Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

Objectives

Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood.

Method

We used an established mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities.

Results

PolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4^th ventricle volume but did not disrupt sensorimotor gating.

Conclusions

Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.     

Early alterations in hippocampal circuitry and theta rhythm generation in a mouse model of prenatal infection: implications for schizophrenia

Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic-polyribocytidilic acid (poly I:C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease.     

Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism

In this review, we provide a synopsis of work on the epidemiologic evidence for prenatal infection in the etiology of schizophrenia and autism. In birth cohort studies conducted by our group and others, in utero exposure to infectious agents, prospectively obtained after biomarker assays of archived maternal sera and by obstetric records was related to an increased risk of schizophrenia. Thus far, it has been demonstrated that prenatal exposure to influenza, increased toxoplasma antibody, genital-reproductive infections, rubella, and other pathogens are associated with schizophrenia. Anomalies of the immune system, including enhanced maternal cytokine levels, are also related to schizophrenia. Some evidence also suggests that maternal infection and immune dysfunction may be associated with autism. Although replication is required, these findings suggest that public health interventions targeting infectious exposures have the potential for preventing cases of schizophrenia and autism. Moreover, this work has stimulated translational research on the neurobiological and genetic determinants of these conditions. ? 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.     

Immune system gene dysregulation in autism and schizophrenia

Gene*environment interactions play critical roles in the emergence of autism and schizophrenia pathophysiology. In both disorders, recent genetic association studies have provided evidence for disease-linked variation in immune system genes and postmortem gene expression studies have shown extensive chronic immune abnormalities in brains of diseased subjects. Furthermore, peripheral biomarker studies revealed that both innate and adaptive immune systems are dysregulated. In both disorders symptoms of the disease correlate with the immune system dysfunction; yet, in autism this process appears to be chronic and sustained, while in schizophrenia it is exacerbated during acute episodes. Furthermore, since immune abnormalities endure into adulthood and anti-inflammatory agents appear to be beneficial, it is likely that these immune changes actively contribute to disease symptoms. Modeling these changes in animals provided further evidence that prenatal maternal immune activation alters neurodevelopment and leads to behavioral changes that are relevant for autism and schizophrenia. The converging evidence strongly argues that neurodevelopmental immune insults and genetic background critically interact and result in increased risk for either autism or schizophrenia. Further research in these areas may improve prenatal health screening in genetically at-risk families and may also lead to new preventive and/or therapeutic strategies. ? 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.     

Prenatal and postnatal animal models of immune activation: Relevance to a range of neurodevelopmental disorders

Epidemiological evidence has established links between immune activation during the prenatal or early postnatal period and increased risk of developing a range of neurodevelopment disorders in later life. Animal models have been used to great effect to explore the ramifications of immune activation during gestation and neonatal life. A range of behavioral, neurochemical, molecular, and structural outcome measures associated with schizophrenia, autism, cerebral palsy, and epilepsy have been assessed in models of prenatal and postnatal immune activation. However, the epidemiology-driven disease-first approach taken by some studies can be limiting and, despite the wealth of data, there is a lack of consensus in the literature as to the specific dose, timing, and nature of the immunogen that results in replicable and reproducible changes related to a single disease phenotype. In this review, we highlight a number of similarities and differences in models of prenatal and postnatal immune activation currently being used to investigate the origins of schizophrenia, autism, cerebral palsy, epilepsy, and Parkinson's disease. However, we describe a lack of synthesis not only between but also within disease-specific models. Our inability to compare the equivalency dose of immunogen used is identified as a significant yet easily remedied problem. We ask whether early life exposure to infection should be described as a disease-specific or general vulnerability factor for neurodevelopmental disorders and discuss the implications that either classification has on the design, strengths and limitations offuture experiments. ? 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.     

Review: Hyperthermia and fever during pregnancy

An episode of hyperthermia is not uncommon during pregnancy. The consequences depend on the extent of temperature elevation, its duration, and the stage of development when it occurs. Mild exposures during the preimplantation period and more severe exposures during embryonic and fetal development often result in prenatal death and abortion. Hyperthermia also causes a wide range of structural and functional defects. The central nervous system (CNS) is most at risk probably because it cannot compensate for the loss of prospective neurons by additional divisions by the surviving neuroblasts and it remains at risk at stages throughout pre- and postnatal life. In experimental animals the most common defects are of the neural tube, microphthalmia, cataract, and micrencephaly, with associated functional and behavioral problems. Defects of craniofacial development including clefts, the axial and appendicular skeleton, the body wall, teeth, and heart are also commonly found. Nearly all these defects have been found in human epidemiological studies following maternal fever or hyperthermia during pregnancy. Suggested future human studies include problems of CNS function after exposure to influenza and fever, including mental retardation, schizophrenia, autism, and cerebral palsy.     

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopamine-mediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed.     

Developmental programming of reproduction and fertility: what is the evidence?

The concept of the foetal/developmental origins of adult disease has been around for ~20 years and from the original epidemiological studies in human populations much more evidence has accumulated from the many studies in animal models. The majority of these have focused upon the role of early dietary intake before conception, through gestation and/or lactation and subsequent interactions with the postnatal environment, e.g. dietary and physical activity exposures. Whilst a number of theoretical models have been proposed to place the experimental data into a biological context, the underlying phenomena remain the same; developmental deficits (of single (micro) nutrients) during critical or sensitive periods of tissue growth alter the developmental pathway to ultimately constrain later functional capacity when the individual is adult. Ageing, without exception, exacerbates any programmed sequelae. Thus, adult phenotypes that have been relatively easy to characterise (e.g. blood pressure, insulin sensitivity, body fat mass) have received most attention in the literature. To date, relatively few studies have considered the effect of differential early environmental exposures on reproductive function and fecundity in predominantly mono-ovular species such as the sheep, cow and human. The available evidence suggests that prenatal insults, undernutrition for example, have little effect on lifetime reproductive capacity despite subtle effects on the hypothalamic-pituitary-gonadal axis and gonadal progenitor cell complement. The postnatal environment is clearly important, however, since neonatal/adolescent growth acceleration (itself not independent from prenatal experience) has been shown to significantly influence fecundity in farm animals. The present paper will expand these interesting areas of investigation and review the available evidence regarding developmental programming of reproduction and fertility. However, it appears there is little strong evidence to indicate that offspring fertility and reproductive senescence in the human and in farm animal species are overtly affected by prenatal nutrient exposure. Nevertheless, it is clear that the developing gonad is sensitive to its immediate environment but more detailed investigation is required to specifically test the long-term consequences of nutritional perturbations during pregnancy on adult reproductive well-being.     

Label-free quantitative proteomic analysis reveals dysfunction of complement pathway in peripheral blood of schizophrenia patients: evidence for the immune hypothesis of schizophrenia

Schizophrenia is a complex mental disease caused by a combination of serial alterations in genetic and environmental factors. Although the brain is usually considered as the most relevant organ in schizophrenia, accumulated evidence suggests that peripheral tissues also contribute to this disease. In particular, abnormalities of the immune system have been identified in the peripheral blood of schizophrenia patients. To screen the serum proteomic signature of schizophrenia patients, we conducted shotgun proteomic analysis on serum samples of schizophrenia patients and healthy controls. High-abundance proteins were eliminated by immunoaffinity before LC-MS/MS analysis. The multivariate statistical test partial least squares-discriminant analysis (PLS-DA) was applied to build models for screening out variable importance in the projection (VIP) and 27 proteins were identified as being responsible for discriminating between the proteomic profiles of schizophrenia patients and healthy controls. Pathway analysis based on these 27 proteins revealed that complement and coagulation cascades was the most significant pathway. ELISA-based activity analyses indicated that the alternative complement pathway was suppressed in schizophrenia patients. Ingenuity pathways analysis was used to conduct the interaction network of 27 proteins. The network exhibited common features such as, nervous system development and function, humoral immune response and inflammatory response, and highlighted some proteins with important roles in the immune system, such as hub nodes. Our findings indicate dysregulation of the alternative complement pathway in schizophrenia patients. The protein interaction network enhances the interpretation of proteomic data and provides evidence that the immune system may contribute to schizophrenia.     

LPS Exposure Increases Maternal Corticosterone Levels,Causes Placental Injury and Increases IL-1Β Levels in Adult Rat Offspring: Relevance to Autism

Maternal immune activation can induce neuropsychiatric disorders, such as autism and schizophrenia. Previous investigations by our group have shown that prenatal treatment of rats on gestation day 9.5 with lipopolysaccharide (LPS; 100 μg/kg, intraperitoneally), which mimics infections by gram-negative bacteria, induced autism-like behavior in male rats, including impaired communication and socialization and induced repetitive/restricted behavior. However, the behavior of female rats was unchanged. Little is known about how LPS-induced changes in the pregnant dam subsequently affect the developing fetus and the fetal immune system. The present study evaluated the hypothalamic-pituitary-adrenal (HPA) axis activity, the placental tissue and the reproductive performance of pregnant Wistar rats exposed to LPS. In the adult offspring, we evaluated the HPA axis and pro-inflammatory cytokine levels with or without a LPS challenge. LPS exposure increased maternal serum corticosterone levels, injured placental tissue and led to higher post-implantation loss, resulting in fewer live fetuses. The HPA axis was not affected in adult offspring. However, prenatal LPS exposure increased IL-1β serum levels, revealing that prenatal LPS exposure modified the immune response to a LPS challenge in adulthood. Increased IL-1β levels have been reported in several autistic patients. Together with our previous studies, our model induced autistic-like behavioral and immune disturbances in childhood and adulthood, indicating that it is a robust rat model of autism.     

Maternal immune activation and autism spectrum disorder: interleukin-6 signaling as a key mechanistic pathway

An emerging area of research in autism spectrum disorder (ASD) is the role of prenatal exposure to inflammatory mediators during critical developmental periods. Epidemiological data has highlighted this relationship showing significant correlations between prenatal exposure to pathogens, including influenza, and the occurrence of ASD. Although there has not been a definitive molecular mechanism established, researchers have begun to investigate this relationship as animal models of maternal infection have support- ed epidemiological findings. Several groups utilizing these animal models have found that activation of the maternal immune system, termed maternal immune activation (MIA), and more specifically the exposure of the developing fetus to maternal cytokines precipitate the neurological, immunological and behavioral abnormalities observed in the offspring of these animals. These abnormalities have correlated with clinical findings of immune dysregulation, neurological and behavioral abnormalities in some autistic individuals. Additionally, researchers have observed genetic variations in these models in genes which regulate neurological and immunological development, similar to what is observed clinically in ASD. Altogether, the role of MIA and cytokine dysregulation, as a key mediator in the neuropathological, behavioral and possibly genetic irregularities observed clinically in autism are important factors that warrant further investigation.     

Influence of postweaning social isolation in the rat on brain development, conditioned behaviour and neurotransmission

There is substantial evidence that early life events influence brain development and subsequent adult behaviour and play an important role in the causation of certain psychiatric disorders including schizophrenia and depression. The underlying mechanism of the effects of these early environmental factors is still not understood. It is a challenge to attempt to model early environmental factors in animals to gain understanding of the basic mechanisms that underlie the long-term effects. This paper reviews the effects of rearing rats from weaning in social isolation and reports some recent results indicating hippocampal dysfunction. Isolation rearing in rats from weaning produces a range of persistent behavioural changes in the young adult, including hyperactivity in response to novelty and amphetamine and altered responses to conditioning. These are associated with alterations in the central aminergic neurotransmitter functions in the mesolimbic areas and other brain regions. Isolation-reared rats have enhanced presynaptic dopamine (DA) and 5-HT function in the nucleus accimbens (NAC) associated with decreased presynaptic 5-HT function in the frontal cortex and hippocampus. Isolation-reared rats have reduced presynaptic noradrenergic function in the hippocampus, but have enhanced presynaptic DA function in the amygdala. These neurochemical imbalances may contribute to the exaggerated response of the isolated rat to a novel stimulus or to stimuli predictive of danger, and isolation-induced behavioural changes. These changes have neuroanatomical correlates; changes which seem to parallel to a certain degree those seen in human schizophrenia. A greater understanding of the processes that underlie these changes should improve our knowledge of how environmental events may alter brain development and function, and play a role in the development of neuropsychiatric disorders.     

Schizophrenia and the neurodevelopmental continuum:evidence from genomics

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention‐deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research.     

Rapporteur report: Epidemiology

Three talks were presented in the session on “Epidemiology”. The first talk was a review of prenatal studies. The second talk presented epidemiological evidence from prenatal studies. The third talk presented general issues regarding the planning of an epidemiological study. It was noted that epidemiological studies of prenatal exposures use data from the early 1980s when ultrasound was first introduced for foetal scans. These studies did not show associations between prenatal ultrasound scanning and childhood cancer, reduced birth weight, impaired childhood growth or neurological development in childhood. However, there was a possible association between prenatal ultrasound scanning and left-handedness in boys. The aetiology of this association remains uncertain.     

Are pre- or postnatal diagnostic X-rays a risk factor for childhood cancer? A systematic review

The risk of cancer after diagnostic X-rays received as fetus or during early childhood has been investigated in many studies. The results of recent epidemiological studies are summarized in a present systematic review. The strategies for literature search, inclusion criteria, and items for study quality assessment were defined in the study protocol. All epidemiological case control and cohort studies published in English between 1990 and 2006 that reported at least the size of the study population and risk estimates were included. Results were summarized separately for pre- and postnatal exposure and for each cancer site. Nineteen case control studies and six cohort studies matched the inclusion criteria. No association of leukemia with prenatal exposures was observed in nine case control studies. Heterogeneous results were found for postnatal exposures and leukemia in four studies. No significant effect of pre- and postnatal X-ray exposure was observed for other cancer sites (non-Hodgkin lymphomas, solid tumors and brain tumors). Most studies have limitations in study design, study size, or exposure measurement, and involve very low exposures. These results thus do not contradict previous evidence accumulated since 1956 indicating risk increases associated with prenatal X-ray exposure. Computed tomography is not covered in the studies and needs to be investigated in the future.     

Cerebral Response to Peripheral Challenge with a Viral Mimetic

It has been well established that peripheral inflammation resulting from microbial infections profoundly alters brain function. This review focuses on experimental systems that model cerebral effects of peripheral viral challenge. The most common models employ the induction of the acute phase response via intraperitoneal injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC). The ensuing transient surge of blood-borne inflammatory mediators induces a “mirror” inflammatory response in the brain characterized by the upregulated expression of a plethora of genes encoding cytokines, chemokines and other inflammatory/stress proteins. These inflammatory mediators modify the activity of neuronal networks leading to a constellation of behavioral traits collectively categorized as the sickness behavior. Sickness behavior is an important protective response of the host that has evolved to enhance survival and limit the spread of infections within a population. However, a growing body of clinical data indicates that the activation of inflammatory pathways in the brain may constitute a serious comorbidity factor for neuropathological conditions. Such comorbidity has been demonstrated using the PIC paradigm in experimental models of Alzheimer’s disease, prion disease and seizures. Also, prenatal or perinatal PIC challenge has been shown to disrupt normal cerebral development of the offspring resulting in phenotypes consistent with neuropsychiatric disorders, such as schizophrenia and autism. Remarkably, recent studies indicate that mild peripheral PIC challenge may be neuroprotective in stroke. Altogether, the PIC challenge paradigm represents a unique heuristic model to elucidate the immune-to-brain communication pathways and to explore preventive strategies for neuropathological disorders.     

Maternal and fetal antibrain antibodies in development and disease

Recent evidence has emerged indicating that the maternal immune response can have a substantial deleterious impact on prenatal development (Croen et al., [2008]: Biol Psychiatry 64:583-588). The maternal immune response is largely sequestered from the fetus. Maternal antibodies, specifically immunoglobulin G (IgG), are passed to the fetus to provide passive immunity throughout much of pregnancy. However, both protective and pathogenic autoantibodies have equal access to the fetus (Goines and Van de Water [2010]: Curr Opin Neurol 23:111-117). If the mother has an underlying autoimmune disease or has reactivity to fetal antigens, autoantibodies produced before or during pregnancy can target tissues in the developing fetus. One such tissue is the fetal brain. The blood brainbarrier (BBB) is developing during the fetal period allowing maternal antibodies to have direct access to the brain during gestation (Diamond et al. [2009]: Nat Rev Immunol; Braunschweig et al. [2011]; Neurotoxicology 29:226-231). It has been proposed that brain injury by circulating brain-specific maternal autoantibodies might underlie multiple congenital, developmental disorders (Lee et al. [2009]: Nat Med 15:91-96). In this review, we will discuss the current state of research in the area of maternal autoantibodies and the development of autism. ? 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.     

Neurobehavioral Dysfunction as a Possible Sentinel of Methylmercury Exposure

The main concern regarding methylmercury neurotoxicity relates to adverse effects on the brain during development. Many environmental chemicals may act as developmental neurotoxicants, but solid documentation from epidemiological studies exists only on methylmercury, lead, and polychlorinated biphenyls (PCBs). Neurobehavioral tests may reveal subtle dysfunctions, but the tests chosen must be valid and appropriate for the setting. In a prospective study in the Faroe Islands, the main neuropsychological functions affected by prenatal methylmercury exposure were attention, language and memory. Deficits in visuospatial function were mainly related to postnatal exposures. These associations were stable after adjustment for confounders and exclusion of the children with the highest exposures to methylmercury and PCBs. Tests with good psychometric properties were more likely to show an association with mercury exposure. Greater sensitivity was also seen with tests administered by specialized academic staff rather than a trained technician. Despite highly significant effects on nervous system function, the deficits were subtle, and mercury exposure explained only a small part of the variation. Available evidence suggests that neurotoxicity may have severe implications on public health, but current methods are not amenable to application as sentinels of adverse health effects in environmental health surveillance.     

Developmental exposure to bisphenol a modulates innate but not adaptive immune responses to influenza A virus infection

Bisphenol A (BPA) is used in numerous products, such as plastic bottles and food containers, from which it frequently leaches out and is consumed by humans. There is a growing public concern that BPA exposure may pose a significant threat to human health. Moreover, due to the widespread and constant nature of BPA exposure, not only adults but fetuses and neonates are also exposed to BPA. There is mounting evidence that developmental exposures to chemicals from our environment, including BPA, contribute to diseases late in life; yet, studies of how early life exposures specifically alter the immune system are limited. Herein we report an examination of how maternal exposure to a low, environmentally relevant dose of BPA affects the immune response to infection with influenza A virus. We exposed female mice during pregnancy and through lactation to the oral reference dose for BPA listed by the US Environmental Protection Agency, and comprehensively examined immune parameters directly linked to disease outcomes in adult offspring following infection with influenza A virus. We found that developmental exposure to BPA did not compromise disease-specific adaptive immunity against virus infection, or reduce the host's ability to clear the virus from the infected lung. However, maternal exposure to BPA transiently reduced the extent of infection-associated pulmonary inflammation and anti-viral gene expression in lung tissue. From these observations, we conclude that maternal exposure to BPA slightly modulates innate immunity in adult offspring, but does not impair the anti-viral adaptive immune response, which is critical for virus clearance and survival following influenza virus infection.     

Potential risk of asthma associated with in utero exposure to xenobiotics

The incidence of asthma, a complex disease and significant public health problem, has been increasing over the last 30 years for unknown reasons. Changes in environmental exposures or lifestyle may be involved. In some cases asthma may originate in utero or in early life. Associations have been found between in utero exposures to several xenobiotics and increased risk of asthma. There is convincing evidence that maternal smoking and/or in utero and perinatal exposure to environmental tobacco smoke are associated with increased risk of asthma. Similar effects have been demonstrated in animal models of allergic asthma. Evidence also suggests that in utero and/or early‐life exposures to various ambient air pollutants may increase the risk of asthma although supporting animal data are very limited. A few studies have suggested that in utero exposure to acetaminophen is associated with increased risk of asthma; however, animal data are lacking. Various vitamin deficiencies and supplements during pregnancy have been studied. In general, it appears that vitamins A, C, and E have protective effects and vitamins D and B may, in some instances, increase the risk, but the data are not conclusive. Some studies related to in utero exposures to polychlorinated biphenyls and bisphenol A and asthma risk are also reported. The underlying mechanisms for an association between xenobiotic exposures and asthma remain a matter of speculation. Genetic predisposition and epigenetic changes have been explored. The developing immune, respiratory, and nervous systems are potential targets. Oxidative stress and modulation of inflammation are thought to be involved. Birth Defects Research (Part C) 99:1–13, 2013. © 2013 Wiley Periodicals, Inc.