搜索结果：Journal of developmental origins of health and disease

There is considerable and intense discussion in the field of intellectual disability/mental retardation about the construct of disability, how intellectual disability fits within the general construct of disability, and the use of the term intellectual disability (Glidden, 2006; Greenspan, 2006; MacMillan, Siperstein, & Leffert, 2006; Schalock & Luckasson, 2004; Switzky & Greenspan, 2006b). This discussion is occurring within the context of competing world views of the philosophical and epistemological underpinnings of the conceptions of intellectual disability/mental retardation (Switzky & Greenspan, 2006a).Increasingly, the term intellectual disability is being used instead of mental retardation. This transition in terminology is exemplified by organization names (e.g., the American Association on Intellectual and Developmental Disabilities—AAIDD, International Association for the Scientific Study of Intellectual Disabilities, President's Committee for People With Intellectual Disabilities), journal titles, and published research (Parmenter, 2004; Schroeder, Gertz, & Velazquez, 2002). A number of questions have emerged with the increased use of the term intellectual disability:Our purpose in this article is to clarify the shift to the term intellectual disability. At the heart of that shift is the understanding that this term covers the same population of individuals who were diagnosed previously with mental retardation in number, kind, level, type, and duration of the disability and the need of people with this disability for individualized services and supports. Furthermore, every individual who is or was eligible for a diagnosis of mental retardation is eligible for a diagnosis of intellectual disability.In addition, in this article we explore why the field is shifting to the term intellectual disability. Increased understanding is based on a clear distinction among the construct used to describe a phenomenon, the term used to name the phenomenon, and the definition used to precisely explain the term and establish the term's meaning and boundaries. In this article we represent the first of a planned series of articles by the AAIDD Committee on Terminology and Classification in which we will share our thoughts and ask for input from the field prior to the anticipated publication in 2009/2010 of the 11th edition of the definition, classification, and systems of supports manual (The Manual).Throughout the article we stress that understanding the term intellectual disability is enhanced by dialogue and clarity. To that end, the following terms will be used:The current construct of disability is focused on the expression of limitations in individual functioning within a social context and represents a substantial disadvantage to the individual. Disability has its genesis in a health condition that gives rise to impairments in body functions and structures, activity limitations, and participation restrictions within the context of personal and environmental factors.The construct of intellectual disability belongs within the general construct of disability. Intellectual disability has evolved to emphasize an ecological perspective that focuses on the person–environment interaction and recognizes that the systematic application of individualized supports can enhance human functioning.The current construct of disability has emerged over the last 2 decades due primarily to an increased understanding of the process of disablement and its amelioration. Major factors in this evolution include (a) the research on the social construction of illness and the extensive impact that societal attitudes, roles, and policies have on the ways that individuals experience health disorders (Aronowitz, 1998); (b) the blurring of the historical distinction between biological and social causes of disability (Institute of Medicine, 1991); and (c) the recognition of the multidimensionality of human functioning (Luckasson et al., 1992, 2002; World Health Organization {WHO}, 2001). Because of these factors, the concept of disability has evolved from a person-centered trait or characteristic (often referred to as a “deficit”) to a human phenomenon with its genesis in organic and/or social factors. These organic and social factors give rise to functional limitations that reflect an inability or constraint in both personal functioning and performing roles and tasks expected of an individual within a social environment (De Ploy & Gilson, 2004; Hahn & Hegamin, 2001; Nagi, 1991; Oliver, 1996; Rioux, 1997).This social–ecological conception of disability is reflected well in current publications of both the American Association on Mental Retardation (AAMR), now the AAIDD, and WHO. In the 2002 Manual (Luckasson et al., 2002), disability was defined as the expression of limitations in individual functioning within a social context and represents a substantial disadvantage to the individual. Similarly, in the World Health Organization's (2001) International Classification of Functioning, disability is described as having its genesis in a health condition (disorder or disease) that gives rise to impairments in body functions and structures, activity limitations, and participation restrictions within the context of personal and environmental factors.The importance of this evolutionary change in the construct of disability is that intellectual disability is no longer considered entirely an absolute, invariate trait of the person (DeKraai, 2002; Devlieger, Rusch, & Pfeiffer, 2003; Greenspan, 1999). Rather, this social–ecological construct of disability, and intellectual disability, (a) exemplifies the interaction between the person and their environment; (b) focuses on the role that individualized supports can play in enhancing individual functioning; and (c) allows for the pursuit and understanding of “disability identity,” whose principles include self-worth, subjective well-being, pride, common cause, policy alternatives, and engagement in political action (Powers, Dinerstein, & Holmes, 2005; Putnam, 2005; Schalock, 2004; Vehmas, 2004).The term intellectual disability is increasingly being used instead of mental retardation. Terminology for what is now referred to as intellectual disability has varied historically. Over the last 200 years, terms have included idiocy, feeblemindedness, mental deficiency, mental disability, mental handicap, and mental subnormality (Goodey, 2005; Mercer, 1992; Schroeder et al., 2002; Stainton, 2001; Trent, 1994; Wright & Digby, 1996).Luckasson and Reeve (2001) discussed five important factors that need to be considered when selecting a term. First, the term should be specific, refer to a single entity, permit differentiation from other entities, and enhance communication. Second, it must be used consistently by different stakeholder groups (e.g., individuals, families, schools, clinicians, lawyers, physicians, professional organizations, researchers, and policy makers). Third, the term must adequately represent current knowledge and be able to incorporate new knowledge as scientific advances occur. Fourth, it should be robust enough in its operationalization to permit its use for multiple purposes, including defining, diagnosing, classifying, and planning supports. Fifth, it should reflect an essential component of naming a group of people, which is to communicate important values, especially towards the group. This aspect of the naming process (i.e., communicating important values) has generated a great deal of discussion, with many individuals asserting that the term mental retardation does not communicate dignity or respect and, in fact, frequently results in the devaluation of such persons (Finlay & Lyons, 2005; Hayden & Nelis, 2002; Rapley, 2004; Snell & Voorhees, 2006).There is an emerging consensus that not only does the term intellectual disability meet these five criteria, but that the term is preferable for a number of reasons. Chief among these are that the term intellectual disability (a) reflects the changed construct of disability described by the AAIDD and WHO, (b) aligns better with current professional practices that focus on functional behaviors and contextual factors, (c) provides a logical basis for individualized supports provision due to its basis in a social–ecological framework, (d) is less offensive to persons with the disability, and (e) is more consistent with international terminology.Defining refers to explaining precisely the term and establishing the term's meaning and boundaries. The authoritative definition of intellectual disability/mental retardation is that of the AAIDD (previously the AAMR). The definition in the 2002 AAMR Manual (Luckasson et al., 2002, p. 1) remains in effect now and for the foreseeable future. This definition is shown here with a minor edit that substitutes the term intellectual disability for mental retardation:Assumptions are an explicit part of the definition because they clarify the context from which the definition arises and indicate how the definition must be applied. Thus, the definition of intellectual disability cannot stand alone. The following five assumptions are essential to the application of the definition of intellectual disability.Significant consequences can result from the way a term is defined. As discussed by Gross and Hahn (2004), Luckasson and Reeve (2001), and Stowe, Turnbull, and Sublet (2006), a definition can make someone (a) eligible or ineligible for services; (b) subjected to something or not subjected to it (e.g., involuntary commitment); (c) exempted from something or not exempted (e.g., from the death penalty); (d) included or not included (as to protections against discrimination and equal opportunity); and/or (e) entitled or not entitled (e.g., as to Social Security benefits).Historically, four broad approaches (i.e., social, clinical, intellectual, and dual-criterion) have been used for purposes of definition and classification. Remnants of these four approaches are still evident in current discussions regarding who is (or should be) diagnosed as an individual with an intellectual disability (see, for example, Switzky & Greenspan, 2006a).Historically, persons were defined or identified as having mental retardation because they failed to adapt socially to their environment. Because an emphasis on intelligence and the role of “intelligent people” in society was to come later, the oldest historical definitional approach focused on social behavior and the “natural behavioral prototype” (Doll, 1941; Goodey, 2006; Greenspan, 2006).With the rise of the medical model, the definitional focus shifted to one's symptom complex and clinical syndrome. This approach did not negate the social criterion but gradually shifted towards a more medical model that included an increase in the relative role of organicity, heredity, and pathology and led to a call for segregation (Devlieger et al., 2003).With the emergence of intelligence as a viable construct and the rise of the mental testing movement, the approach changed to an emphasis on intellectual functioning as measured by an intelligence test and reflected in an IQ score. This emphasis led to the emergence of IQ-based statistical norms as a way to both define the group and classify individuals within it (Devlieger, 2003).The first formal attempt to systematically use both intellectual functioning and adaptive behavior to define the class was found in the 1959 American Association on Mental Deficiency (AAMD) Manual (Heber, 1959), in which mental retardation was defined as referring to subaverage general intellectual functioning that originates during the developmental period and is associated with impairments in maturation, learning, and social adjustment. In the 1961 AAMD Manual (Heber, 1961), maturation, learning, and social adjustment were folded into a single, largely undefined new term, adaptive behavior, that has been used in all subsequent AAMR manuals. The dual-criterion approach also has included age of onset as an accompanying element.Although the term or name has changed over time, an analysis of the definitions used over the last 50+ years shows that the three essential elements of intellectual disability/mental retardation— limitations in intellectual functioning, behavioral limitations in adapting to environmental demands, and early age of onset—have not changed substantially. A summary of this analysis is presented in Appendix A (definition) and Appendix B (age of onset criterion).Consistency is also reflected in related concepts and definitions not shown in Appendices A and B. For example, Scheerenberger (1983) reported that the major elements (intellectual deficits, problems coping with the demands of everyday life, and onset during the developmental period) common to the current definition were used by professionals in the United States as early as 1900. Similarly, the National Research Council (2002, pp. 1–5) reported that the first formal AAMR/AAIDD definition of the phenomenon was in 1910. This definition defined such persons as being feebleminded, with development arrested at an early age or as evidenced by an inability to manage the demands of daily life or keep up with peers. Analogously, the Individuals With Disabilities Education Act of 2004 defines mental retardation as significantly subaverage general intellectual functioning, existing concurrently with deficits in adaptive behavior, and manifesting during the developmental period that adversely affects a child's educational performance.Appendix C summarizes how the establishment of boundaries has been operationalized in the AAMR/AAIDD manuals since 1959. Two essential points are evident in these operationalizations. First, the cut-off criterion, based on SDs from a population mean, pertained primarily to the IQ element. As of the 2002 AAMR Manual, a corresponding cut-off criterion was established for the adaptive behavior element. Second, SDs currently are and primarily have been used to establish the boundary of intellectual disability.The three appendices show clearly how both the definition and its operationalization have remained consistent over time. The minor changes that have occurred reflect three phenomena: (a) advances in understanding of intellectual functioning and adaptive behavior; (b) advances in measurement theory and strategies that permit the use of statistical procedures to control for measurement error (standard error of measurement), practice effects, and normative changes over time; and (c) the essential role of clinical judgment in the administration, scoring, and interpretation of psychometric instruments (Schalock & Luckasson, 2005; Schalock et al., 2007).This historical consistency supports the trend in the field and the conclusion of the major organizations that regardless of the term used to name this disability, the same population has been described. This conclusion is the same as that drawn by The President's Committee for People With Intellectual Disabilities (2004), which stated,This conclusion is critical because of the essential role that the term mental retardation plays in public policy. For example, in the United States, a diagnosis of mental retardation is commonly used to determine eligibility under state and federal disability programs, such as Individuals With Disabilities Education Act—IDEA(2004), Social Security Disability Insurance, and Medicaid Home and Community Based Waiver. In addition, the term mental retardation is also used for citizenship and legal status, civil and criminal justice, early care and education, training and employment, income support, health care, and housing and zoning (Schroeder et al., 2002).Intellectual disability is the currently preferred term for the disability historically referred to as mental retardation, and the authoritative definition and assumptions promulgated by the AAIDD (previously the AAMR) remain the same. The term intellectual disability covers the same population of individuals who were diagnosed previously with mental retardation in number, kind, level, type, and duration of the disability, and the need of people with this disability for individualized services and supports. Furthermore, every individual who is or was eligible for a diagnosis of mental retardation is eligible for a diagnosis of intellectual disability.The fact that the construct of intellectual disability belongs within the general construct of disability helps one understand why the term intellectual disability has emerged as a preferred term to replace mental retardation. The term intellectual disability (a) reflects the changed construct of disability proposed by AAIDD and WHO; (b) aligns better with current professional practices that are focused on functional behaviors and contextual factors; (c) provides a logical basis for individualized supports provision due to its basis in a social–ecological framework; (d) is less offensive to persons with disabilities; and (e) is more consistent with international terminology.We anticipate that discussions will continue in an attempt to further refine the construct of intellectual disability, improve the reliability of diagnosis, and better understand these aspects of human functioning: the nature of intelligence, adaptive behavior, and disablement. In addition, the field will continue to examine the relationships between people with intellectual disability and other defined groups (such as those with learning disability, developmental disability, and traumatic brain injury); the provision of individualized supports to enhance individual functioning; the impact of the consumer and reform movements on the field; the effects of terminology upon peoples' lives; and the impact of an increased understanding of the biomedical, genetic, and behavioral aspects of the condition (Luckasson, 2003; Schalock & Luckasson, 2004; Switzky & Greenspan, 2006a). At this time and for the foreseeable future, the definition and assumptions of intellectual disability/mental retardation remain those promulgated by AAMR in 2002; the term, however, is changed to intellectual disability.1959 (Heber): Mental retardation refers to subaverage general intellectual functioning which originates during the developmental period and is associated with impairment in one or more of the following: (1) maturation, (2) learning, (3) social adjustment. (p. 3)1961 (Heber): Mental retardation refers to subaverage general intellectual functioning which originates during the developmental period and is associated with impairment in adaptive behavior. (p. 3)1973 (Grossman): Mental retardation refers to significantly subaverage general intellectual functioning existing concurrently with deficits in adaptive behavior, and manifested during the developmental period. (p. 1)1983 (Grossman): Same as 1973. (p. 1)1992 (Luckasson et al.): Mental retardation refers to substantial limitations in present functioning. It is characterized by significantly subaverage intellectual functioning, existing concurrently with related limitations in two or more of the following applicable adaptive skill areas: communication, self-care, home living, social skills, community use, self-direction, health and safety, functional academics, leisure, and work. Mental retardation manifests before age 18. (p. 1)2002 (Luckasson et al.): Mental retardation is a disability characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social, and practical adaptive skills. This disability originates before age 18. (p. 1)1968 (DSM–II): Mental retardation refers to subnormal general intellectual functioning which originates during the developmental period and is associated with impairment of either learning and social adjustment or maturation, or both. (These disorders were classified under “chronic brain syndrome with mental deficiency” and “mental deficiency” in DSM–I.) (p. 14)1980 (DSM–III): The essential features are: (1) significantly subaverage general intellectual functioning, (2) resulting in, or associated with, deficits or impairments in adaptive behavior, (3) with onset before the age of 18. (p. 36)1987 (DSM–III–R): The essential features of this disorder are: (1) significantly subaverage general intellectual functioning, accompanied by (2) significant deficits or impairments in adaptive functioning, with (3) onset before age of 18. (p. 28)1994 (DSM–IV): The essential feature of mental retardation is significantly subaverage general intellectual functioning (Criterion A) that is accompanied by significant limitations in adaptive functioning in at least two of the following skill areas: communication, self-care, home living, social/interpersonal skills, use of community resources, self-direction, functional academic skills, work, leisure, health, and safety (Criterion B). The onset must occur before age 18 years (Criterion C). Mental retardation has many different etiologies and may be seen as a final common pathway of various pathological processes that affect the functioning of the central (p. Same as (p. A state of mental from or from an early due to (p. A state of mental (p. A state of social at or to at resulting from developmental of (p. which originates during the developmental period (i.e., (p. manifested during the developmental period age at 18 (p. manifested during the developmental period of time between conception and the (p. et Mental retardation manifests before age 18. et This disability originates before age 18. (p. (Heber): one the population of the age group on of general intellectual functioning. (p. 3)1961 (Heber): one the population (p. 3)1973 (Grossman): Two or more SDs the population (p. (Grossman): IQ of or on of is as a and be to or (p. (Luckasson et al.): IQ of to or based on that one or more general intelligence (p. (Luckasson et al.): two SDs the mean, the error of measurement for the instruments used and the and (p. (Luckasson et al.): that is at least two SDs the of either (a) one of the following three of adaptive conceptual, social, or or (b) an on a of conceptual, social, and practical skills. (p.

The notion that schizophrenia has its origins long before the emergence of the clinical syndrome dates back at least to Kraepelin, who proffered that behavior peculiarities in children who later manifest dementia praecox were an expression of the “morbid pathology” at that time of life. In the 1920s, E. Southard, Harvard Professor of Psychiatry and Neuropathology, interpreted his neuropathological findings in brain tissue from patients with schizophrenia as being of developmental origin. L. Bender, an influential Boston psychiatrist and neuropathologist of the 1940s, labeled schizophrenia a “congenital encephalopathy”. B. Fish of the University of California at Los Angeles started in the 1960s a series of landmark studies of high risk children and described neurological “dysmaturation” as a hallmark of these individuals during early childhood. In 1986, in a paper entitled The pathogenesis of schizophrenia: a neurodevelopmental theory1, I elaborated on these earlier ideas in the context of two traditional neurological principles: neuroanatomical localization of function and the implications of the state of brain maturation for clinical translation. I argued that the “lesion” in schizophrenia occurred early in development and involved distributed neural circuitries, that no single etiology had a monopoly on the underlying pathology, and that clinical and biological heterogeneity reflects inter-individual variation in the extent of this pathology. I attempted to espouse a further amplification of these principles a year later in the paper Implications of normal brain development for the pathogenesis of schizophrenia2, by arguing that, while the pathology associated with schizophrenia may occur during early brain development, it was not a sufficient explanation for the condition. I highlighted the deterministic role of brain maturation for the clinical expression of psychosis and suggested that what is unique about schizophrenia is neither its pathology nor its cause, but the interaction of the pathology with the normal course of maturation of the brain systems affected by it. I also raised the provocative possibility that the pathology in schizophrenia “may not reflect a discrete event or illness process at all, but rather one end of the developmental spectrum that for genetic and/or other reasons 0.5% of the population will fall into”. In other words, rather than being an illness in a traditional sense, schizophrenia may reflect a quantitative developmental physiological deficit, a “liability factor that seems to be inherited”. The association of specific genes with schizophrenia allowed for a more detailed approach to this story, which P. Levitt and I discussed in 20113. Studies of structural chromosomal defects, such as velocardiofacial syndrome, Klinefelter's syndrome and NRXN1 deletions, illustrated the variable clinical expressivity (“pleiotropy”) of these genetic factors, such that cases of schizophrenia, autism and intellectual disability were associated with each of them. We proffered that, as schizophrenia is not something someone has, but a diagnosis that someone is given, it made sense to consider the syndrome not as a disease, but rather as a state of brain development and function based on an altered developmental trajectory with changing repercussions throughout life, much like autism and intellectual disability. The more granular insights about genetics and epigenetics prompted us to observe that schizophrenia appears to be on a developmental continuum with other behavioral disorders with onset in childhood, including autism, intellectual disability and epilepsy, arising perhaps from overlapping biological risk factors that may each have distinct covariates. Schizophrenia reflects the relatively least “noise” burden of this group of developmental disturbances. We expropriated the concepts of C. Waddington in further suggesting that, as individuals on a particular developmental trajectory move forward, “the subtle course corrections from early cell differentiation and circuit construction become increasingly amplified and compounded as the phenotypic endpoint becomes increasingly mature and the circuits involved take on increasingly complex functions”. Schizophrenia, we suggested, involved alterations in molecular trajectories that converge on relatively late maturating mechanisms for tuning cortical microcircuitry, involving the interplay between glutamate and GABA neurons (now popularly referred to as “excitatory-inhibitory balance”). From the background of this perspective, I found the paper by Owen and O'Donovan4 appearing in this issue of the journal to be most timely and informative. These investigators have been at the leading edge of a generation of landmark genetic studies, based on rapidly developing molecular techniques for surveying genetic variation across the genome and the availability of large samples of case and control subjects generated by teams of investigators sharing data across many international research centers. The results of this work have permanently transformed the landscape of psychiatric research, from its long history principally of phenomenology into a mainstream scientific discipline with objective insights about basic causative mechanisms. At the core of their discussion is the notion of a neurodevelopmental gradient, with genetic and biological overlap between schizophrenia and other neurodevelopmental disorders, including autism, attention-deficit/hyperactivity disorder, intellectual disability and epilepsy. This evolving idea is now strengthened by evidence which they review of relatively rare, but putatively deleterious, variations in the same genes and genomic regions being associated with each of these syndromes, and the burden of deleterious variation being greater in intellectual disability than autism, which is greater than in schizophrenia. These are potentially seminal insights. It is also noteworthy that the shared genetic associations in each of these disorders span large fractions of the genome, implicating many and diverse pathways to risk. Overall, consistent with their conclusions, these findings would seem to implicate a relative burden of developmental “noise” that is a common factor in neurodevelopmental disorders, in which more “noise” has a greater impact on function and adaptation. Less consistent with this notion, however, is the overlap between common variants and this spectrum of developmental disorders. Current data suggest that most genetic risk for schizophrenia is accounted for by common variants, and the overlap here with more traditional neurodevelopmental disorders, such as intellectual disability and autism, is less strong5. It is also important to note that sharing genetic components with disorders that arise early in development, while suggestive, does not establish a neurodevelopmental origin for schizophrenia. A more direct test of this possibility is differential expression analysis in fetal and postnatal brain of genes associated with schizophrenia and other neurodevelopmental disorders. Jaffe et al6 have shown that genes associated with schizophrenia, autism and intellectual disability are preferentially expressed during fetal life, in contrast to genes associated with bipolar disorder and neurodegenerative disorders, which are preferentially expressed after birth. Surprisingly, these authors also found that epigenetic changes associated with fetal life are enriched for positive schizophrenia genome-wide association study (GWAS) loci and that epigenetic changes in brain associated with the manifest illness also are enriched for fetal epigenetic marks7. Epigenetic changes around the time of onset of schizophrenia were surprisingly not enriched for GWAS loci and were not enriched in the brains of deceased individuals who had schizophrenia at the time of their death. These surprising results suggest that both genetic and environmental events related to schizophrenia risk, at least those that leave epigenetic marks in the brains of patients with schizophrenia, are related principally to fetal life. However, these data are still circumstantial support for a neurodevelopmental origin of schizophrenia. Perhaps the strongest evidence to date for a “smoking gun” are recent data showing that a sizable fraction of the genes in the schizophrenia GWAS significant loci directly influence placental biology and placental health and can predict complicated pregnancy, a well-recognized risk factor for schizophrenia8. This may offer new opportunities for developing primary prevention strategies early in life. Finally, a recent highly provocative and influential publication by Boyle et al9 argues that “many complex traits are driven by enormously large numbers of variants of small effects, potentially implicating most regulatory variants that are active in disease-relevant tissue”. The authors go on to suggest that disease risk is driven mostly by genes with no direct relevance to disease, but which act as modifiers of more fundamental biologic processes, perhaps related to individual genetic backgrounds and environmental experience. This proposal echoes the question of whether psychiatric disorders are really “diseases” rather than varying states of brain development that have a particular way of expressing difficulties in particular environmental contexts, based on genomic background, development and experience. If this is so, the primary public health challenge may not be in defining the genetics, but in defining the functional state of the brain when it matters most. Daniel R. Weinberger Lieber Institute for Brain Development; Departments of Psychiatry, Neurology and Neuroscience, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

The prenatal period, childhood, and adolescence are critical periods of development characterized by high plasticity. As an extension of the Developmental Origins of Health and Disease (DOHaD) paradigm, known as Origins of Paternal Health and Disease (POHaD), recent studies in rodents provide evidence that paternal obesity is associated not only with infertility but also with an increased risk of metabolic disorders in the offspring. In rodents, litter size reduction is used to induce lactational overfeeding by increasing the amount of breast milk to pups, which causes metabolic and reproductive disorders in adulthood. This work evaluated the metabolic and reproductive alterations in the offspring of males raised in normal or small litter (SL) in the prepubertal period and in adult life. The results show that paternal obesity due to early overfeeding affects the offspring in a sex-specific manner. During the prepubertal period, male offspring of SL fathers showed decreased Lee index, tibia length, and HDL plasma levels, and increased weight of gastrocnemius muscle, while female offspring of SL fathers only showed reduced HDL plasma levels. In adulthood, male offspring of overfed males showed glucose intolerance and reduced food intake and triglycerides plasma levels, signs of metabolic dysfunction. Female offspring of overfed males showed delayed puberty onset and higher prevalence of infertile periods in the estrous cycles, indicating a potential susceptibility to reproductive dysfunction. The results of the current study show that paternal obesity due to early overfeeding affects energy balance and reproduction of their offspring in a sex-specific manner.

Maternal malnutrition affects millions of people worldwide in two main ways: through food insecurity and hunger, as well as through diets high in ultra-processed, low-nutrient foods. These effects are often linked to deficiencies in specific macronutrients and micronutrients, which can lead to organ-specific consequences in the biological development of the child-a context explored within the framework of the Developmental Origins of Health and Disease (DOHaD). Given the extensive effects of maternal protein restriction (MPR) on offspring development, this review focuses specifically on low-protein diets and their impact on various organs and systems. It compiles both experimental and epidemiological data across different developmental stages. Poor maternal nutrition can impair embryonic and fetal development, creating a stressful microenvironment for both mother and child from the earliest stages of life. This stress can leave epigenetic marks that influence health and disease outcomes later in life. Numerous studies have documented the wide-ranging consequences of malnutrition, highlighting its detrimental effects on metabolic, molecular, and phenotypic systems. This narrative review aims to present both the immediate and long-term effects of exposure to MPR throughout the lifespan of the offspring.

Environmental exposure to micro- and nanoplastics (MNPs) can have significant impacts on the development of chronic health conditions in children and adults. MNPs are byproducts generated from the ubiquitous and daily use of plastics. A growing body of literature points to MNPs' affecting human metabolic and reproductive health, yet research into their potential impacts is still in its infancy. Due to recent evidence demonstrating accumulation of MNPs within human metabolic and reproductive tissues, their potential for inducing physiological and epigenetic dysregulations is postulated. This is especially critical for future generations as epigenetic disturbances within individuals can be inherited. Currently, the mechanisms for how MNPs exert their effects are still under investigation. In this scenario, the developmental origins of health and disease (DOHaD) offers insight on the influence of environmental exposures in the periconceptual, fetal, and early phases of life towards the development of noncommunicable diseases later in life. DOHaD investigates these interactions through an epigenetic lens as epigenetics bridges environmental exposures and changes in gene expression outside of the DNA sequence itself. In this review, we provide an overview on current research that describes MNPs' contribution towards the development of metabolic and reproductive dysfunction as well as their potential to impact future generations through the DOHaD paradigm possibly mediated by epigenetic modifications.

Tryptophan, an essential amino acid in mammals that is obtained from the diet, has impacts on early life and development. This amino acid is being studied under the Developmental Origins of Health and Disease (DOHaD) concept, which has led to findings of factors from conception to early childhood that affect health and susceptibility to disease. Tryptophan is metabolized mainly through 2 pathways, serotonin (5-HT) and kynurenine. The kynurenine pathway, active in the brain, gut, liver, and placenta, breaks down over 95% of tryptophan and plays roles in inflammation, neurotransmission, immune responses, and immune modulation during pregnancy. The serotonin pathway uses up to 5% tryptophan, mainly in the gut, adipose tissues, pancreatic cells, and central nervous system. Serotonin also regulates responses to environmental changes, including sleep, cognition, and feeding behavior. Key enzymes in these pathways include trp-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO) in the kynurenine pathway and tryptophan hydroxylase type 1 (TPH1) and type 2 (TPH2) in the serotonin pathway. The fetus-placental unit manages tryptophan metabolism. Serotonin and kynurenine are crucial for placental health and fetal development. Serotonin adjusts placental blood volume and aids neurodevelopment. Kynurenine metabolites protect the fetus from maternal immunity and offer initial neuroprotection. At birth, infants switch from placental nutrients to breast milk, which is rich in tryptophan and protective bioactive molecules. Tryptophan, derived solely from breast milk, is crucial for infants. Its levels are high in newborns, 2-4 times higher than in adults during the first 3 weeks postpartum, and then gradually declining to adult levels by the fourth week. Due to the remarkable role of tryptophan in organic development, disturbances in tryptophan metabolism at different life stages, fetal or postnatal, may lead to modifications of its metabolism related to pathological states in adult life. We bring some of this evidence to this review.

The Developmental Origins of Health and Disease (DOHaD) paradigm posits that early environmental factors may influence a child’s development and long-term health outcomes. Developmental programming (DP) is central to this paradigm, whereby specific early life exposures during critical periods of development are associated with changes to physiological and metabolic pathways, potentially predisposing individuals to disease. However, no standard definition of DP exists, and various terms have been used to describe similar processes. This analysis aimed to develop a conceptual definition for DP to inform interdisciplinary research, education, and practice. Walker and Avant’s eight-step method was employed to analyze the literature, incorporating elements of Rogers’ evolutionary approach to present the temporal and contextual evolution of the concept. A systematic search of MEDLINE with the EBSCOhost database was performed using the search term “developmental programming,” resulting in 95 titles included in this review. Defining attributes associated with DP include epigenetics, ontogeny, critical periods, and plasticity. Antecedents for DP may include maternal and infant nutrition, maternal disease and medication, lifestyle choices, environmental exposures, and stress. The potential consequences include cardiovascular disease, metabolic disorders, diabetes, neurodevelopmental disorders, endocrine disruption, reproductive issues, and mental health conditions. Effective healthcare provider education, knowledge dissemination, and addressing the social determinants of health through a population health approach are essential to translate DP theory and empirical evidence into practice. A common language and understanding of DP can improve the interdisciplinary advancement of DOHaD research to inform practice and education.

Developmental programming has emerged as one of the major biological principles and biomedical issues of this century because of its potential for long-term, even transgenerational, effects on the health and productivity of offspring. Livestock models have been widely used to establish the mechanisms of developmental programming in fetuses and offspring, and accordingly present data with dual benefits; both serving animal agricultural purposes and providing insights for biomedical applications. Livestock models have furthered our understanding of how developmental processes can influence postnatal health and productivity in the short- and long-term. In addition, because livestock are key to agricultural sustainability and food security, studies in livestock contribute to human livelihood. In this review, we will focus on the influence of maternal nutrition in livestock models on developmental outcomes. Maternal nutritional models include global nutrient intake (over- and under-nutrition) and supplementation of specific macro and micronutrients. Specifically, we will review the effects of maternal nutrition on: placental function, key metabolic tissues of the fetus/offspring (visceral tissues, skeletal muscle, and immune system), genetics, epigenetics, and transgenerational programming, parturition, and the underlying mechanism of developmental programming. Lastly, we will focus on gaps in knowledge and future research directions.

The fetus and neonate are especially vulnerable to toxic effects of polychlorinated biphenyls (PCBs), that have been shown to perturb behavioral and neuropsychological development. This study aimed to examine the long-term effects of developmental exposure to PCBs. Doses selected were environmentally relevant to those found in epidemiological studies, on the central nervous system (CNS) of adult rat offspring. Pregnant Sprague Dawley rats were fed cookies that contained a mixture of fourteen PCBs or vehicle (corn oil) daily. PCB doses were 0.011 mg/kg maternal body weight/day ("low") or 1.10 mg/kg maternal body weight/day ("high"), for 42 days throughout gestation and lactation. Adult offspring were euthanized on postnatal day 450. A battery of immunohistochemical markers of brain structure and function were selected to assess possible effects of developmental PCB exposure. Using a 3&#xd7;2 factorial design (treatment and sex), two-way analysis of variance revealed significant effects of treatment through the CNS, with no main effect of sex or interaction effects. In comparison with controls, both low and high dose developmental PCB exposure significantly (p < 0.05) increased inhibitory enzyme glutamic acid decarboxylase (GAD67) immunoreactivity in the cerebellar vermis, and decreased lipofuscin autofluorescence in the locus coeruleus (LC). Low dose developmental PCB exposure significantly decreased the perimeter of endothelial cells in the periaqueductal gray, ventral orbitofrontal cortex; and decreased lipofuscin in the dorsal striatum, compared to controls. Findings support the Developmental Origins of Health and Disease concept, which broadly posits that early-life perturbations may influence health trajectories over the lifespan.

A molecular understanding of lung organogenesis requires delineation of the timing and regulation of the cellular transitions that ultimately form and support a surface capable of gas exchange. Although the advent of single-cell transcriptomics has allowed for the discovery and identification of transcriptionally distinct cell populations present during lung development, the spatiotemporal dynamics of these transcriptional shifts remain undefined. With imaging-based spatial transcriptomics, we analyzed the gene expression patterns in 17 human infant lungs at varying stages of development and injury, creating a spatial transcriptomic atlas of approximately 1.2 million cells. We applied computational clustering approaches to identify shared molecular patterns among this cohort, informing how tissue architecture and molecular spatial relationships are coordinated during development and disrupted in disease. Recognizing that all preterm birth represents an injury to the developing lung, we created a simplified classification scheme that relies upon the routinely collected objective measures of gestational age and lifespan. Within this framework, we have identified cell type patterns across gestational age and life span variables that would likely be overlooked when using the conventional "disease versus control" binary comparison. Together, these data represent an open resource for the lung research community, supporting discovery-based inquiry and identification of targetable molecular mechanisms in both normal and arrested human lung development.NEW & NOTEWORTHY Mapping the spatial and temporal transcriptional relationships during lung development is fundamental to understanding regeneration and chronic lung disease; however, the classification of samples as control or disease is especially challenging in the setting of preterm birth (itself a lung injury). Here, we report the largest neonatal lung transcriptomic atlas to date and an analysis framework based only on gestational age and lifespan, providing a new resource for hypothesis generation to the lung community.

Maternal tobacco smoke exposure is associated with impaired fetal growth and long-term disease risk (DOHaD, Developmental Origins of Health and Disease). Whether placental steroid hormones are independently altered remains a matter of debate. We quantified six placental steroids (estradiol, estriol, estrone, progesterone, testosterone, and pregnanediol) using HPLC-Corona CAD in 70 deliveries (C = 30; PS = 20; AS = 20). Distributional differences were assessed with Kruskal-Wallis and pairwise Mann-Whitney tests with Benjamini-Hochberg (BH) control. Adjusted associations used log-linear OLS with HC3 robust SE: Model A (gestational age, maternal BMI, newborn sex) and Model B (Model A + birth weight), reported as percent change vs. controls, computed as (exp(&#x3b2;) - 1) &#xd7; 100 with 95% CI. Secondary analyses tested (i) multiclass logistic classification of C/PS/AS from the steroid panel (5-fold stratified CV) and (ii) prediction of birth weight (OLS and 2-component PLS). All six steroids differed by group (BH-adjusted p ranging from 9.18 &#xd7; 10-12 to 6.66 &#xd7; 10-8). In Model A, AS vs. C showed lower estrogens/progestins (estradiol, -46.2%; estriol, -24.7%; estrone, -25.9%; progesterone, -28.2%; pregnanediol, -31.4%) and higher testosterone (+40.8%); these effects persisted in Model B after adjusting for birth weight. The panel classified C/PS/AS with 0.900 cross-validated accuracy (weighted OvR AUC 0.994). Hormones poorly predicted birth weight (PLS CV R2 = -0.777). Maternal active and passive smoking is associated with a coherent and independent disruption of placental steroidogenesis. A targeted placental steroid panel offers biologically meaningful early markers relevant to DOHaD.

Recent reports suggest that New Zealanders underestimate the burden of non-communicable diseases (NCDs) on society, perceiving NCDs as standalone problems to be managed by affected individuals. This belief conflicts with the Developmental Origins of Health and Disease (DOHaD) hypothesis that NCD risk is rooted in early-life environmental exposures. For the research community to contribute towards shifting societal beliefs, we need to know more about NZers' understanding of how NCDs develop and have the potential to track this over time. To address this, we conducted a face-to-face survey of 702 Auckland adults in 2015-16, repeated in 2022-23 with 814 online and 96 face-to-face respondents. An increased recognition of links between mental health and obesity was the only change observed between the earlier and later cohorts. Overall, of the 59% familiar with the term 'non-communicable disease', 73% accurately described NCD characteristics and gave examples. Online, tertiary-educated and non-male respondents were more likely to identify various social determinants of health in addition to individual behaviours as contributors to metabolic disease risk. More than twice as many subjects strongly agreed that preconception health of mothers could affect the health of the child than that of fathers. Maternal nutrition was recognised by most as important for fetal health, but 49% disagreed or did not know if it could affect adult health. These results indicate that regardless of subject sampling or data collection method, adult New Zealanders have little appreciation of the significance of the early-life environment in relation to NCD risk across the lifespan.

Maternal mental health represents a significant global health burden, not only in terms of maternal wellbeing, but also for the impact it has on child development. The relationship between maternal mental health and deleterious environmental exposures to the fetus is one mechanism of risk transmission. This study utilizes network analysis to a) explore how maternal mental health is associated with a wide array of fetal exposures, and b) examine how these exposures cluster together. A total of 485 pregnant women were recruited from the Mercy Hospital for Women in Melbourne, Australia between 2011-2017, as part of the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS). The MPEWS includes measures of mental health diagnosis and symptoms, psychotropic medication, smoking, alcohol, substance use, and a wide range of lifestyle factors in the first and third trimesters of pregnancy. Regularized Partial Correlation Modelling was used to examine the network of relationships between maternal mental health and fetal exposures due to environmental factors, lifestyle and medications. For women diagnosed with mental health disorders there are relatively higher rates of exposure to smoking, anxiety and depression symptoms, psychotropic medications, pregnancy health conditions and less than optimal lifestyle factors. Factors such as physical exercise and folate supplementation show strong patterns of partial correlation. Trait anxiety emerged as the central variable in the network with the highest strength of relationship to all other exposure variables. The current study shows the value of approaching fetal exposures as a complex network of associated aspects of maternal lifestyle, mental health and environment. Viewing exposures together may assist clinical and public health interventions to target multiple associated risk factors, rather than the current focus on individual exposures. The preconception and perinatal periods offer important opportunities for the prevention of teratogenic fetal exposures and the promotion of a healthy start to life.

Research into the Developmental Origins of Health and Disease (DOHaD) has established links between environmental exposures in early life and later-life health outcomes. Emerging interventions typically focus on improving maternal nutrition and neonatal healthcare practices yet often neglect to assess or enhance subject understanding of potential long-term impacts or to communicate the benefits of maximising parental health prior to conception. This study critically evaluates a survey tool developed to measure knowledge of non-communicable diseases (NCDs) and early-life contributors to lifelong health. The rationale behind the wording and format of the questions is examined alongside options for coding and statistical interpretation of the data. Considerations for implementation are discussed, illustrated by key findings arising from tracking of the tool's application in Aotearoa New Zealand over ten years. We demonstrate that the survey tool can be adapted for use in a variety of contexts, producing both quantitative and qualitative baseline data suitable for informing health promotion interventions and monitoring changes in population knowledge. This research also highlights a key difference between awareness of and understanding of scientific concepts and the importance of distinguishing between these when considering public engagement with science.

Several studies have been published studying association between parental low birth weight (BW) and neonatal outcomes of their children. To date no systematic review and meta-analysis (SRM) has been published to quantify the impact of maternal and paternal BW on outcomes in the next generation. The aim of this SRM was to analyse the association between parental BW and anthropometric and metabolic outcomes in their children.Electronic databases were searched for studies documenting BW of parents and children with neonatal outcomes. Primary outcome was to evaluate impact of parental BW on occurrence of&#xa0;LBW in children. Secondary outcomes were to assess impact of parental BW on occurrence of macrosomia, small for gestational age (SGA), preterm labour/delivery, and burden of non-communicable disease in later life.We screened 54,961 articles, data from 14 studies (320,515 parent-child pairs), which fulfilled all criteria, were analysed. Maternal LBW was associated with higher chances of neonatal LBW [odds ratio (OR)1.95 (95% CI:1.56-2.46); P < 0.01; I2 = 91%], neonatal SGA [OR 2.29(95% CI:1.72-3.05); P < 0.01; I2 = 37%], lower chances of neonatal macrosomia [OR 0.50 (95% CI:0.39-0.65); P < 0.01; I2 = 35%] and had no impact on preterm labour/delivery [OR1.20(95% CI:0.67-2.16); P = 0.53; I2 = 88%]. Maternal macrosomia was associated with higher neonatal macrosomia [OR 2.66 (95% CI:2.44-3.16); P < 0.01; I2 = 48%], lower SGA [OR 0.40(95% CI:0.29-0.53); P < 0.01; I2 = 0%] and preterm labour/delivery [OR 0.77 (95% CI:0.63-0.94); P < 0.01; I2 = 4%]. Paternal but not maternal LBW was predictor of metabolic syndrome and diabetes in adulthood.Maternal LBW is an important predictor of LBW and SGA in neonates. Maternal macrosomia is an important predictor of neonatal macrosomia; is protective against SGA and preterm labour/childbirth. Neonatal size of parents is reflected in neonatal size of their children.

The obesogenic maternal environment can lead to cardiac hypertrophy in the offspring. The aim of this study was to investigate whether (-)-epicatechin (Epi) modify the expression of genes related to pathological cardiac hypertrophy (CH), and its physiological pathway, in offspring obese by programing. Four groups of eight male offspring Wistar rats of 110 days were randomly selected to control groups [C and offspring of maternal obesity (MO)] or to Epi groups (C + Epi or MO + Epi). In heart tissue, we evaluated the size of the ventricular walls and cavities, presence of fibrosis, mRNA and protein of Myh6, Myh7, Anp, Bnp, Acta 1, Col1a1, Akt, and Mtor. We observed an increase of the heart weight/body ratio in groups treated with Epi. Only in MO group, heart area and its perimeter were increased, as well as Myh7 and Anp mRNA. We found a significant decrease of fibrosis area in male offspring treatment with Epi. In Epi group Anp mRNA was decreased whilst Anp protein in MO group was increased; further, a decrease in Col1a1 protein was found in MO group. In conclusion, the maternal obesity activates pathological CH markers reactivating fetal cardiac genes involved in histological changes observed in cardiac tissue. Epi treatment decreased the content of collagen area and expression of some fetal cardiac genes participating in this pathway in offspring of maternal obesity.

Maternal diabetes, a common pregnancy complication, has long-term implications for both mother and offspring. While the developmental origins of metabolic health from prenatal diabetes exposure are well known, cognitive consequences in offspring are still being explored. The timing of hyperglycemia during pregnancy that most affects cognitive development and whether these effects persist into adulthood remains unclear. This study aimed to determine the association between trimester-specific hyperglycemia exposure and adult cognition in the offspring of women with pregestational diabetes. The Transgenerational Effect on Adult Morbidity (TEAM) Study evaluated health outcomes in young adult offspring of mothers with pregestational diabetes who participated in a Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati (1978-1995). The TEAM Study visit (March 2018 - August 2022) included a comprehensive clinical examination and cognitive assessment (Wechsler Abbreviated Scale of Intelligence - II). Linear regression estimated the association between prenatal hyperglycemia and offspring's perceptual reasoning and verbal comprehension. The mean age at follow-up was 32.1 years. Hyperglycemia during pregnancy was inversely associated with cognitive measures, controlling for confounders including maternal education and pre-pregnancy obesity. Higher glycohemoglobin in the second and third trimesters was significantly linked to lower IQ scores, matrix reasoning, and vocabulary subtest scores. Third-trimester hyperglycemia was also associated with lower block design subtest scores. In summary, hyperglycemia, particularly in the latter half of pregnancy, was associated with lower cognitive ability in adult offspring of women with pre-pregnancy pregestational diabetes.

Maternal deficiency of vitamin B12 (B12) is associated with neural tube defects, fetal growth restriction, and future risk of non-communicable disease in the offspring. Little is known about the molecular basis of these associations. We hypothesized that B12 regulates the expression of fetal genes, thereby influencing fetal growth and fetal programming. We investigated the association of B12 and other micronutrient concentrations in the cord blood with gene expression in the cord blood mononuclear cells. We performed a Weighted Gene Co-expression Network Analysis (WGCNA) on cord blood transcriptome of babies born in a pre-conception trial Pune Rural Intervention in Young Adolescents of B12 and multi-micronutrients (MMN). The gene modules (clusters) in WGCNA that showed a significant correlation with cord blood B12 and MMN were subjected to gene ontology (GO) analysis. WGCNA generated 23 different modules. Cord blood B12 concentrations were strongly correlated with modules of genes involved in methylation reactions and gene regulation. Cord B2 concentrations correlated with gene modules associated with demethylation reactions. Vitamins B6 and B9 did not show a unique association either with gene modules or specific GO terms. Our results demonstrate that maternal B12 may regulate expression of fetal genes involved in methylation reaction. This is a novel suggestion for the role of B12 in fetal growth, development, and the Developmental Origins of Health and Disease paradigm.

The impact of maternal nutrition during the peri-conception period on offspring sex remains unclear. Therefore, this study aimed to explore the association between maternal nutritional intake around conception and offspring sex. Data were collected from the Japan Environment and Children's Study, which enrolled 97,510 mother-child pairs. The effect of maternal intake of fats, proteins, and fatty acids on offspring sex was analyzed, adjusting for maternal demographics and lifestyle factors. Overall, maternal intake of total fatty acids, saturated fatty acids (SFAs), polyunsaturated fatty acids (PUFAs), n-3 PUFA, n-6 PUFA, and protein and the ratios of n-6/n-3 and SFA/energy showed no consistent associations with offspring sex.However, further analyses revealed notable patterns related to maternal age and energy intake. Among mothers with high energy intake (&#x2265;4,000 kcal/day), higher residual protein intake was associated with increased odds of having a male child (aOR, 1.87; 95% CI, 1.17-2.98). In mothers aged under 20 years, increased n-3 PUFA intake was linked to higher odds of male births, while a higher n-6/n-3 ratio was associated with lower odds of male births. Additionally, among mothers aged 20-35 years, higher n-3 PUFA intake was associated with decreased odds of having a male child (aOR, 0.89; 95% CI, 0.82-0.98).These findings indicate that while no consistent overall relationship was observed, certain maternal nutritional patterns may influence offspring sex, highlighting the need for further research on maternal diet and reproductive outcomes.