Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

Addictions are highly heritable disorders, with heritability estimates ranging from 39% to 72%. Multiple studies suggest a link between paternal drug abuse and addiction in their children. However, patterns of inheritance cannot be explained purely by Mendelian genetic mechanisms. Exposure to drugs of abuse results in epigenetic changes that may be passed on through the germline. This mechanism of epigenetic transgenerational inheritance may provide a link between paternal drug exposure and addiction susceptibility in the offspring. Recent studies have begun to investigate the effect of paternal drug exposure on behavioral and neurobiological phenotypes in offspring of drug‐exposed fathers in rodent models. This review aims to discuss behavioral and neural effects of paternal exposure to alcohol, cocaine, opioids, and nicotine. Although a special focus will be on addiction‐relevant behaviors, additional behavioral effects including cognition, anxiety, and depressive‐like behaviors will be discussed.     

Transgenerational inheritance of stress pathology

It is becoming increasingly evident that maternal exposure to adversity during pregnancy leads to life-long effects in offspring. While there appears to be some commonality in the effects of maternal stress on endocrine and behavioral outcomes in the first generation offspring, it is clear that effects are highly dependent on species, sex and age, as well as on the time in pregnancy when stress is experienced. Recent studies have identified that the effects of maternal stress are not confined to the first generation and that they can extend over multiple generations. These effects are also evident in humans. While our understanding of the potential mechanisms by which transgenerational programming of the stress response occurs remain largely undetermined, recent studies have begun to identify potential mechanisms of transfer. These include modified maternal adaptations to pregnancy, altered maternal behavior and transgenerational epigenetic programming. Such transgenerational programming of stress responses and pathologies has important societal consequences as it could provide a biological explanation for the generational persistence of human behaviors in populations exposed to adversity.     

Prenatal nicotine exposure alters neuroanatomical organization of the developing brain

Although there has been considerable research conducted regarding the long‐term effects of prenatal exposure to nicotine, there has been little examination of how this experience influences brain development. This study was designed to examine if there are morphological changes (dendritic branching, dendritic length, and spine density) in medial prefrontal cortex, orbital frontal cortex, parietal cortex, and nucleus accumbens associated with exposure to nicotine during gestation. Nicotine or saline was administered to pregnant Long Evans dams for the duration of pregnancy. Golgi‐Cox techniques were used to examine neuroanatomy of offspring at postnatal day 21. The dendritic changes identified in rats exposed to nicotine prenatally resembled neuroanatomical changes that are identified in rats administered with nicotine in adulthood. Of the 18 anatomical parameters measured, 11 exhibited significant modification, with two parameters apical and basilar spine density in parietal cortex demonstrating sex‐dependent modification. These early changes in anatomy and behavior have important implications for later plasticity and long‐term well‐being. Synapse 66:950–954, 2012. © 2012 Wiley Periodicals, Inc.     

Lifetime stress experience: transgenerational epigenetics and germ cell programming

The transgenerational epigenetic programming involved in the passage of environmental exposures to stressful periods from one generation to the next has been examined in human populations, and mechanistically in animal models. Epidemiological studies suggest that gestational exposures to environmental factors including stress are strongly associated with an increased risk of neurodevelopmental disorders, including attention deficit-hyperactivity disorder, schizophrenia, and autism spectrum disorders. Both maternal and paternal life experiences with stress can be passed on to offspring directly during pregnancy or through epigenetic marks in the germ cell. Animal models of parental stress have examined relevant offspring phenotypes and transgenerational outcomes, and provided unique insight into the germ cell epigenetic changes associated with disruptions in neurodevelopment. Understanding germline susceptibility to exogenous signals during stress exposure and the identification of the types of epigenetic marks is critical for defining mechanisms underlying disease risk.     

Birth signalling hormones and the developmental consequences of caesarean delivery

Rates of delivery by caesarean section (CS) are increasing around the globe and, although several epidemiological associations have already been observed between CS and health outcomes in later life, more are sure to be discovered as this practice continues to gain popularity. The components of vaginal delivery that protect offspring from the negative consequences of CS delivery in later life are currently unknown, although much attention to date has focused on differences in microbial colonisation. Here, we present the case that differing hormonal experiences at birth may also contribute to the neurodevelopmental consequences of CS delivery. Levels of each of the ‘birth signalling hormones’ (oxytocin, arginine vasopressin, epinephrine, norepinephrine and the glucocorticoids) are lower following CS compared to vaginal delivery, and there is substantial evidence for each that manipulations in early life results in long‐term neurodevelopmental consequences. We draw from the research traditions of neuroendocrinology and developmental psychobiology to suggest that the perinatal period is a sensitive period, during which hormones achieve organisational effects. Furthermore, there is much to be learned from research on developmental programming by early‐life stress that may inform research on CS, as a result of shared neuroendocrine mechanisms at work. We compare and contrast the effects of early‐life stress with those of CS delivery and propose new avenues of research based on the links between the two bodies of literature. The research conducted to date suggests that the differences in hormone signalling seen in CS neonates may produce long‐term neurodevelopmental consequences.     

Epigenetic perspective on the developmental effects of bisphenol A

Bisphenol A (BPA) is an estrogenic environmental toxin widely used in the production of plastics and ubiquitous human exposure to this chemical has been proposed to be a potential risk to public health. Animal studies suggest that in utero and early postnatal exposure to this compound may produce a broad range of adverse effects, including impaired brain development, sexual differentiation, behavior, and immune function, which could extend to future generations. Molecular mechanisms that underlie the long-lasting effects of BPA continue to be elucidated, and likely involve disruption of epigenetic programming of gene expression during development. Several studies have provided evidence that maternal exposure to BPA results in postnatal changes in DNA methylation status and altered expression of specific genes in offspring. However, further studies are needed to extend these initial findings to other genes in different tissues, and to examine the correlations between BPA-induced epigenetic alterations, changes in gene expression, and various phenotypic outcomes. It will be also important to explore whether the epigenetic effects of BPA are related to its estrogenic activity, and to determine which downstream effector proteins could mediate changes in DNA methylation. In this review, we will highlight research indicating a consequence of prenatal BPA exposure for brain, behavior, and immune outcomes and discuss evidence for the role of epigenetic pathways in shaping these developmental effects. Based on this evidence, we will suggest future directions in the study of BPA-induced epigenetic effects and discuss the transgenerational implications of exposure to endocrine disrupting chemicals.     

Examining the relationship between perinatal depression and neurodevelopment in infants and children through structural and functional neuroimaging research

Abstract

Depression is the most common perinatal psychiatric disorder, but little is known about how it may impact offspring neurodevelopment, as well as the mechanisms by which it may confer transgenerational psychiatric risk. This review presents imaging studies conducted to evaluate the relationship between perinatal depression (PND) and infant and child neurodevelopment. Altered structural and functional connectivity is implicated in children exposed to PND and anxiety. Overall, there are changes in connectivity between amygdala and the prefrontal cortex. Studies suggest decreased hippocampal growth in the first 6 months after birth, decreased cortical thickness in children, and increased amygdala volumes, that are more pronounced in female offspring. Future research is needed to understand the impact of PND on development so that early interventions which promote mother–infant bonding and cognitive development may improve developmental outcomes in children exposed to PND, reducing later risk of psychopathology.     

Effects of prenatal exposure to cocaine or related drugs on rat developmental and neurological indices

Although increasing numbers of infants born to cocaine abusing mothers are of grave concern, little is known of the long term development of these children. To determine the long term effects of cocaine on a developing fetus, gravid rats were dosed SC throughout pregnancy with either saline, amfonelic acid (AFA, 1.5 mg/kg), amitriptyline (10 mg/kg) or cocaine (15 mg/kg b.i.d.) and the male pups fostered by surrogate rats. Compared to saline offspring, cocaine- and amitriptyline-exposed litters were underweight at birth, but there were no differences between groups at 15 or 30 days of age. There were more birth defects and stillbirths in cocaine-exposed offspring, however, there were no differences in male/female sex ratios or litter size in any group. Number of days to righting reflex was delayed in the cocaine-exposed group, but there were no changes in time to eye opening. Cocaine- and amitriptyline-exposed pups were hyperactive at 30 days of age, though no differences were found in an initial 15-min exploration period. Only the AFA-exposed offspring were hyperactive at 60 days postnatal. Since cocaine and amitriptyline decreased birth weights, this effect may be related to the nondopaminergic effects of cocaine. These data demonstrate that cocaine exposure in utero at relevant doses can affect neonatal outcome and long term development in rat offspring.     

Growth,head growth,and neurocognitive outcome in children born very preterm: methodological aspects and selected results

In light of the growing number of surviving children born very preterm, there is an increasing focus on their long‐term outcomes in terms of growth, metabolic status, and neurocognitive development. Therefore, it is of importance to follow such children from birth onwards with the aim of identifying the causes of atypical development, developing preventative measures, and improving outcomes. Since such long‐term follow‐up needs to be conducted with the least possible burden, clinical investigations such as anthropometry and neurocognitive tests, if conducted rigorously, will continue to have a predominant role. The aim of this review is to discuss the complexity of longitudinal anthropometry in children born very preterm and to provide an overview of the main studies that have examined associations between growth, in particular head growth, and neurocognitive outcomes at around school age.     

Long‐term effects of cannabinoids on development/behaviour

Cannabis‐derived products such as cannabidiol are now increasingly prescribed for different refractory childhood epilepsy syndromes. This raises the question about cognitive and behavioural safety of chronic use in young children. As there are no long‐term data to answer this question, we can look for indirect evidence. In this short review, we focus on three lines of research: data obtained from the randomised controlled trials with cannabidiol, data on the consequences of prenatal cannabis exposure, and data on the effect of adolescent cannabis use. No hard conclusions can be drawn, mainly because of methodological problems (dosage of THC and other cannabis‐derived products, duration of exposure, concordant addiction to other drugs, genetic factors, educational level, etc.), however, long‐term data show a possible negative and lasting effect on cognitive and especially behavioural functions. Externalising behavioural problems and a decrease in IQ have been reported as a result of chronic cannabis use. Clearly, long‐term studies using large childhood epilepsy cohorts are needed to confirm or refute these findings.     

Prenatal drug exposure and neurodevelopmental programming of glucocorticoid signalling

Prenatal neurodevelopment is dependent on precise functioning of multiple signalling pathways in the brain, including those mobilised by glucocorticoids (GC) and endocannabinoids (eCBs). Prenatal exposure to drugs of abuse, including opioids, alcohol, cocaine and cannabis, has been shown to not only impact GC signalling, but also alter functioning of the hypothalamic‐pituitary‐adrenal (HPA) axis. Such exposures can have long‐lasting neurobehavioural consequences, including alterations in the stress response in the offspring. Furthermore, cannabis contains cannabinoids that signal via the eCB pathway, which is linked to some components of GC signalling in the adult brain. Given that GCs are frequently used in pregnancy to prevent complications of prematurity, and also that rates of cannabis use in pregnancy are increasing, the likelihood of foetal co‐exposure to these compounds is high and may have additional implications for long‐term neurodevelopment. Here, we present a discussion of GC signalling and the HPA axis, as well as the effects of prenatal drug exposure on these pathways and the stress response, and we explore the interactions between GC and EC signalling in the developing brain and potential for neurodevelopmental consequences.     

Benefits and limits of anticholinergic use in schizophrenia: Focusing on its effect on cognitive function

All currently available antipsychotic drugs are the dopamine D₂ receptor antagonists and are capable of producing extrapyramidal side‐effects (EPS). Anticholinergic drugs are primarily used to treat EPS or prevent EPS induced by antipsychotics in the treatment of psychosis and schizophrenia. However, they can cause a variety of distressing peripheral side‐effects (e.g. dry mouth, urinary disturbances, and constipation) and central adverse effects (e.g. cognitive impairment, worsening of tardive dyskinesia, and delirium). Disturbances in cognitive abilities are cardinal features of schizophrenia from its earliest phases and account for much of the functional disability associated with the illness. It is likely that long‐term concomitant administration of anticholinergics exacerbates the underlying cognitive impairment in patients with schizophrenia and subsequently affects patients' quality of life. Thus, current treatment guidelines for schizophrenia generally do not recommend the prophylactic and long‐term use of anticholinergics. However, the high use of long‐term anticholinergic drugs with antipsychotics has been identified as an important issue in the treatment of schizophrenia in several countries. To assess the benefits and limits of anticholinergic use in psychosis and schizophrenia, this article will provide a brief review of the pharmacology and clinical profiles of anticholinergic drugs and will focus on their effects on cognitive function in schizophrenia, particularly during the course of the early phase of the illness. In addition, we will address the effects of discontinuation of anticholinergics on cognitive function in patients with schizophrenia and provide a strategy for adjunctive anticholinergic use in patients treated with long‐acting injectable antipsychotics.     

Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring

Teratological investigations have demonstrated that agents that are relatively harmless to the mother may have significant negative consequences to the fetus. Among these agents, prenatal alcohol, nicotine or cannabis exposure have been related to adverse offspring outcomes. Although there is a relatively extensive body of literature that has focused upon birth and behavioral outcomes in newborns and infants after prenatal exposure to maternal smoking, drinking and, to a lesser extent, cannabis use, information on neurobehavioral and cognitive teratogenic findings beyond these early ages is still quite limited. Furthermore, most studies have focused on prenatal exposure to heavy levels of smoking, drinking or cannabis use. Few recent studies have paid attention to low or moderate levels of exposure to these substances. This review endeavors to provide an overview of such studies, and includes animal findings and potential mechanisms that may explain the mostly subtle effects found on neurobehavioral and cognitive outcomes. It is concluded that prenatal exposure to either maternal smoking, alcohol or cannabis use is related to some common neurobehavioral and cognitive outcomes, including symptoms of ADHD (inattention, impulsivity), increased externalizing behavior, decreased general cognitive functioning, and deficits in learning and memory tasks.     

Endocrine disruption of gene expression and microRNA profiles in hippocampus and hypothalamus of California mice: Association of gene expression changes with behavioural outcomes

The hypothalamus and hippocampus are sensitive to early exposure to endocrine disrupting chemicals (EDCs). Two EDCs that have raised particular concerns are bisphenol A (BPA), a widely prevalent chemical in many common household items, and genistein (GEN), a phyto‐oestrogen present in soy and other plants. We hypothesised that early exposure to BPA or GEN may lead to permanent effects on gene expression profiles for both coding RNAs (mRNAs) and microRNAs (miRs), which can affect the translation of mRNAs. Such EDC‐induced biomolecular changes may affect behavioural and metabolic patterns. California mice (Peromyscus californicus) male and female offspring were developmentally exposed via the maternal diet to BPA (5 mg kg^‐1 feed weight low dose [LD] and 50 mg kg^‐1 feed weight upper dose [UD]), GEN (250 mg kg^‐1 feed weight) or a phyto‐oestrogen‐free diet (AIN) control. Behavioural and metabolic tests were performed at 180 days of age. A quantitative polymerase chain reacttion analysis was performed for candidate mRNAs and miRs in the hypothalamus and hippocampus. LD BPA and GEN exposed California mice offspring showed socio‐communication impairments. Hypothalamic Avp, Esr1, Kiss1 and Lepr were increased in LD BPA offspring. miR‐153 was elevated but miR‐181a was reduced in LD BPA offspring. miR‐9 and miR‐153 were increased in the hippocampi of LD BPA offspring, whereas GEN decreased hippocampal miR‐7a and miR‐153 expression. Correlation analyses revealed neural expression of miR‐153 and miR‐181a was associated with socio‐communication deficits in LD BPA individuals. The findings reveal a cause for concern such that developmental exposure of BPA or GEN in California mice (and potentially by translation in humans) can lead to long standing neurobehavioural consequences.     

The persistence of maternal distress and symptoms of distress in adult offspring

This study examined the influence of maternal psychological distress symptoms during offspring’s preschool, middle childhood, and adolescent years on the distress symptoms of offspring in adulthood. Data were derived from the British Cohort Study, a longitudinal study of children born in a one-week period in 1970. Results indicated that greater symptoms of maternal distress that persisted over multiple stages of offspring development were generally associated with greater symptoms of distress in adult offspring. The effect of greater maternal distress symptoms that persisted across preschool, middle childhood, and adolescence on adult offspring, however, was not significantly different from the long term effects of a single, but early, exposure to maternal distress once offspring’s psychosocial adjustment during adolescence was considered. The relationship between mother and offspring distress symptoms did not vary for male and female offspring. The results provide general support for a cumulative effect perspective in that continuous exposure to maternal distress symptoms had negative consequences in adulthood, and that the adult effect of exposure in early or middle childhood was explained by adolescent adjustment.     

Individual prediction of long‐term outcome in adolescents at ultra‐high risk for psychosis: Applying machine learning techniques to brain imaging data

An important focus of studies of individuals at ultra‐high risk (UHR) for psychosis has been to identify biomarkers to predict which individuals will transition to psychosis. However, the majority of individuals will prove to be resilient and go on to experience remission of their symptoms and function well. The aim of this study was to investigate the possibility of using structural MRI measures collected in UHR adolescents at baseline to quantitatively predict their long‐term clinical outcome and level of functioning. We included 64 UHR individuals and 62 typically developing adolescents (12–18 years old at recruitment). At six‐year follow‐up, we determined resilience for 43 UHR individuals. Support Vector Regression analyses were performed to predict long‐term functional and clinical outcome from baseline MRI measures on a continuous scale, instead of the more typical binary classification. This led to predictive correlations of baseline MR measures with level of functioning, and negative and disorganization symptoms. The highest correlation (r = 0.42) was found between baseline subcortical volumes and long‐term level of functioning. In conclusion, our results show that structural MRI data can be used to quantitatively predict long‐term functional and clinical outcome in UHR individuals with medium effect size, suggesting that there may be scope for predicting outcome at the individual level. Moreover, we recommend classifying individual outcome on a continuous scale, enabling the assessment of different functional and clinical scales separately without the need to set a threshold. Hum Brain Mapp 38:704–714, 2017. © 2016 Wiley Periodicals, Inc.