of genetic loci most strongly associated
    with obesity risk (e.g., polymorphisms of the FTO gene (Albuquerque
    et al., 2013; Deliard et al., 2013; Leon-Mimila et al., 2013)), it appears
    that factors such as early developmental processes may moderate this
    susceptibility. For example, among carriers of the FTO risk alleles, infants with a lower body mass index (BMI) are at increased risk of developing childhood obesity (Sovio et al., 2011). Thus, it is the phenotypic specification of the initial settings or set-points of central and
    peripheral systems implicated in energy balance homeostasis that appears
    to play a major role in determining susceptibility for future obesity
    (adiposity) risk (Schwartz et al., 2017). We note that the U.S. Endocrine
    Society recently published a scientific position statement arguing that
    based on the convergence of evidence, obesity should now be conceptualized as a disorder of the energy homeostasis system, rather than
    simply arising from the accumulation of excess weight. Moreover, they
    emphasized the need to elucidate underlying mechanisms, with a major
    focus on developmental influences (Schwartz et al., 2017).
    et al., 2015; Friedman, 2018). Furthermore, over and beyond effects of
    events during pregnancy, the importance of maternal preconceptional
    conditions is becoming increasingly evident (Haire-Joshu and Tabak,
    2016), as some of their long-term effects carry forward and spill over
    into pregnancy to impact key gestational biology-related endocrine,
    immune and metabolic processes implicated in fetal programming of
    childhood obesity risk. In light of these considerations, we submit that
    maternal exposure to childhood maltreatment (CM) may constitute a
    novel, important, and as-yet-underappreciated and understudied condition of interest. We have previously published a perspective paper
    that describes our conceptual formulation by which maternal CM exposure may contribute to fetal programming of offspring brain development (Buss et al., 2017). While the current paper shares many
    commonalities and arguments within the context of the broader framework of CT exposure and fetal programming, we focus here on the
    different and equally important outcome of offspring obesity risk.
    This perspectives paper begins with an overview of the problem of
    childhood obesity and the evidence for preconception and prenatal
    exposures and conditions that may influence susceptibility to development of obesity via the process of fetal programming of health and
    disease risk. Next, we address the issue of childhood maltreatment, with
    a brief overview of its prevalence and long-term health consequences.
    We then summarize findings that suggest the long-term effects of CM
    may not be restricted to the life span of the exposed individual alone,
    but also may be transmitted across generations to influence the development and health of their offspring, including offspring obesity risk.
    We then present our conceptual framework to describe the three key
    elements which may plausibly explain an intergenerational transmission of the effects of maternal CM on childhood obesity risk; i) spillover
    of the adverse behavioral, psychological and physiological sequelae of
    maternal CM from the preconceptional to prenatal life stage; ii) the
    impact of these sequelae on various gestational biological pathways
    that may program the developing fetus for an increased susceptibility
    towards obesity in childhood; iii) the potential interaction of prenatal
    and postnatal states and conditions related to maternal CM exposure,
    which could further explain the risk for obesity development in the
    child. We also present recommendations for future directions to advance this field of research and lastly, highlight the public health significance of this framework.
    2.2. Role of developmental processes
    A growing and converging body of epidemiological, clinical and
    experimental evidence in humans and animals now supports the concept that phenotypic specification of complex traits (such as the initial
    setting of the energy balance homeostasis system) is an emergent property of developmental processes in early life, particularly during the
    intrauterine period (i.e., the process of fetal programming of health and
    disease risk) (Langley-Evans, 2006; Padmanabhan et al., 2016). In this
    regard, it also is evident, firstly, that the proximate mechanism by which
    gestational conditions impact phenotypic specification is ultimately
    biological in nature (Catalano and Shankar, 2017); secondly, that stressrelated maternal-placental-fetal endocrine, immune/ inflammatory,
    oxidative and metabolic pathways may play a particularly prominent
    role in this process (Entringer et al., 2015); and thirdly, that a constellation of upstream maternal biophysical, behavioral, psychological
    and clinical states exert a major influence on gestational biology
    (Keenan et al., 2018; Stephenson et al., 2018). Thus, primary prevention (of the establishment of increased susceptibility for obesity) implies not only the identification of relevant modifiable risk factors, but
    also and importantly, the critical time period(s) for intervention.
    With the exception of new and controversial germline gene-editing
    approaches (Ormond et al., 2017), the prenatal period may represent
    one of the earliest possible windows for deploying primary prevention
    strategies to target potentially modifiable risk factors that influence
    gestational biology, in order to influence the individual’s susceptibility
    for developing obesity. Furthermore, developmental trajectory models
    suggest that complex phenotypes emerge through a series of interactions or conditional probabilities. That is, the likelihood of acquiring
    any given phenotype is shaped by events and environments at earlier,
    critical stages of development (Barker, 2002). For example, the effects
    of genes on fetal growth and birth outcomes are conditioned by the
    intrauterine and fetal environment; the effects of birth outcomes on
    infant growth and health status are conditioned by events and environments during the early infancy period, and so forth.
    2. The problem of childhood obesity
    Obesity represents one of the most urgent national and global health
    challenges because of its high prevalence and adverse health, economic
    and societal consequences (Kelly et al., 2013; McPherson, 2014;
    Schwartz et al., 2017). Childhood obesity is a particularly grave concern because children with obesity are substantially more likely to be
    affected by obesity in adulthood (Serdula et al., 1993; Whitaker et al.,
    1997) and to develop obesity-related disorders at younger ages
    (Dabelea and Harrod, 2013; Freedman et al., 2001) and of greater severity (Dietz, 1998; Fagot-Campagna et al., 2001; Freedman et al.,
    2007). The ramifications are alarming: Owing to the increase in obesity,
    life expectancy in developed countries is projected to decrease for the
    first time in recent history (Olshansky et al., 2005).
    2.1. Susceptibility
    The extent of any given individual’s exposure to obesogenic factors
    clearly is an important determinant of her or his likelihood of developing obesity. However, it also is evident that individuals vary widely
    in terms of the magnitude of effects of obesogenic exposures on obesity
    risk. In other words, they exhibit differences in their susceptibility for
    developing obesity (Albuquerque et al., 2017). Thus, primary prevention of obesity may necessitate not only addressing the obesogenic
    exposure part of the equation, but also and critically importantly, the
    determinants of individual differences in susceptibility to the effects of
    2.3. Role of maternal preconceptional state
    It is clear that maternal exposures and experiences during
    Psychoneuroendocrinology 116 (2020) 104659
    K.L. Lindsay, et al.
    spectrum disorder (Collishaw et al., 2007; Plant et al., 2013; Roberts
    et al., 2013), and obesity (Leonard et al., 2017; Roberts et al., 2014).
    The time windows, mechanisms and pathways are not well understood,
    and their elucidation is an area of considerable scientific and public
    health interest and importance.
    In this context, the prevailing paradigm posits that the child’s brain
    represents the primary outcome of interest (Buss et al., 2017; Everaerd
    et al., 2015; McLaughlin et al., 2014). However, we submit that another
    child outcome of at least equal importance and public health significance may also be implicated – that of childhood obesity risk. Direct
    evidence comes from two recent large cohort studies. In a study of
    16,774 mother-child dyads, Roberts et al. reported an approximately 50
    % increased incidence of obesity among children (aged 9–14 yrs) of
    CM-exposed mothers, with the most pronounced effect in children
    whose mothers were most severely abused (Roberts et al., 2014). Also,
    in another study of 6718 mother-child dyads, Leonard et al. reported a
    21 % increased risk of obesity among children (aged 2–5 yrs) whose
    mothers were physically abused in childhood (Leonard et al., 2017).
    Indirect evidence comes from the convergence of a large body of epidemiological, clinical and experimental findings in humans and animals
    that suggest all the above-described maternal states that, on one hand,
    constitute the adverse sequelae of CM exposure, also are, on the other
    hand, associated with increased risk of obesity in their offspring (Midei
    et al., 2010, 2013; Rikknen et al., 2002; Tamayo et al., 2010).
    pregnancy can potentially impact embryonic/fetal development, in
    part, via their effects on gestational biology. But what of exposures and
    experiences that may have occurred earlier, prior to conception? Could
    some of these, when a woman becomes pregnant, also impact gestational biology (which in turn may affect offspring phenotypes such as
    energy balance homeostasis set points and risk for obesity and metabolic dysfunction)? Growing evidence suggests that certain maternal
    pre-conceptional states and conditions do exert a substantial influence
    on gestational biology (Lewis et al., 2015; Moussa et al., 2016) and fetal
    development. Indeed, there is increasing recognition that the time
    window for potential intervention on the process of fetal programming
    of obesity risk and associated comorbidities should be extended to the
    maternal pre-conception period (Haire-Joshu and Tabak, 2016;
    Mumford et al., 2014).
    With respect to maternal pre-conceptional factors that may promote
    fetal programming of obesity risk, high maternal BMI and associated
    comorbid states (e.g. diabetes, metabolic syndrome) and unhealthy
    lifestyle behaviors (e.g. poor diet and sedentariness) have received
    considerable attention to date (Drake and Reynolds, 2010; Lane et al.,
    2015). However, other exposures over a woman’s life course, and
    particularly exposure to adversity during the early life period, may also
    exert long term effects on physiology and health. Upon becoming
    pregnant, these long-term effects may spill-over into the gestational
    period to influence aspects of maternal-placental-fetal biology that are
    implicated in the process of fetal programming of obesity risk.
    4. Conceptual framework: intergenerational transmission of the
    effects of maternal exposure to CM on offspring obesity risk
    3. The problem of childhood maltreatment exposure
    3.1. Prevalence and long-term health consequences of CM exposure
    We articulate here a trans-disciplinary, lifespan framework for the
    intergenerational, mother-to-child transmission of the effects of maternal exposure to CM on offspring obesity risk. This framework is
    based on principles from evolutionary and developmental biology, and
    it integrates the concepts of biological embedding of life experiences and
    fetal origins of health and disease risk (see Fig. 1). Its major elements are
    as follow: 1) When women who had been exposed to maltreatment in
    their childhood become pregnant, many or all of the long-term biological, biophysical, behavioral and psychological sequelae of CM exposure (e.g., endocrine, immune and metabolic dysfunction, obesity,
    unhealthy diet (over- or under nutrition), substance abuse, depression,
    stress hyper-responsiveness) may carry forward and spill over into their
    gestational state (Barrios et al., 2015; Hollingsworth et al., 2012; Moog
    et al., 2012; Nagl et al., 2015; Slopen et al., 2015). 2) Next, through the
    process of fetal programming, the CM experience of one generation
    (mother) may influence the health of the subsequent generation (child),
    thereby creating an intergenerational cycle. Intergenerational transmission in utero is largely determined by the degree to which the developing placental-fetal unit receives and transduces biological signals
    indicative of maternal state (in this case, of maternal CM-related alterations in her systemic physiology), and by the extent to which such
    signals participate in offspring phenotypic specification. Additional
    pathways of inter-generational transmission of maternal CM’s sequelae
    may include effects of CM exposure on germ line epigenetic characteristics, oocyte cytoplasm/follicular fluid biology, and infant microbiome acquisition. 3) Our model recognizes that the prenatal and
    postnatal effects of maternal CM sequelae on childhood obesity risk
    may not be mutually exclusive, and thus, also considers the mediating
    or moderating effects of CM-related postnatal factors such as breast
    feeding and the quality of mother-child attachment. However, we
    submit it is important to ascertain whether such intergenerational effects start in utero, as elucidation of the earliest transmission windows
    and mechanisms is necessary to develop efficacious strategies for primary prevention. The plausibility of each component of our model is
    supported by empirical evidence in not only the general population
    (Entringer et al., 2012a; Godfrey and Barker, 2001; Wadhwa, 2005;
    Wadhwa et al., 2011), but also more specifically by findings among
    offspring of CM exposed women (Leonard et al., 2017; Roberts et al.,
    The detrimental effects of stress exposure on health and disease risk
    are well established. They are particularly pronounced when stress
    occurs during critical developmental periods (Heim and Binder, 2012).
    Although stress is a ubiquitous feature of modern life, certain stressors
    stand out in terms of their salience and consequences. Childhood maltreatment – physical, sexual or emotional abuse, or physical or emotional
    neglect – likely represents one of the most pervasive and pernicious stressors
    in society in terms of its widespread prevalence and devastating long-term
    consequences. Estimates from the Centers for Disease Control and Prevention and others suggest a majority of children are exposed to one or
    more traumatic events in their lifetimes (CDC, 2010; Hussey et al.,
    2006), and that 30–40 % of adult women have experienced at least one,
    and 15–25 % more than one type of CM (Scher et al., 2004). CM produces a suite of adverse and long-lasting biological, biophysical, behavioral and psychological sequelae including depression, post-traumatic stress disorder, substance abuse, unhealthy dietary practices,
    risky sexual behavior, obesity, premature menarche, and dysregulated
    neural, endocrine, immune and metabolic function that may result in
    chronic inflammation and elevated cardiometabolic disease risk factors
    (Afifi et al., 2009; Anda et al., 2006; Dong et al., 2004; Felitti et al.,
    1998; Heim et al., 2010; Jakubowski et al., 2018; Min et al., 2013;
    Rasmussen et al., 2019). In the context of pregnancy and fetal development, it is apparent that many of these adverse sequelae of CM,
    singly and collectively, represent the very same constellation of maternal risk factors that have been implicated in the process of fetal
    programming of obesity risk.
    3.2. Intergenerational transmission of the adverse sequelae of CM exposure
    Emerging evidence now suggests that among women, the long
    shadow cast by childhood maltreatment may not be restricted to their
    lifespan, but also may be transmitted to their children. Indeed, children
    of CM-exposed mothers, in the absence of CM exposure to themselves,
    exhibit alterations in stress physiology systems (Bierer et al., 2014;
    Brand et al., 2010; Jovanovic et al., 2011), behavioral disorders (conduct problems, internalizing and externalizing behavior), autism
    Psychoneuroendocrinology 116 (2020) 104659
    K.L. Lindsay, et al.
    Fig. 1. Intergenerational transmission during gestation of the effects of maternal exposure to childhood maltreatment: a conceptual framework.
    genetic variants account for less than 5% of variation in BMI (Locke
    et al., 2015; Speliotes et al., 2010). Growing evidence supports the
    concept that the origins of obesity can be traced to the intrauterine period of
    life (Entringer et al., 2012b; Oken and Gillman, 2003), at which time
    the developing fetus responds to suboptimal conditions by producing
    structural and functional changes in cells, tissues and organ systems
    (Barker, 2002; Gluckman and Hanson, 2004b). Many of these changes,
    such as altered set points in hypothalamic circuits that regulate appetite
    and satiety (Cripps et al., 2005), reduced pancreatic β-cell mass (Portha
    et al., 2011), impaired adipocyte (PPAR-ɣ) function (Desai and Ross,
    2011), and reduced insulin sensitivity (Catalano et al., 2009) have
    important long-term consequences for the propensity for developing
    obesity and associated disorders through one or both of two processes:
    they may influence magnitude and choice of dietary intake, and they
    may influence the biological fate of energy intake. It is important to
    note that these intrauterine effects set the stage, but by no means negate
    the importance of postnatal influences such as infant nutrition and
    feeding practices. In fact, the effects of fetal programming may interact
    additively or multiplicatively with such postnatal effects. Thus, we
    suggest that incorporation of the life course perspective to the fetal
    programming paradigm provides the optimal framework for elucidating
    key pathways underlying the intergenerational transmission during
    gestation of maternal CM experience on newborn and infant adiposity.
    We also note here that the concept of intergenerational transmission
    of the adverse sequelae of maternal CM exposure is not new. Indeed,
    previous research has established the existence of such effects, but with
    a primary focus on child neurodevelopmental/ behavioral phenotypes
    as the principal outcome of interest; on the child’s postnatal period of
    life as the primary transmission window; and on the quality of maternal
    parenting behavior as the primary transmission pathway. What is novel
    about our hypothesis is the formulation that childhood obesity risk may
    represent an additional and at least equally important outcome of interest and public health significance; that the process of intergenerational transmission may start as early as during the child’s intrauterine
    period of life; and that stress-related maternal-placental-fetal gestational biology may represent a key transmission pathway. We also note
    that while maternal obesity (which is one of the long-term consequences of CM exposure (Hollingsworth et al., 2012; Midei et al.,
    2010)) represents an example of a condition that may mediate the link
    between maternal CM and offspring obesity risk, the intergenerational
    effects of maternal CM likely include but may not be restricted to this
    pathway alone. In this paper we discuss several other equally plausible
    candidate pathways.
    5. Relevance of the fetal programming approach
    Development is a plastic process, wherein a range of different
    phenotypes can be expressed from a given genotype. The concept of
    fetal programming describes the journey across the multi-contoured
    landscape from genotype to phenotype, whereby the embryo/fetus
    seeks, receives, and responds to the intrauterine environment during
    sensitive periods of proliferation, differentiation and maturation, resulting in structural and functional changes in cells, tissues, organ
    systems and homeostatic set points. These changes, independently or
    through interactions with subsequent processes and environments, may
    confer critical long-term consequences for future health and disease
    susceptibility (Entringer et al., 2012a; Gluckman and Hanson, 2004a;
    Hanson et al., 2011).
    5.2. From the perspective of intergenerational effects of maternal CM
    To date, the literature on the intergenerational effects of maternal
    CM exposure has focused on the child’s early postnatal period of life as
    the primary transmission window. However, the application of the fetal
    programming paradigm may shed new light on the potential for
    transmission to begin at an earlier time period (during the highly sensitive period of gestation and in utero development). The concept that a
    woman’s pre-conceptional state may have important implications for
    her child’s intrauterine development is supported by the key tenets of
    evolutionary and life history theory (Kermack et al., 1934). CM experience represents a critical cue of extrinsic morbidity and unpredictability that may change life history strategies and alter morphological, physiological and behavioral traits (Braendle et al., 2011)
    that, in turn, impact the state in which a woman enters pregnancy. The
    plausibility of our hypothesis that the adverse effects of maternal CM on
    child obesity risk may start during the intrauterine period comes from
    a) studies we have recently published demonstrating the first direct
    links between maternal CM exposure and i) placental-fetal stress biology
    via production and trajectory of placental corticotrophin-releasing
    5.1. From the perspective of childhood obesity risk
    As discussed earlier, the magnitude of cumulative exposure to
    obesogenic conditions only partially accounts for obesity risk (Sluyter
    et al., 2013; Willyard, 2014). There are large individual differences in
    susceptibility for weight gain and fat mass accretion upon exposure to
    an identical degree of excess energy intake (Brehm et al., 2005;
    Warwick and Schiffman, 1992). Furthermore, currently-identified
    Psychoneuroendocrinology 116 (2020) 104659
    K.L. Lindsay, et al.
    2015), HPA axis hypersensitivity (Moog et al., 2012), and obesity
    (Hollingsworth et al., 2012; Nagl et al., 2015). Moreover, the pre-preconception and/or prenatal presence of several of the same states and
    conditions that happen to be CM sequelae has been shown to impact
    gestational biology. These include psychological (depression, PTSD),
    dysregulated HPA-axis activity (Christian, 2014; Christian et al., 2010),
    metabolic (chronic inflammation, elevated lipids, insulin resistance)
    (Heerwagen et al., 2013; Winzer et al., 2004), biophysical (obesity,
    elevated fat mass) (Friedman, 2015; Stirrat et al., 2016), and behavioral
    (smoking, drug abuse) (Collier et al., 2015; Somm et al., 2008; Xia
    et al., 2014) factors. In many instances, the biological effects of maternal exposure to CM or adult preconceptional abuse have also been
    documented in fetal (cord) blood (Moog et al., 2012; Sternthal et al.,
    hormone (CRH) (Moog et al., 2016), a key regulator of fetal growth,
    parturition, and childhood obesity risk (Gillman et al., 2006; Wadhwa
    et al., 2004); ii) increased susceptibility for maternal hypothyroidism
    during pregnancy (Moog et al., 2017a); iii) altered fetal brain development during gestation, characterized by a lower cortical gray matter
    volume in the newborn (Moog et al., 2017b); and b) observations that
    the above-described CM sequelae are associated with biological alterations during pregnancy that, in turn, may directly or indirectly be
    linked to childhood obesity risk (Donahue et al., 2011; Donnelly et al.,
    2015; Gademan et al., 2014; Gillman et al., 2006; Hellmuth et al., 2016;
    Josefson et al., 2014; Moon et al., 2013; Much et al., 2013; SchaeferGraf et al., 2011; Stirrat et al., 2014; Teague et al., 2015).
    6. Mechanisms for the intergenerational transmission of the
    effects of maternal CM on offspring obesity
    6.1.2. Role as transducers between the maternal and fetal compartments of
    the sequelae of maternal CM
    Current evidence links the above-mentioned biological pathways
    and specific biomarkers across the maternal and fetal compartments,
    supporting the plausibility that information about the existence of unfavorable external environmental conditions, which have been “sensed”
    by maternal biology, also utilize these same biological systems as a
    pathway for the mother-to-fetus transmission of this information. For
    example, prenatal stress induction in animals elevates maternal and
    fetal cortisol, with a high correlation between their respective concentrations (Rakers et al., 2015). Levels of the pro-inflammatory cytokine Interleukin (IL)-6 are similarly correlated in maternal and cord
    blood among pregnancies delivered by elective Cesarean section (i.e., in
    the context of absence of the acute physiological stress of labor) (VegaSanchez et al., 2010). Maternal metabolic dysregulation such as poor
    glycemic control is reflected in elevated cord blood C-Peptide, a biomarker of fetal insulin secretion (Josefson et al., 2014; Scholtens et al.,
    2014; Walsh et al., 2014). Maternal and fetal leptin also are highly
    correlated (Josefson et al., 2014; Luo et al., 2013; Walsh et al., 2014),
    while plasma free fatty acids are correlated between maternal and fetal
    compartments in normoglycemic as well as pregnancies affected by
    gestational diabetes mellitus (Schaefer-Graf et al., 2008, 2011).
    The biological pathway by which maternal states impact intrauterine development is a longitudinal process, beginning before
    conception and extending into the postnatal period, and which may
    involve several mechanisms including; i) transduction and reception of
    biological signals across the placental-fetal unit that participate in fetal
    development and phenotypic specification (including, but not limited to
    the establishment of de novo epigenetic alterations in the embryo/fetus/
    child), ii) preconceptional effects on (maternal) oocytes and follicular
    fluid composition, iii) the composition and activity of the maternal
    microbiome prior to and during gestation, and iv) postnatal processes
    including feeding practices, mother-child attachment, and infant microbiome acquisition.
    6.1. Maternal and fetal gestational biology
    A crucial component of our formulation is the question of whether
    maternal CM sequelae can influence those specific aspects of gestational
    biology that participate in fetal programming of child obesity risk. In
    this regard, we propose that maternal and fetal endocrine, immune/
    inflammatory, metabolic and lipid biology collectively constitute an
    attractive candidate mechanism. Firstly, these systems are responsive to
    all classes of intrauterine perturbations linked to maternal CM sequelae
    (sensors); secondly, they extensively mediate communication between
    maternal and fetal compartments (transducers); and thirdly, they play
    an essential, obligatory role in orchestrating and producing variation in
    key events underlying cellular growth, replication and differentiation in
    the brain (regions and circuitry underlying energy balance homeostasis) and peripheral tissues (adipocytes, pancreas, liver, muscle) related to obesity and metabolic dysfunction-related phenotypes (effectors) (Fowden et al., 2006; Matthews, 2000; Thompson and Al-Hasan,
    6.1.3. Role as effectors of fetal programming of newborn and childhood
    obesity risk
    Substantial human and animal literature suggests that dysregulation
    of the gestational biological systems mentioned above is associated
    with increased childhood adiposity and obesity risk, thereby suggesting
    that these same biological ligands act on targets within the fetal compartment to causally produce phenotypic effects that underlie the outcomes of interest (in this case, offspring obesity/adiposity). For example, cortisol and corticotrophin releasing hormone (CRH) in
    gestation predict macrosomia (Stirrat et al., 2014) and early childhood
    central adiposity (Gillman et al., 2006). IL-6 has been identified as
    among the strongest prenatal predictors of child adiposity (Radaelli
    et al., 2006), while other inflammatory markers have also been implicated (Mestan et al., 2010). Biomarkers of maternal and fetal metabolic dysregulation such as poor maternal glycemic control and insulin
    resistance (Schaefer-Graf et al., 2011; Scholtens et al., 2014), elevated
    cord blood C-peptide (Hou et al., 2014; Regnault et al., 2011), and
    elevated maternal/fetal leptin (Donnelly et al., 2015; Josefson et al.,
    2014; Walsh et al., 2014), all have been linked to child adiposity. Triglycerides in maternal and cord blood also are strongly associated with
    adiposity at birth (Nayak et al., 2013; Schaefer-Graf et al., 2008;
    Scholtens et al., 2014) and in childhood (Gademan et al., 2014). Prenatal fatty acid profiles are emerging as predictors of childhood obesity
    risk (Schaefer-Graf et al., 2008; Scholtens et al., 2014) and are reported
    to exert an even larger effect than triglycerides and lipoproteins on
    offspring BMI, body fat percentage, and waist-to-height ratio (Gademan
    et al., 2014). Maternal omega-6 fatty acid status is associated with birth
    weight (Much et al., 2013) and percent body fat at 4 years of age (Moon
    6.1.1. Role as sensors of the adverse sequelae of maternal CM exposure
    Substantial evidence in non-pregnant women demonstrates the
    persistent, life-long impact of CM on endocrine, metabolic, and inflammatory pathways, suggesting that in the context of pregnancy and
    fetal development these biological systems may act as sensors of a
    constellation of unfavorable external environmental conditions related
    to maternal CM exposure. For instance, CM induces endocrine dysregulation via dysregulated cortisol response and hypothalamic-pituitaryadrenal (HPA)-axis reactivity (Carpenter et al., 2009; Klaassens et al.,
    2009), promotes chronic inflammation via elevated pro-inflammatory
    cytokines (Friedman et al., 2015; Matthews et al., 2014), and is associated with adverse metabolic and lipid profiles via increased risk of
    type 2 diabetes mellitus (Rich-Edwards et al., 2010; Thomas et al.,
    2008) and the metabolic syndrome (Midei et al., 2013). Previous research and our own published and preliminary studies suggest there is a
    continuity and spill-over effect from the pre-conceptional to the gestational state of many of the conditions that are CM sequelae, such as
    maternal depression (Barrios et al., 2015), inflammation (Slopen et al.,
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    K.L. Lindsay, et al.
    altered by preconception states and conditions during the process of
    oocyte growth and maturation. For example, maternal obesity prior to
    conception, a common sequelae of CM exposure, is associated with
    altered oocyte endoplasmic reticulum (ER) stress signaling (Latham,
    2015), resulting in reduced mitochondrial membrane potential and
    increased autophagy (Wu et al., 2015). As such, oocyte mitochondrial
    dysfunction may contribute to the intergenerational transmission of
    obesity (Turner and Robker, 2015). Studies of women undergoing in
    vitro fertilization also indicate that psychosocial stress (An et al., 2013;
    Turner et al., 2013) and heightened physiological reactivity to stress
    (Facchinetti et al., 1997) is associated with reduced oocyte competence
    and failure to conceive. Although alterations in oocyte cytoplasm have
    not yet been studied in relation to maternal CM exposure, it is plausible
    that the adverse lifelong sequelae of CM (i.e., stress in this context)
    could affect oocyte quality and mitochondrial function across all stages
    of oocyte development and maturation, thereby influencing aspects of
    fetal development that are associated with increased susceptibility for
    excess adiposity via inherited cellular metabolic dysfunctions. While
    this mechanism has not yet been studied in humans, there is supporting
    evidence from animal studies (Turner and Robker, 2015). Luzzo et al.
    demonstrated that blastocysts from female mice with obesity, after
    transfer to females without obesity for gestation, resulted in low birth
    weight phenotype offspring at risk of subsequent increased adiposity
    and glucose intolerance (Luzzo et al., 2012).
    et al., 2013), while a raised omega-6/omega-3 ratio in cord blood demonstrated a strong positive association with child adiposity at age 3
    years (Donahue et al., 2011).
    6.2. Epigenetic characteristics
    Several epigenetic states/characteristics are prospectively associated
    with adiposity and metabolic dysfunction (Godfrey et al., 2011; Lin
    et al., 2017), and growing evidence supports a role for certain environmental exposures/conditions in the production of some of these
    epigenetic characteristics (Bays & Scinta, 2015; Godfrey et al., 2011).
    From the developmental perspective, epigenetic inter-generational
    transmission of obesity risk may occur via one or both of two possible
    routes; i) inheritance of maternally-derived epigenetic alterations in the
    germ line (oocytes), and ii) de novo production of epigenetic marks in
    the offspring via exposure to maternal conditions during intrauterine
    life. There is currently very limited evidence (and only among animal
    studies) to suggest that some epigenetic marks can survive the erasure
    and re-establishment of epigenetic characteristics that occurs shortly
    after fertilization. Animal models of early life stress have demonstrated
    that some epigenetic inheritance may be possible through the paternal
    germ line (Gapp et al., 2014; Soubry et al., 2014), as environmental
    conditions can influence the miRNA composition of sperm. In this way,
    it is plausible that paternal CM exposure also may contribute to the
    intergenerational transmission of CM effects on offspring health, but
    thus far this concept has only been studied in the context of paternal
    stress and offspring brain development (Yeshurun and Hannan, 2019).
    Furthermore, epigenetic inheritance has not yet been demonstrated
    through the maternal germ line, which would be required to support
    the inter- and trans-generational transmission of effects of early life
    exposures, including that of CM (Daxinger and Whitelaw, 2012).
    However, it is plausible that de novo production of epigenetic alterations in the developing fetus, via the sequelae of maternal CM exposure
    (Palma-Gudiel et al., 2015), may contribute to the developmental
    programming of childhood obesity (Heerwagen et al., 2010; Laker
    et al., 2013). For example, several animal studies have demonstrated
    that maternal obesity and in utero exposure to excess maternal lipids
    can impact gene pathways of metabolic importance for the developing
    fetus, including those for lipid oxidation (Bruce et al., 2009), insulin
    resistance (Yan et al., 2010), cellular differentiation (Kirchner et al.,
    2010; Zhu et al., 2008), adipogenesis (Muhlhausler et al., 2007), and
    brain circuitry affecting appetite regulation and feeding behavior
    (Chang et al., 2008). In a longitudinal human cohort study, unbalanced
    maternal diet in pregnancy was associated with alterations in DNA
    methylation in the adult offspring within genes for 11-betahydroxysteroid dehydrogenase type 2 (cortisol regulation), glucocorticoid receptor, and insulin-like growth factor-2, which were positively associated with increased adiposity and blood pressure (Drake et al., 2012).
    However, maternal obesity and poor diet are only two sequelae associated with exposure to CM. The potential effects of maternal stress and
    other behavioral, psychological and physiological sequelae of CM on
    epigenetic alterations during fetal development require significantly
    more research in longitudinal human studies.
    6.4. Maternal and infant microbiome
    A rapidly growing and convergent body of literature has linked
    characteristics of the infant gut microbiome with the subsequent development of offspring disorders, including obesity (Luoto et al., 2013).
    The composition of the infant microbiome is determined by not only
    perinatal and early postnatal exposures (such as mode of delivery, infant feeding practices, antibiotic use) but also directly and indirectly by
    the composition and activity of the maternal microbiome during
    pregnancy (Soderborg et al., 2016). Recent evidence indicates the
    presence of microbial DNA in the placenta, amniotic fluid, meconium
    and umbilical cord blood from healthy pregnancies without intrauterine infection (Funkhouser and Bordenstein, 2013), suggesting
    some mechanism(s) for direct microbial transfer between the maternal
    and fetal compartments in utero, which may subsequently shape the
    composition of the infant microbiome. While research in this area is
    currently in its infancy, one hypothesized mechanism is that maternal
    microbes reach the placenta via the bloodstream after translocation
    across the gut epithelium (Jenmalm, 2017; Soderborg et al., 2016).
    Maternal gut and cervicovaginal microbes may indirectly influence
    obesity risk in the child via alterations to systemic maternal biology
    (e.g., enhanced inflammation, increased availability of metabolic fuels)
    (Basu et al., 2011), facilitating fetal programming of brain and peripheral tissues with predisposition for greater adiposity during in utero
    development and early childhood. Furthermore, the maternal microbiome composition and activity may influence the development of the
    fetal immune system (Jenmalm, 2017), which then would be expected
    to play a role in the establishment of the newborn and infant microbiome.
    Thus, an increasing body of empirical and experimental evidence
    suggests that the determinants of the maternal microbiome composition
    before and during pregnancy may contribute to the intergenerational
    transfer of obesity risk. Maternal overweight, obesity and unhealthy
    periconceptional diet are currently the primary exposures under study
    in this regard, and have each been associated with an altered microbiome during pregnancy (Collado et al., 2008; Gohir et al., 2015a;
    Santacruz et al., 2010), which in turn affects the infant microbiota
    acquisition, composition and activity (Collado et al., 2010; Gohir et al.,
    2015b). Additional factors which are also known sequelae of CM exposure, such as psychological stress (Gur and Bailey, 2016), depression
    (Daniels et al., 2017), substance abuse (Engen et al., 2015; Volpe et al.,
    6.3. Oocyte cytoplasm and mitochondrial function
    The cytoplasm of the oocyte and follicular fluid constitutes the very
    first environmental exposure for a fertilized egg (in humans it takes
    about 24−36 hrs post fertilization for the newly-conceived individual’s
    full DNA complement to be assembled from maternal and paternal
    chromosomes). The quality of the oocyte cytoplasm is known to impact
    many outcomes including early embryonic survival, establishment and
    maintenance of pregnancy, fetal development, and even adult disease
    risk (Krisher, 2004). The structure and function of mitochondria, cellular proteins, and RNA molecules contained in the oocyte cytoplasm
    are central to these processes (Van Blerkom, 2011), and these may be
    Psychoneuroendocrinology 116 (2020) 104659
    K.L. Lindsay, et al.
    highlighted as a critical window of intervention (Lakshman et al., 2012;
    Nader et al., 2012; Wojcicki and Heyman, 2010). Indeed, prenatal interventions have targeted gestational weight gain, diet, and exercise in
    pregnancy, however, these measures have demonstrated limited success
    in influencing birth weight and offspring adiposity (Dodd et al., 2014;
    Poston et al., 2015; Walsh et al., 2012). We suggest that a greater
    emphasis on improving preconception health may be required to
    ameliorate the intergenerational transmission of obesity (Haire-Joshu
    and Tabak, 2016; Mumford et al., 2014). Thus, adopting a fetal programming approach to investigate the intergenerational transmission of
    the effects of maternal CM on offspring obesity risk offers the potential
    and new opportunity to identify a vulnerable target population, and
    specific behavioral, biological and/or psychological pathways amenable to intervention that may help tackle the growing burden of
    childhood obesity.
    The multitude of adverse health sequelae experienced by individuals exposed to CM highlights their increased healthcare requirements across their lifespan (Arnow, 2004; Hulme, 2000). Moreover, the
    American College of Obstetricians and Gynecologists report that female
    survivors of sexual abuse may be less likely to seek appropriate prenatal
    care services compared to non-exposed women (American College of
    Obstetricians and Gynecologists, 2011), thus increasing the likelihood
    for adverse pregnancy and neonatal outcomes. Therefore, our perspective highlights the urgency for public health policies and practices
    to identify, engage with and treat women with CM exposure, in order to
    address their own health requirements and possibly reduce the risk of
    adverse health consequences for their unborn children.
    Another important factor to consider in identifying vulnerable population groups is maternal socioeconomic status (SES). A bidirectional
    relationship may exist between SES and CM, such that the incidence of
    CM is higher among families of lower SES (Lefebvre et al., 2017; Walsh
    et al., 2019), and exposure to CM is subsequently associated with lower
    SES in adulthood, even after adjusting for childhood SES (Zielinski,
    2009). Furthermore, lower SES is associated with a higher likelihood of
    developing obesity in childhood and across the life-course (Andrea
    et al., 2017; Newton et al., 2017). Thus, SES may lie on the causal
    pathway between maternal CM exposure and intergenerational transmission of its effects on offspring obesity risk, highlighting the need to
    develop efficacious public health strategies to improve the health and
    wellbeing of socially disadvantaged women, with potential impact on
    health outcomes for subsequent generations.
    2014) and socioeconomic disadvantage (Miller et al., 2016), have also
    been associated with alterations in microbiome composition in nonpregnancy studies. Empirical evidence suggests that early life trauma
    may impact the process of microbial colonization, or may have differential effects based on how the microbiota influence the HPA axis in
    early life development (Daniels et al., 2017).
    6.5. Postnatal factors
    Our model recognizes that maternal CM exposure may exert independent postnatal effects on child obesity risk, and furthermore, that
    prenatal and postnatal effects may interact in programming susceptibility for obesity. An important and potentially modifiable early
    postnatal factor contributing to childhood obesity is infant diet/feeding
    practices, particularly breastfeeding and its duration (Hunsberger et al.,
    2013; Oddy et al., 2014), which may also mitigate the impact of earlier
    adverse prenatal exposures (Gibbs and Forste, 2014). A study from a
    large Norwegian cohort (N = 53,934) reported that women with CMexposure had a 41 % increased risk of ceasing breastfeeding before 4
    months postnatal (Sorbo et al., 2015), and similar findings have been
    reported in a smaller Canadian cohort (Boston, 2012). Moreover, it is
    evident that many sequelae of CM, including depression (AhlqvistBjorkroth et al., 2016), anxiety (Arifunhera et al., 2015), abuse exposure in adulthood (Silverman et al., 2006), and obesity (Wojcicki,
    2011), are associated with reduced breastfeeding initiation and/or
    Another early-life factor that is significantly associated with offspring obesity risk is poor quality maternal-child attachment (Anderson
    and Whitaker, 2011), which may also be affected by maternal CM exposure and psychological state (Mogi et al., 2011). While the mechanism underlying this link is uncertain, poor quality maternal-child
    attachment may affect the development of children’s emotion regulation and stress response systems, with subsequent effects on appetite,
    sleep and activity (Anderson et al., 2012). Furthermore, maternal psychosocial states in pregnancy such as anxiety and depression, which are
    also CM sequelae, have been associated with ‘fussy’ child temperament
    (Austin et al., 2005), a characteristic linked to shorter breastfeeding
    duration (Niegel et al., 2008), early introduction of solid foods (Wasser
    et al., 2011), and altered parental sensitivity/attachment (Planalp and
    Braungart-Rieker, 2013). Thus, there is evidence for interaction effects
    between CM sequelae and postnatal factors that are strongly implicated
    in the development of childhood adiposity.
    As discussed in the previous section, the infant microbiome is another postnatal factor believed to play an important role in the development of childhood obesity. While we have outlined how the effects of
    maternal CM exposure and its sequelae may influence the infant microbiome acquisition, composition and activity via the maternal microbiome, we hypothesize that these effects are likely to persist
    throughout the postnatal period (e.g. altered microbial and immune
    composition of breastmilk, suboptimal feeding practices), potentially
    augmenting the adverse effects of prenatal programming mechanisms.
    However, we are not currently aware of any studies describing the association of maternal CM exposure with infant microbiome composition, neither from the perspective of fetal programming or postnatal
    8. Research directions
    It is evident from the review of literature presented in this paper
    that there is a strong scientific premise underlying each component of
    the proposed model for intergenerational transmission of the effects of
    maternal CM on offspring obesity risk. However, longitudinal studies
    across intrauterine life and extending into the postnatal period are required to verify our hypotheses, and to investigate the proposed fetal
    programming mechanisms. While animal studies have provided an initial platform to investigate the gestational biological effects of preconception or prenatal stress and subsequent influence on offspring
    obesity, there are no appropriate animal models for CM exposure. Thus,
    human studies are warranted that systematically characterize the gestational environment in which offspring of mothers with CM-exposure
    While observational, longitudinal studies of this nature may provide
    important insight to the intergenerational effects of CM exposure on
    offspring obesity, we acknowledge that this study design suffers several
    limitations, particularly with respect to causal inference. Knowledge
    gleaned from observational studies regarding the most vulnerable population groups and mechanisms of transmission of CM effects should,
    therefore, be targeted in future intervention studies. Given the multitude of adverse effects of CM exposure on the mother, future interventions should consider integrating behavioral, psychological and
    7. Identifying vulnerable population groups and informing public
    health measures
    The long-term burden of the development of obesity-related comorbidities in childhood and adult life cannot be ignored, and ongoing,
    effective early-life intervention strategies for obesity prevention are
    required (Institute of Medicine, 2011; Lakshman et al., 2012). While the
    majority of national public health policies currently target school-aged
    children and adolescents, the growing body of evidence for prenatal
    programming of susceptibility to childhood obesity has been repeatedly
    Psychoneuroendocrinology 116 (2020) 104659
    K.L. Lindsay, et al.
    pharmacological modalities in an attempt to mitigate the effects of the
    sequelae of maternal CM on fetal programming pathways related to
    susceptibility to offspring obesity. Ideally, such interventions should
    target the preconception period in an effort to improve the embryonic/
    fetal environment from the time of conception.
    New approaches to identify and interpret information from placental and fetal exosomes in the maternal compartment may advance
    our understanding of which biological factors in the fetal compartment
    play key roles in obesity-related phenotypic specification in the offspring. There is also much scope for further animal and human studies
    to investigate the impact of maternal CM exposure on de novo epigenetic alterations, oocyte biology, the composition and activity of the
    maternal microbiome and acquisition and establishment of the infant
    microbiome. For example, longitudinal case-control studies among
    women undergoing in vitro fertilization could reveal whether maternal
    CM exposure is associated with alterations in oocyte cytoplasm or mitochondrial function, and whether such alterations predict downstream
    adiposity and cardiometabolic outcomes in the offspring. Similarly,
    comparing the microbiome composition and activity of CM and non-CM
    exposed women before and during pregnancy, and follow-up with the
    infant microbiome, growth and adiposity, could provide insight as to
    whether microbial composition and colonization plays a role in transmitting the effects of maternal CM on offspring obesity risk.
    Furthermore, future studies examining the transmission of the effects of
    CM exposure must carefully consider the moderating effects of prenatal
    conditions and exposures on postnatal factors in the intergenerational
    transfer of obesity risk among this vulnerable population.
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    9. Conclusions
    In summary, childhood abuse and neglect represent one of the most
    pervasive, persistent and pernicious stressors in our society. Emerging
    evidence now suggests the adverse consequences of CM may not be
    restricted to the exposed women alone, but may also be transmitted to
    their children. The perspective outlined in this article proposes that the
    intergenerational transmission of the adverse effects of maternal CM
    may start as early as the child’s intrauterine period of life, via a culmination of gestational biological pathways, in order to increase the
    propensity for obesity in the offspring. Longitudinal prospective studies
    are required to test this hypothesis, and to elucidate intrauterine biological processes that may be amenable to intervention. Ultimately, the
    aim would be to break the vicious cycle of the enduring consequences
    of early life stress passed down from a vulnerable population of abused
    women, to the even more vulnerable population of their unborn children.
    Declaration of Competing Interest
    This work was supported by the National Institutes of Health, grant
    numbers K99 HD-096109, R01 MH-105538, R01 MD-01078, R01 AG050455 and UG3 OD-023349. These funding sources had no role in the
    preparation and writing of the manuscript, or the decision to submit the
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