Effects Of Perinatal Lead Exposure Research Articles

Effect of perinatal lead exposure on intestinal microbiota of rats: preliminary results

Effect of perinatal lead exposure on intestinal microbiota of rats: preliminary results

The effect of perinatal lead exposure on dopamine receptor D2 expression in morphine dependent rats

The aim of this study was to investigate the behavioral and molecular effects of pre- and postnatal lead (Pb) exposure on the expression of morphine withdrawal and tolerance in adult rats. Rats were orally treated with 0.1% (1000ppm) lead acetate from conception, through gestation, up to postnatal day (PND) 28. Subsequently, behavioral experiments were conducted on adult (PND 60) male rats. To assess behavioral effects of morphine dependence in Pb-exposed rats two experimental models were used: naloxone-precipitated withdrawal signs and the assessment of morphine tolerance to antinociceptive effect in the tail-immersion test. Morphine withdrawal and tolerance were more expressed in Pb-exposed morphine administered rats than in morphine administered rats. In the case of morphine withdrawal signs the analysis of protein (Western blotting) and mRNA (RT PCR) expression revealed significantly higher dopamine D2 receptor (D2R) expression in prefrontal cortex, but not in striatum and hippocampus, in Pb-exposed morphine administered rats than in morphine administered rats. Differently, in the case of morphine tolerance the significant upregulation of D2R protein and mRNA expression in hippocampus, but not in prefrontal cortex or striatum, was demonstrated in Pb-exposed and morphine administered rats in comparison with morphine administered. These findings suggest that in morphine withdrawal and tolerant rats the perinatal Pb-exposure can affect D2R expression in brain region-specific manner. Immunohistochemical assessment of D2R expression in hippocampus showed translocation of D2R from membrane-cytoplasm in control rats to nucleus in morphine administered rats. Perinatal Pb-exposure did not induce the changes in the localization of D2R irrespective of morphine effect.

Sex and rearing condition modify the effects of perinatal lead exposure on learning and memory

Developmental lead (Pb) exposure is associated with cognitive impairments in humans and rodents alike. In particular, impaired spatial learning and memory, as assessed using the Morris water maze (MWM), has been noted in developmentally Pb-exposed rats. Although sex and rearing environment can influence MWM performance in normal animals, the interactions of sex and rearing environment on the impact of developmental Pb exposure on hippocampal-dependent processes has not been well characterized. The present study examined the effects of perinatal exposure (i.e., gestation through weaning) to different levels of Pb (250, 750 and 1500ppm Pb acetate in food) in males and females raised in a non-enriched environment (standard cage with 3 animals and no toys) or an enriched environment (large cage containing a variety of toys that were changed twice weekly). Testing in the MWM began at postnatal day 55. Behavioral outcomes were influenced by sex and rearing environment, with complex interactions with Pb exposure. In non-Pb exposed control animals, beneficial effects of environmental enrichment on spatial learning and memory were observed in males and females, with greater effects in females. Pb exposure in females mitigated at least some of the benefits of enrichment on learning, particularly at the lowest and highest exposure levels. In males, enrichment conferred a modest learning advantage and for the most part, Pb exposure did not affect this. However, in males with the highest Pb exposure, enrichment did help to overcome detrimental effects of Pb on learning. In females, any potential benefit to reference memory contributed by enrichment was muted by exposure to Pb and for the most part, this was not reproduced in males. Thus, there are complex interactions between sex, environment, and Pb exposure on spatial learning and memory. Environmental manipulation is a potential risk modifier of developmental Pb exposure and interacts with other factors including sex and amount of Pb exposure to affect the functional influences of Pb on the brain.

Toxic effects of perinatal lead exposure on the brain of rats: Involvement of oxidative stress and the beneficial role of antioxidants

The aim of this study was to determine whether changes in the activities of antioxidant enzymes occur in the brain of lead-exposed rats (300mgPb/L in drinking water) and to investigate the potential benefit of the administration of some natural antioxidants (Zn 20mg/L+vitamins A 50.000U/L, C 2g/L, E 500mg/L and B6 500mg/L) during pregnancy and lactation.Lead exposure caused a significant increase in brain TBARS (23%) vs. control, whereas co-administration of antioxidants+lead was effective in reducing TBARS levels. The catalase activity in brain samples of the lead group was enhanced 99% vs. control, but no changes were found in the remainder of the groups. No statistically significant effect of lead and/or antioxidants in brain SOD activity was noted. Acid phosphatase activity was enhanced in both lead groups but no changes were found in alkaline phosphatase activity. Finally, a statistically significant decrease (−35%) of acetylcholinesterase activity was noted in the lead+antioxidants group. This study provides evidence of the beneficial role of antioxidants in early status of brain development in rats against lead exposure.

Developmental lead exposure attenuates methamphetamine dose-effect self-administration performance and progressive ratio responding in the male rat

Perinatal (gestation/lactation) lead exposure modifies the reinforcement efficacy of various psychoactive drugs (e.g., cocaine, opiates) across the phases of initial selection, use, and abuse [Nation J.R., Cardon A.L., Heard H.M., Valles R., Bratton G.R. Perinatal lead exposure and relapse to drug-seeking behavior in the rat: a cocaine reinstatement study. Psychopharmacol 2003;168: 236–243.; Nation J.R., Smith K.R., Bratton G.R. Early developmental lead exposure increases sensitivity to cocaine in a self-administration paradigm. Pharmacol Biochem Behave 2004; 77: 127–13; Rocha A., Valles R., Cardon A.L., Bratton G.R., Nation J.R. Enhanced acquisition of cocaine self-administration in rats developmentally exposed to lead. Neuropsychopharmacol 2005; 30: 2058–2064.]. However, changes in sensitivity to methamphetamine across the phases of drug abuse have not been examined in animals perinatally exposed to lead. Because the mainstream popularity of methamphetamine in the United States is increasing and lead exposure continues to be widespread, an examination of this drug and how it may be modified by perinatal exposure to lead is warranted. The studies reported here examined the effects of perinatal lead exposure on adult self-administration of intravenous (i.v.) methamphetamine across the maintenance phase of drug addiction. Experiment 1 examined dose-effect patterns in control and lead-exposed animals. Experiment 2 evaluated control and lead-exposed animals in a progressive ratio task. Female rats were administered a 16-mg lead or a control solution for 30 days prior to breeding with non-exposed males. Exposure continued through pregnancy and lactation and was discontinued at weaning (postnatal day [PND] 21). Animals born to control or lead-exposed dams received indwelling jugular catheters as adults (PND 70) and subsequently were randomly assigned to one of the two studies, using only one male rat per litter for each study. The data showed a general attenuation of the reinforcement efficacy of methamphetamine in animals perinatally exposed to lead, as compared to control animals.

Developmental lead exposure alters methamphetamine self-administration in the male rat: Acquisition and reinstatement

The rate of acquisition of drug self-administration and the return to drug seeking are important elements of the overall drug profile, and are essential factors in understanding risks associated with drug abuse. Experiment 1 examined the effects of perinatal (gestation/lactation) lead exposure on adult rates of acquisition of intravenous (i.v.) methamphetamine self-administration. Experiment 2 investigated the effects of perinatal lead exposure on drug-maintained responding in a reinstatement (relapse) paradigm. In Experiment 1, female rats were gavaged daily with 0 or 16 mg lead for 30 days prior to breeding with nonexposed males. Lead exposure continued through gestation and lactation and was discontinued at weaning (postnatal day [PND] 21). Male rats born to control or lead-exposed dams were tested daily as adults in an acquisition paradigm that incorporated both Pavlovian and operant components. An initial 3-h autoshaping period preceded a 3-h self-administration period. For 35 daily training sessions i.v. methamphetamine infusions [inf] (0.02 mg/kg) were paired with the extension and retraction of a lever (autoshaping), while inf occurred during self-administration only when a lever press was executed (FR-1). In Experiment 2 animals developmentally exposed to lead were trained on an FR-2 to self-administer methamphetamine (0.04 mg/kg/inf) and then placed on an extinction schedule prior to receiving intraperitoneal (i.p.) priming injections of saline, 0.50, 1.00, or 1.50 mg/kg methamphetamine. The findings from Experiment 1 showed that acquisition was delayed in rats born to lead-exposed dams gavaged daily with 16 mg lead throughout gestation and lactation when a 0.02-mg/kg/inf of methamphetamine served as the reinforcement outcome. Additional data from Experiment 2 indicated priming cues (injections of methamphetamine [i.p.]) administered after extinction were less likely to occasion a return to drug seeking (relapse) in the 16-mg group relative to the 0-mg control group. These results suggest perinatal lead exposure alters patterns of methamphetamine self-administration during the adult cycle.

The effects of the GABA A antagonist bicuculline on cocaine self-administration in rats exposed to lead during gestation/lactation

The present investigation examined the effects of perinatal lead exposure on cocaine self-administration following a GABA A antagonist pretreatment. Female rats were exposed to either 0 or 16 mg lead daily for 30 days prior to breeding with unexposed males. Beginning on postnatal day (PND) 75, control ( N=10) and lead-exposed ( N=8) animals were trained to self-administer 0.50 mg/kg cocaine intravenously (IV). After stable responding was established, animals were tested at 0.03 and 0.06 mg/kg cocaine delivered intravenously (IV), combined with intraperitoneal (IP) administration of either saline, 0.50, 1.00 or 2.00 mg/kg bicuculline (a GABA A antagonist). The results showed that control animals increased self-administration responding at a cocaine dose of 0.06 mg/kg as bicuculline dose increased. Lead-exposed animals exhibited an opposite pattern, i.e., a decrease in active (cocaine) lever responding occurred as the bicuculline dose was increased. Results at the 0.03 mg/kg cocaine dose failed to show group separation, or significant changes consequent to the bicuculline pretreatment. The data suggest that GABA antagonism results in increased reward potency of a low dose of cocaine and further, that this effect is differentially expressed in animals exposed to perinatal lead.

The effects of perinatal exposure to lead on the discriminative stimulus properties of cocaine and related drugs in rats.

Developmental lead exposure may alter responsiveness to cocaine well into adulthood, and ultimately influence drug-use patterns. The present study examined the effect of perinatal lead exposure on the discriminative stimulus properties of cocaine. Female rats were treated with 0, 8, or 16 mg lead daily for 30 days before breeding with untreated males. This exposure regimen continued through gestation and until postnatal day (PND) 21, i.e., weaning. At PND 60 male pups were trained to discriminate between saline and cocaine (5 mg/kg) injections. After acquisition, a series of generalization/substitution tests were performed using a cumulative dosing procedure. Developmental lead exposure produced subsensitivity to SKF-82958 (D1-like dopamine receptor agonist), quinpirole (D2-like dopamine receptor agonist), and apomorphine (mixed D1-like/D2-like dopamine receptor agonist); but no differences were evident among lead-treatment groups on generalization/substitution tests with cocaine, d-amphetamine, or GBR-12909. Furthermore, when the kappa-opioid receptor agonist U69,593 was administered prior to cocaine (5 mg/kg), generalization to the cocaine stimulus decreased in control rats, but generalization in lead-exposed rats was not altered. Group differences were not evident in tolerance or recovery of tolerance to cocaine following repeated cocaine administration (60 mg/kg per day for 14 days). Furthermore, no differences were found across groups in concentrations of lead in brain, although pups exposed to 16 mg lead had slightly elevated blood lead concentrations (<7 microg/dl). These results further a growing research literature that suggests developmental lead exposure can produce long-lasting changes in drug responsiveness, even after exposure to the toxicant has been discontinued.

Developmental Lead Exposure Alters the Stimulatory Properties of Cocaine at PND 30 and PND 90 in the Rat

The aim of this study was to examine the effects of perinatal lead exposure on locomotor responding following acute and repeated cocaine challenges (sensitization). Adult female rats were gavaged daily with 0, 8, or 16 mg lead acetate for 30 days prior to breeding. This exposure regimen was maintained throughout gestation and lactation (perinatal exposure). On Day 21, male pups were weaned and lead exposure was discontinued for the remainder of the study. Beginning on postnatal day (PND) 30 or PND 90, and continuing for 14 successive days, separate groups of perinatally-exposed animals were presented with challenges of 10 mg/kg cocaine HCl (i.p.), and tested for locomotor responding. Following this testing period, dose-effect profiles were determined, with animals receiving daily injections of 0, 10, 20, and 40 mg/kg cocaine. The results indicated that both at PND 30 and PND 90 lead-exposed animals were less responsive to the initial administration of cocaine, but exhibited a supersensitivity to the stimulatory effects associated with repeated administration of cocaine, i.e., behavioral sensitization to cocaine was augmented by perinatal lead exposure. Analyses of blood lead levels following the completion of testing revealed that lead levels were below detectable limits for all animals (< 1 μg/dl). Collectively, these findings show that developmental lead contamination produces changes in cocaine sensitivity long after exposure has been discontinued and the toxicant has gained clearance from blood.

Developmental cholinotoxicity of lead: loss of septal cholinergic neurons and long-term changes in cholinergic innervation of the hippocampus in perinatally lead-exposed rats

The effects of perinatal lead exposure on choline acetyltransferase-immunoreactive (ChAT-IR) cell counts in the medial septum and AChE-positive fiber counts in the hippocampus were examined in relation to changes in cholinergic markers in the septohippocampal pathway of the rat. Maternal exposure to 0.2% lead acetate in drinking water from gestational day 16 through weaning at post-natal day 21 (P21) induced in the offspring a 30% reduction in septal ChAT activity and a 20% reduction in ChAT-IR cell profile counts in the medial septum/vertical diagonal band (MS/vDB). These changes were seen as early as P7, persisted through 2 months post-exposure (P81), and were followed by recovery of ChAT activity but not the ChAT-IR cell numbers, at 3 months post-exposure (P112). The loss of ChAT activity and ChAT-IR neurons in the septum was temporally associated with a reduction of ChAT activity (30%), hemicholinium-3 (HC-3) binding (40%), and AChE-positive fiber counts (13–15%) in the hippocampus. The hippocampal ChAT activity and AChE-positive fiber counts returned to control levels by P112 whereas HC-3 binding was restored to normal levels by P200. These results indicate that perinatal, low-level lead exposure induces loss of septohippocampal cholinergic projection neurons in neonate animals, resulting in a deficit in hippocampal cholinergic innervation that persists into young adulthood. The disruption of cholinergic septohippocampal system may be an important factor in lasting cognitive impairments associated with early Pb exposure.

Cholinergic denervation-like changes in rat hippocampus following developmental lead exposure

We investigated the effects of developmental lead exposure from embryonic day 16 (E16) through postnatal day 28 (PN28), on cholinergic and catecholaminergic markers in the septohippocampal pathway in rats through fourth month of age. Lead exposure resulted in a persistent 30–40% reduction of [ 3H]hemicholinium-3 ([ 3H]HC-3) binding in the hippocampus through PN120, and 20–30% reduction of septal and hippocampul choline acetyltransferase (ChAT) activity which persisted through PN84 but returned to control levels in both septum and hippocampus at PN112. The muscarinic ligand [ 3H]quinuclidinyl benzylate ([ 3H]QNB) binding was reduced in the septum at PN28 but did not differ significantly from controls at PN56–PN112. Neither short- nor long-term effects of Pb exposure on [ 3H]QNB binding were seen in the hippocampus. Similar to the effects of fimbria-fornix transection, Pb exposure resulted in a long-term 50–90% increase of tyrosine hydroxylase(TH) activity in the hippocampus, although neither treatment affected TH activity in the septum. The lead-induced increase in hippocampul TH was significantly attenuated by superior cervical ganglionectomy. It is concluded that the effects of perinatal lead exposure resemble in several respects those seen following surgical disruption of the septohippocampal pathway in adult animals. The denervation-like effects in the hippocampus may be an important factor in long-term learning and cognitive impairments following developmental exposure to low-levels of lead.

Effect of perinatal lead exposure on morphine tolerance in the neonatal rat

Administration of lead (at 300 and 1000 ppm) in the maternal drinking water from conception to postnatal day 10 increased the sensitivity of 10-day rat pups to noxious stimuli and disrupted the dose-response relationship to morphine antinociception. Lead-exposed rats could be made tolerant to morphine over a 5-day period (twice daily injections of 5 mg/kg morphine, postnatal days 5–10) and antinociceptive responses in tolerant rats were also disrupted by lead exposure.

Lack of effect of perinatal lead exposure on K-opioid receptor function

The effects of lead exposure have been studied upon the behavioural and diuretic responses to the k-opioid receptor agonist U-50488H in neonatal rats. Lead was administered in the maternal drinking water (100, 300 and 1000 ppm) from conception to postnatal day 14. The hyperactivity, wall climbing behaviours and diuretic effects of U-50488H (0.1–30 mg/kg i.p.) in 5- and 20-day-old rat pups were unaffected at all 3 lead dose levels. Lead treatment per se produced a decrease in activity at 20 days. These results con- trast with our previously reported disruption of μ- and δ-opioid receptor systems following perinatal lead exposure and suggest that the toxic effects of this metal may be confined to particular types of opioid receptor.

Effects of perinatal lead exposure on the ontogenesis of μ-opioid receptors in rat brain

Effects of perinatal lead exposure on the ontogenesis of μ-opioid receptors in rat brain

Ontogeny of catecholamine and gaba levels in rat brain: Lack of effect of perinatal lead exposure

In this study we report the ontogeny of noradrenaline, adrenaline, dopamine, and γ-aminobutyric acid (GABA) in the rat striatum and the effect of perinatal exposure to low levels of lead. Lead administered in the maternal drinking water (100, 300 and 1000 ppm) from conception to weaning had no effect on the ontogeny of catecholamines. There was a 50% decrease in the levels of GABA at 10 days in rats exposed to the highest dose of lead, but no other changes were observed in lead-exposed rats at 21 and 30 days of age. These results contrast with our previously reported decrease in the levels of striatal proenkephalin products in lead-exposed rats, and suggest that this inhibitory effect of lead does not represent a generalised neurochemical toxicity.