Elsevier

NeuroToxicology

Volume 32, Issue 1, January 2011, Pages 83-99
NeuroToxicology

Interactions of lifetime lead exposure and stress: Behavioral, neurochemical and HPA axis effects

https://doi.org/10.1016/j.neuro.2010.09.004Get rights and content

Abstract

Lead (Pb) and stress co-occur as risk factors, share biological substrates and produce common adverse effects. We previously found that prenatal restraint stress (PS) or offspring stress (OS) could enhance maternal Pb-induced behavioral, brain neurotransmitter level and HPA axis changes. The current study examined how lifetime Pb exposure, consistent with human environmental exposure, interacts with stress. Dams were exposed to Pb beginning 2 mos prior to breeding (0, 50 or 150 ppm in drinking water), PS on gestational days 16 and 17, or the combination. Offspring continued on the same Pb exposure as the dam. A subset of Pb + PS offspring also received 3 additional stress challenges (OS), yielding 9 exposure groups/gender: 0-NS, 0-PS, 0-OS, 50-NS, 50-PS, 50-OS, 150-NS, 150-PS and 150-OS. As with maternal Pb (Virgolini et al., 2008a), lifetime Pb and stress influenced Fixed Interval (FI) behavior primarily in females. Relative to 0-NS control, reductions in postreinforcement pause (PRP) times were seen only with combined Pb + PS (50-PS, 50-OS, 150-PS). Stress increased FI response rates when Pb alone was without effect (150-PS, 150-OS), but gradually mitigated rate increases produced by Pb alone (50-PS, 50-OS), effects that appear to be due primarily to PS, as they were of comparable magnitude in PS and OS groups. Individual subject data suggest that enhanced Pb and PS effects reflect increasing numbers of subjects shifting to the high end of the normal range of FI performance values, consistent with a dose–response type of Pb + stress additivity. Consistent with reports of cortico-striatal mediation of both interval timing (PRP) and FI rates, principal component analyses suggested potential mediation via altered frontal cortex norepinephrine, reduced nucleus accumbens dopaminergic control and enhanced striatal monoamine control. Altered FI performance, whether occurring through changes in response rate, PRP, or both, represent behavioral inefficiency and potentially sub-optimal or even dysfunctional resource/energy use.

Introduction

Significant successes in lowering blood lead (PbB) levels have been achieved in countries that removed Pb from paint and gasoline. Even in such places, however, many residual consequences of the prior uses of Pb still remain. In the U.S., for example, such consequences include the lifetime elevated exposures experienced by the current elderly segment of the population, an exposure that has been posited to contribute to several diseases and disorders in this age group (van Wijngaarden et al., 2009, Cheng et al., 2001, Gerr et al., 2002, Kim et al., 1995, Opler et al., 2004, Rajan et al., 2007, Rhodes et al., 2003, Menke et al., 2006). Sustained contamination from the prolonged use of Pb in paint and gasoline also underlies the current elevations of blood Pb that now preferentially impact low socioeconomic, medically underserved inner city children residing in old housing stock, i.e., the same communities that also sustain low follow-up rates after initial identification of elevated Pb exposures (Haley and Talbot, 2004, Kemper et al., 2005). The impact of this problem has been significantly broadened by the growing recognition of adverse cognitive effects in children at increasingly lower blood Pb levels (Canfield et al., 2003, Lanphear et al., 2005). Of course, elevated Pb burden also remains a significant problem in countries where leaded gasoline remains in use and/or where environmental regulations remain secondary to industrial development (He et al., 2009).

Although our understanding of the neurotoxic effects of Pb and the mechanism(s) by which they are achieved has increased substantially over the years, both as a result of human and experimental studies, this understanding reflects the effects of Pb exposure examined in isolation (Cory-Slechta, 2005). Human environmental Pb exposure, like all environmental chemical exposures, actually occurs in the context of numerous other risk factors for various diseases and disorders, including genetic and host risk factors, as well as other environmental exposures, some of which could conceivably have the potential to modify Pb-associated neurotoxicity (Cory-Slechta, 2005). For example, dietary calcium/iron levels can substantially alter Pb kinetics and its distribution across organ systems (Hashmi et al., 1989a, Hashmi et al., 1989b, Mahaffey et al., 1973, Mahaffey, 1974). Time of the year (season) can change blood Pb levels (Kemp et al., 2007), and aging has been shown to modify kinetics of Pb as well as its behavioral consequences (Cory-Slechta, 2005, Cory-Slechta, 1990a, Cory-Slechta and Pokora, 1991, Cory-Slechta et al., 1991).

Stress is considered a risk factor for a variety of human diseases and disorders (Bruce et al., 2009, De Vriendt et al., 2009, Evans and Schamberg, 2009, Figueredo, 2009, Flaherty et al., 2009, Kitaoka-Higashiguchi et al., 2009, Miller et al., 2009, Vere et al., 2009, Von Korff et al., 2009). Higher levels of stress with consequent sustained elevation of glucocorticoids have been postulated to account for the increased incidence of many diseases and disorders found in low socioeconomic status (SES) communities (Flaherty et al., 2009, Lupien et al., 2001, Lupien et al., 2000, Munck et al., 1984, Cohen et al., 2006, Pallares et al., 2007). Like Pb exposure, stress may be present at any time throughout the lifespan, and, depending upon what has been deemed an individual's allostatic load, i.e., the abrasion produced by the body's necessity to respond repeatedly to stress challenges (McEwen and Seeman, 1999), it can have pronounced and, particularly in the case of prenatal stress, permanent adverse consequences (Beydoun and Saftlas, 2008, McEwen, 2008, Rinaudo and Lamb, 2008).

In addition to co-occurrence as risk factors, particularly for low SES communities (Jones et al., 2009, Gaitens et al., 2009), Pb and stress also share common biological substrates and produce similar adverse consequences (Cory-Slechta et al., 2004, Cory-Slechta et al., 2008, Rossi-George et al., 2009, Virgolini et al., 2005, Virgolini et al., 2006, Virgolini et al., 2008a, Virgolini et al., 2008b). Both Pb and stress, for example, act on the hypothalamic–pituitary–adrenal (HPA) axis (Cory-Slechta et al., 2004, Rossi-George et al., 2009, Vyskocil et al., 1991, de Kloet et al., 1998, McEwen, 2007). In fact, maternal Pb exposure, like prenatal stress, induces a permanent change in HPA axis function that includes hypercortisolism as a consequence (Cory-Slechta et al., 2004, Cory-Slechta et al., 2008, Rossi-George et al., 2009, Virgolini et al., 2006, Virgolini et al., 2008a). Both Pb and stress, moreover, have been associated with deficits in cognition and attention (Canfield et al., 2003, Anderson and Armstead, 1995, Bellinger et al., 1994, Bradley and Corwyn, 2002, Canfield et al., 2004, Cory-Slechta, 1995, Dietrich et al., 2001, Dohrenwend, 1973, Needleman et al., 1996, Schwartz, 1994), a finding that may reflect their common targeting of brain dopamine and glutamatergic systems in regions including nucleus accumbens and hippocampus that are critical to mediation of such behaviors (Barrot et al., 2000, Cory-Slechta et al., 1998, Cory-Slechta et al., 1999, Diorio et al., 1993, Lowy et al., 1993, Moghaddam, 2002, Piazza et al., 1996, Pokora et al., 1996, Rouge-Pont et al., 1998).

Based upon their co-occurrence and shared biological substrates and consequences, we predicted the potential for enhanced toxicity in response to combined exposures to Pb and stress. Consistent with this assertion, enhanced effects were observed in behavioral, neurochemical and glucocorticoid outcomes in response to combined maternal Pb and stress in rats (Rossi-George et al., 2009, Virgolini et al., 2008a, Virgolini et al., 2008b, Cory-Slechta et al., 2009). For example, female offspring exposed maternally to 50 ppm Pb showed increases in response rates on a Fixed Interval (FI) schedule of reinforcement, a behavior highly sensitive to Pb (Cory-Slechta and Weiss, 1985) and exhibiting extensive cross-species generality (Kelleher and Morse, 1969), that were even further increased in groups subjected to Pb combined with prenatal (PS) followed by offspring stress (OS). The magnitude of the 50 ppm Pb + stress changes produced effect levels comparable to those associated with a higher Pb exposure level, 150 ppm, indicative of Pb and PS + OS stress additivity. Corresponding changes in catecholamines, particularly frontal cortex NE, 5HT and 5HIAA were also seen (Virgolini et al., 2008a). Male offspring have shown enhanced effects of maternal Pb combined with prenatal stress in further delaying glucocorticoid negative feedback (Rossi-George et al., 2009).

These prior studies of Pb exposure combined with PS ± OS were focused on determining the component of risk conferred specifically by early developmental Pb exposures. Human environmental Pb exposure is, of course, continuous across the life span. Therefore, through both acute effects of ongoing exposure, as well as accumulation and potential redistribution over time (Cory-Slechta, 1990a, Cory-Slechta, 1990b, Cory-Slechta et al., 1989, Drasch et al., 1987, Manea-Krichten et al., 1991), continuous or lifetime Pb exposure may exhibit a different pattern of interactions with stress than occurs with maternal Pb exposure alone. The current study used the same behavioral (Fixed Interval schedule-controlled performance), neurochemical and glucocorticoid measures employed in those studies of maternal Pb exposure to determine the interactions of lifetime Pb exposure, including levels just at those deemed to be of concern for children by the Centers for Disease Control, with PS ± OS.

Our prior studies have confirmed the importance of nucleus accumbens, striatal and frontal cortex monoamines in the mediation of Fixed Interval performance per se, as well as suggesting mediation of maternal Pb + stress effects (Virgolini et al., 2008a, Cory-Slechta et al., 1998, Cory-Slechta et al., 1997, Cory-Slechta et al., 2002, Evans and Cory-Slechta, 2000). The corticolimbic system, impacted by both Pb and stress, operates as a coordinated interacting network, rather than as individual regions with specific functions (Morgane et al., 2005), with dysfunction attributable to disruption of corresponding excitatory-inhibitory balance in these systems. Therefore, in addition to characterizing the nature of lifetime Pb ± stress interactions, evaluation of the relationships between associated neurotransmitter and corticosterone changes with FI performance were explored to provide initial information on potential mechanisms of combined Pb and stress-induced behavioral consequences.

Section snippets

Dams and Pb exposure

Three-week-old female Long Evans rats (Charles River, Germantown, NY) were randomly assigned to receive distilled deionized water drinking solutions with Pb acetate at concentrations of 0, 50 or 150 ppm, the same concentrations used with maternal Pb exposure ± stress which yielded blood Pb levels (PbBs) in dams at weaning averaging < 3, 11–12, and 31 μg/dl, respectively (Virgolini et al., 2008a). These PbBs are associated with similar behavioral deficits in rodents and children (Canfield et al.,

PbB concentrations

PbBs from dams measured after 3 mos of Pb exposure and at weaning, and from male and female offspring at 2 mos of age, and at the termination of behavioral testing are shown in Fig. 1. PbBs increased in a concentration-related manner (F(2,84) = 1004, p < 0.0001), with values averaging <3, 11–16 and 25–33 μg/dl at 0, 50 and 150 ppm, respectively, across groups (p < 0.0001, all comparisons). A main effect of treatment group (F(8,84) = 4.62, p = 0.0001) reflected the slightly higher levels of dams exposed to

Discussion

In addition to multiple effects of Pb, PS and OS alone, the current study also confirms that, when combined, lifetime Pb exposure and stress can produce enhanced effects in rats. In females, increased FI overall response rates as compared to 0-NS control were observed in the 150-PS and 150-OS but not the 150-NS, 0-PS or 0-OS groups. PRP times were reduced only with combined Pb and stress, i.e., in the 50-PS, 50-OS, and 150-PS, but not in the 0-PS, 0-OS, 50-NS or 150-NS groups (Fig. 4, Table 1).

Acknowledgements

Supported in part by grants ES01212 (D. Cory-Slechta) and ES01247 (T. Gasiewciz).

References (113)

  • T. De Vriendt et al.

    Chronic stress and obesity in adolescents: scientific evidence and methodological issues for epidemiological research

    Nutr Metab Cardiovasc Dis

    (2009)
  • R Diaz et al.

    Codistribution of the dopamine D3 receptor and glucocorticoid receptor mRNAs during striatal prenatal development in the rat

    Neurosci Lett

    (1997)
  • K.N. Dietrich et al.

    Early exposure to lead and juvenile delinquency

    Neurotoxicol Teratol

    (2001)
  • G.A. Drasch et al.

    Lead in human bones. Investigations of an occupationally non-exposed population in southern Bavaria (FRG). I: Adults

    Sci Total Environ

    (1987)
  • S.B. Evans et al.

    Prefrontal cortical manipulations alter the effects of intra-ventral striatal dopamine antagonists on fixed-interval performance in the rat

    Behav Brain Res

    (2000)
  • V.M. Figueredo

    The time has come for physicians to take notice: the impact of psychosocial stressors on the heart

    Am J Med

    (2009)
  • E.G. Flaherty et al.

    Adverse childhood exposures and reported child health at age 12

    Acad Pediatr

    (2009)
  • K. He et al.

    Blood lead levels of children and its trend in China

    Sci Total Environ

    (2009)
  • M. Joels

    Corticosteroid effects in the brain: U-shape it

    Trends Pharmacol Sci

    (2006)
  • M. Kern et al.

    Stimulatory and inhibitory effects of inorganic lead on calcineurin

    Toxicology

    (2000)
  • J.M. Koolhaas et al.

    The temporal dynamics of the stress response

    Neurosci Biobehav Rev

    (1997)
  • H.J. Little et al.

    Selective increases in regional brain glucocorticoid: a novel effect of chronic alcohol

    Neuroscience

    (2008)
  • S.J. Lupien et al.

    Child's stress hormone levels correlate with mother's socioeconomic status and depressive state

    Biol Psychiatry

    (2000)
  • M. Manea-Krichten et al.

    Comparative increases of lead and barium with age in human tooth enamel, rib and ulna

    Sci Total Environ

    (1991)
  • B.S. McEwen

    Understanding the potency of stressful early life experiences on brain and body function

    Metabolism

    (2008)
  • W.H. Meck et al.

    Cortico-striatal representation of time in animals and humans

    Curr Opin Neurobiol

    (2008)
  • B. Moghaddam

    Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders

    Biol Psychiatry

    (2002)
  • P.J. Morgane et al.

    A review of systems and networks of the limbic forebrain/limbic midbrain

    Prog Neurobiol

    (2005)
  • D.A. Morilak et al.

    Role of brain norepinephrine in the behavioral response to stress

    Prog Neuropsychopharmacol Biol Psychiatry

    (2005)
  • M.E. Pallares et al.

    Effects of prenatal stress on motor performance and anxiety behavior in Swiss mice

    Physiol Behav

    (2007)
  • A. Rossi-George et al.

    Alterations in glucocorticoid negative feedback following maternal Pb, prenatal stress and the combination: a potential biological unifying mechanism for their corresponding disease profiles

    Toxicol Appl Pharmacol

    (2009)
  • J. Schwartz

    Low-level lead exposure and children's IQ: a meta-analysis and search for a threshold

    Environ Res

    (1994)
  • S.S. al-Zahrani et al.

    Destruction of central noradrenergic neurones with DSP4 impairs the acquisition of temporal discrimination but does not affect memory for duration in a delayed conditional discrimination task

    Psychopharmacology (Berlin)

    (1997)
  • N.B. Anderson et al.

    Toward understanding the asociation of socioeconomic status and health: A new challenge for the biopsychosocial approach

    Psychosom Med

    (1995)
  • M. Barrot et al.

    The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-dependent

    Eur J Neurosci

    (2000)
  • D.C. Bellinger et al.

    Attentional correlates of dentin and bone lead levels in adolescents

    Arch Environ Health

    (1994)
  • H. Beydoun et al.

    Physical and mental health outcomes of prenatal maternal stress in human and animal studies: a review of recent evidence

    Paediatr Perinat Epidemiol

    (2008)
  • R.H. Bradley et al.

    Socioeconomic status and child development

    Annu Rev Psychol

    (2002)
  • M.A. Bruce et al.

    Social environmental stressors, psychological factors, and kidney disease, J

    Investig Med

    (2009)
  • R.L. Canfield et al.

    Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter

    N Engl J Med

    (2003)
  • R.L. Canfield et al.

    Impaired neuropsychological functioning in lead-exposed children

    Dev Neuropsychol

    (2004)
  • Y. Cheng et al.

    Bone lead and blood lead levels in relation to baseline blood pressure and the prospective development of hypertension: the Normative Aging Study

    Am J Epidemiol

    (2001)
  • S. Cohen et al.

    Socioeconomic status is associated with stress hormones

    Psychosom Med

    (2006)
  • D.A. Cory-Slechta

    Alterations in tissue Pb distribution and hematopoietic indices during advanced age

    Arch Toxicol

    (1990)
  • D.A. Cory-Slechta

    Relationships between lead-induced learning impairments and changes in dopaminergic, cholinergic and glutamatergic neurotransmitter system functions

    Annu Rev Pharmacol Toxicol

    (1995)
  • D.A. Cory-Slechta

    Comparative neurobehavioral toxicology of heavy metals

  • Cory-Slechta DA. Studying toxicants as single chemicals: does this strategy adequately identify neurotoxic risk?...
  • D.A. Cory-Slechta et al.

    Behavioral manifestations of prolonged lead exposure initiated at different stages of the life cycle: I. Schedule-controlled responding

    Neurotoxicology

    (1991)
  • D.A. Cory-Slechta et al.

    Alterations in schedule-controlled behavior of rodents correlated with prolonged lead exposure

  • D.A. Cory-Slechta et al.

    Behavioral manifestations of prolonged lead exposure initiated at different stages of the life cycle: II. Delayed spatial alternation

    Neurotoxicology

    (1991)
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