A hypothesis about how early developmental methylmercury exposure disrupts behavior in adulthood

Abstract

Events that disrupt the early development of the nervous system have lifelong, irreversible behavioral consequences. The environmental contaminant, methylmercury (MeHg), impairs neural development with effects that are manifested well into adulthood and even into aging. Noting the sensitivity of the developing brain to MeHg, the current review advances an argument that one outcome of early MeHg exposure is a distortion in the processing of reinforcing consequences that results in impaired choice, poor inhibition of prepotent responding, and perseveration on discrimination reversals (in the absence of alteration of extradimensional shifts). Neurochemical correlates include increased sensitivity to dopamine agonists and decreased sensitivity to gamma-aminobutyric acid (GABA) agonists. This leads to a hypothesis that the prefrontal cortex or dopamine neurotransmission is especially sensitive to even subtle gestational MeHg exposure and suggests that public health assessments of MeHg based on intellectual performance may underestimate the impact of MeHg in public health. Finally, those interested in modeling neural development may benefit from MeHg as an experimental model.

Cocaine self-administration in male and female rats perinatally exposed to PCBs: Evaluating drug use in an animal model of environmental contaminant exposure.

“…Likewise, other studies using animal models have reported that developmental exposure to lead (Clifford et al, 2011; D. K. Miller, Nation, & Bratton, 2000, 2001; Nation, Miller, & Bratton, 2000), cadmium (Nation & Miller, 1999), manganese (Guilarte et al, 2008; McDougall et al, 2008; Reichel et al, 2006), and methylmercury (Eccles & Annau, 1982; Newland, Reed, & Rasmussen, 2015; Rasmussen & Newland, 2001; Reed et al, 2008; Wagner, Reuhl, Ming, & Halladay, 2007) alter dopamine neurotransmission and alter the response to experimenter -administered psychostimulants during adulthood, often in a sex-specific manner. This is the first study to demonstrate that rats perinatally exposed to PCBs exhibit differences in the propensity to acquire self -administration of cocaine and is one of a handful of other studies demonstrating monoamine-disrupting environmental contaminants such as lead (Nation, Cardon, Heard, Valles, & Bratton, 2003; Nation, Smith, & Bratton, 2004; Rocha, Valles, Bratton, & Nation, 2008; Rocha, Valles, Cardon, Bratton, & Nation, 2005; Rocha, Valles, Hart, Bratton, & Nation, 2008; Valles, Rocha, Cardon, Bratton, & Nation, 2005) and cadmium (Cardon, Rocha, Valles, Bratton, & Nation, 2004) can also alter psychostimulant self-administration in adulthood after perinatal exposure.…”

Adolescent methylmercury exposure affects choice and delay discounting in mice

“…If adolescent MeHg exposure reduced reinforcer efficacy, then that would mean that adolescent MeHg exposure has a different effect than prenatal exposure. Gestational MeHg exposure is associated with enhanced breakpoints and higher response rates for food in rats (Paletz, Craig-Schmidt, & Newland, 2006; Reed, Banna, Donlin, & Newland, 2008), suggesting gestational MeHg exposure increases the impact of reinforcement on responding (Newland et al, 2015). This effect is in the opposite direction of that seen following adolescent exposure here and would represent a distinction between the behavioral effects of gestational and adolescent MeHg exposure.…”

“…These doses were selected because they produce approximately 0, 40, and 400 μg/kg/day of MeHg, respectively, in mice. These exposures cause also irreversible behavioral deficits, but no gross sensorimotor impairment, when exposure occurred during gestation in rats (Newland et al, 2015). MeHg exposure spanned PND 21 through 59.…”

“…In laboratory models, gestational MeHg exposure impairs the acquisition of choice (Newland, Reile, & Langston, 2004; Newland, Yezhou, Logdberg, & Berlin, 1994) and spatial- and visual-discrimination reversals (Paletz, Day, Craig-Schmidt, & Newland, 2007; Reed, Paletz, & Newland, 2006). MeHg-induced alterations to the dopamine neurotransmitter system are thought to underlie these behavioral impairments (Newland, Reed, & Rasmussen, 2015). Developmental MeHg exposure increases sensitivity to dopamine transporter inhibitors, such as amphetamine (Rasmussen & Newland, 2001) and cocaine (Reed & Newland, 2009), and increases DA neurotransmitter levels and DA reuptake in the adult rat brain (Bartolome et al, 1982; Bartolome, Whitmore, Seidler, & Slotkin, 1984).…”

Adolescent methylmercury exposure: Behavioral mechanisms and effects of sodium butyrate in mice

“…Methylmercury (MeHg) is an environmental neurotoxicant found in fish and is a significant public-health concern (National Research Council, 2000). In animal models, gestational exposure to doses of MeHg that encompass human exposures impairs reversal learning and choice in adulthood (Newland et al, 2008, 2004; Reed et al, 2006), suggesting deficiencies in executive functioning (Newland et al, 2015). However, the long-term behavioral effects of MeHg exposure in adolescence remain under explored.…”