Animal Models of Childhood Exposure to Lead or Manganese: Evidence for Impaired Attention, Impulse Control, and Affect Regulation and Assessment of Potential Therapies

Abstract

Behavioral disorders involving attention and impulse control dysfunction, such as ADHD, are among the most prevalent disorders in children and adolescents, with significant impact on their lives. The etiology of these disorders is not well understood, but is recognized to be multifactorial, with studies reporting associations with polygenic and environmental risk factors, including toxicant exposure. Environmental epidemiological studies, while good at establishing associations with a variety of environmental and genetic risk factors, cannot establish causality. Animal models of behavioral disorders, when properly designed, can play an essential role in establishing causal relationships between environmental risk factors and a disorder, as well as provide model systems for elucidating underlying neural mechanisms and testing therapies. Here, we review how animal model studies of developmental lead or manganese exposure have been pivotal in (1) establishing a causal relationship between developmental exposure and lasting dysfunction in the domains of attention, impulse control, and affect regulation, and (2) testing the efficacy of specific therapeutic approaches for alleviating the lasting deficits. The lead and manganese case studies illustrate how animal models can advance knowledge in ways that are not possible in human studies. For example, in contrast to the Treatment of Lead Poisoned Children (TLC) human clinical trial evaluating succimer chelation efficacy to improve cognitive functioning in lead-exposed children, our developmental lead exposure animal model showed that succimer chelation can produce lasting cognitive benefits if chelation sufficiently reduces brain lead levels. In addition, this study revealed that succimer treatment in the absence of lead exposure produces lasting cognitive dysfunction, highlighting potential risks of chelation in off-label uses, such as the treatment of autistic children without a history of lead exposure. Our animal model of developmental manganese exposure has demonstrated that manganese can cause lasting attentional and sensorimotor deficits, akin to an ADHD-inattentive behavioral phenotype, thereby providing insights into the role of environmental exposures as contributors to ADHD. These studies have also shown that oral methylphenidate (Ritalin) can fully alleviate the deficits produced by early developmental Mn exposure. Future work should continue to focus on the development and use of animal models that appropriately recapitulate the complex behavioral phenotypes of behavioral disorders, in order to determine the mechanistic basis for the behavioral deficits caused by developmental exposure to environmental toxicants, and the efficacy of existing and emerging therapies.

Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD

“…Our rodent model of developmental Mn exposure recapitulates many of the adverse behavioral symptoms reported in ADHD children. While the neurobiological mechanisms underlying ADHD and related symptoms are not well understood, studies suggest that the combination of multiple environmental and biological risk factors lead to hypofunctioning of the catecholaminergic system within the fronto-cortico-striatal loop and other neural circuits underlying executive attention and emotion regulation [102][103][104][105][106] . Similarly, studies from our lab and others have demonstrated that developmental Mn exposure causes hypofunctioning of the catecholaminergic system in the prefrontal cortex and striatum [22][23][24] , including reducing stimulated dopamine and norepinephrine release 24,25 , and altered levels of dopaminergic and noradrenergic system proteins [22][23][24] .…”

Methylphenidate alleviates cognitive dysfunction from early Mn exposure: Role of catecholaminergic receptors

“…First, they are essential for testing the causal relationship between well-defined Mn exposures and these neurobehavioral symptoms. Second, they can facilitate determining the underlying neurobiological bases for the symptoms, which can inform the findings from pediatric epidemiologic studies and guide treatment options (Smith & Strupp, 2023). Our prior animal model studies have shown that developmental oral Mn exposure at levels corresponding to the exposure risk faced by newborns and young children can produce abnormalities in attentional processes and sensorimotor function, as well as hypofunctioning of the catecholaminergic fronto-cortico-striatal system that lasts into adulthood (Beaudin, Nisam, & Smith, 2013;Beaudin, Strupp, Strawderman, et al, 2017a;Conley et al, 2020a;Lasley et al, 2020a).…”

A New Look at Animal Models of Neurological Disorders

“…In this issue of Neurotherapeutics, authors illustrate how critical novel information can be provided by well-chosen animal models of a variety of neurological disorders. These insights range from a better understanding the impact of environmental factors, primarily heavy metals, on the developing brain as reviewed by Smith and Strupp [1], to novel information on multiple sclerosis provided by state-of-theart imaging techniques when used in animal models of the disorder as described by Buttigieg et al [2].…”