Sherry A. Ferguson

Prenatal Bisphenol A Exposure Alters Sex-Specific Estrogen Receptor Expression in the Neonatal Rat Hypothalamus and Amygdala

Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERα) and ESR2 (ERβ) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6-21 with vehicle, 2.5 or 25 μg/kg bw/day BPA, or 5 or 10 μg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naïve control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naïve control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure.

Behavioral effects in monkeys exposed to 2,3,7,8-TCDD transmitted maternally during gestation and for four months of nursing

Abstract Behavioral effects that were detected in TCDD-exposed monkey offspring included alterations in the social behavior of the mother-infant dyad and of peer groups of the offspring after weaning. Performance on learning tasks was correlated with TCDD concentration in body fat.

Effects of postnatal lead exposure on open field behavior in monkeys

Nursery-reared rhesus monkeys were treated with either no lead or moderate levels of lead from day eight or nine until day 365 after birth. All subjects were at or below 5 micrograms/dl blood lead levels for at least 1.5 years by the time of the present study conducted at 4 years of age. Data were collected in a primate version of the open field test which proved sensitive to several behavioral alterations in the lead-treated monkeys. These significant differences included a failure to habituate as evidenced by number of sectors entered, increased durations of activity and environmental exploration, and a longer latency to enter the open field. Most of these effects were compatible with a hypothesis of hippocampal dysfunction in the lead-treated monkeys and appeared to indicate enduring lead-induced alterations. These results provide further support for a correlation between early lead exposure and hippocampal dysfunction. Additionally, the utility of a primate version of the open field test for behavioral toxicological studies is substantiated.

Neonatal PCP Is More Potent than Ketamine at Modifying Preweaning Behaviors of Sprague-Dawley Rats

Treatment with N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine (KET) or phencyclidine (PCP), can trigger apoptotic neurodegeneration in neonatal rodents; however, little is known about the behavioral alterations resulting from such treatment. Here, rats were sc treated with saline; 10 mg/kg PCP on postnatal days (PNDs) 7, 9, and 11; 20 mg/kg KET (six injections every 2 h on PND 7); or a regimen of ketamine and 250 mg/kg L-carnitine (KLC) both administered on PND 7 with additional 250 mg/kg doses of L-carnitine given on PNDs 8-11. Postinjection, the home cage behavior of each pup was categorized on PNDs 7-11. Slant board and forelimb hang behaviors were examined on PNDs 8-11 and 12-16, respectively. The initial KET or KLC injections on PND 7 elevated abnormal home cage activity (i.e., paresis and paddling); however, KLC pup behavior returned to normal by the fourth injection, indicating the protective effects of L-carnitine against NMDA antagonist toxicity. PCP treatment caused substantial abnormal home cage activity on each injection day (PNDs 7, 9, and 11). Latencies to turn on the slant board were significantly longer on PND 8 for KET- and PCP-treated pups and PND 10 for PCP-treated pups. On PND 12, the forelimb hang time of PCP-treated pups was significantly shorter. Body weight was decreased on PNDs 8-18 in PCP-treated pups and PNDs 8-10 in KET-treated pups. These data indicate that developmental NMDA antagonist treatment causes short-term behavioral alterations which appear related to motor coordination and may be cerebellar in nature. Furthermore, single PCP injections appear more potent at altering behavior than multiple injections of KET.

Home cage behavior and lead treatment in rhesus monkeys : a comparison with open-field behavior

Nursery-reared rhesus monkeys were treated with no (n = 4) or moderate levels of lead (n = 4) during the first postnatal year. Mean blood lead levels peaked at 55 micrograms/dl at 5 weeks of age, averaged 36 micrograms/dl for the remainder of the first year postpartum, and declined to < or = 5 micrograms/dl for the 4 monkeys by 2.3 years of age. Previously, the lead-treated monkeys exhibited increased environmental exploration and decreased inactivity in a nonhuman primate version of the open field when tested at 4, 5, and 6 years of age (5,6). The current study was designed to assess behavior in the home cage of these monkeys at 6 years of age to determine: (a) whether the increased exploration was specific to the open field, and (b) any lead-related behavioral alterations specific to the home cage. Each monkey was observed twice weekly for 10 weeks and the duration and frequency of 17 behaviors were recorded. Lead treatment did not result in significant alterations in any of the six behaviors which occurred with enough frequency to warrant analysis. As a whole, all monkeys were either inactive or engaged in self-grooming for a large proportion of the test session. Less frequent were behaviors such as locomotion, environmental exploration, and self-directed behaviors. The distribution of behavioral activities in the home cage differed from that in the open field. Potential reasons for the expression of significant lead-related effects in the open field and not in the home cage are discussed as well as the differences in distribution of behavioral activities.

Controlled exposure of female rhesus monkeys to 2,3,7,8-TCDD; Cognitive behavioral effects in their offspring

Abstract Offspring exposed to TCDD in utero and for four months of nursing were compared to cohort controls on a battery of behavioral measures. On spatial discrimination reversal learning, the exposed subjects were facilitated at lower TCDD dose, and exhibited a dose-dependent decrement as the TCDD dose increased.

A nonhuman primate version of the open field test for use in behavioral toxicology and teratology

As reviewed here, little work has been done on testing nonhuman primates individually in open field paradigms. Hence, normative data from three studies of rhesus monkeys are presented. Important criteria for describing the pattern of activity exhibited by monkeys in the open field are introduced and the effects of gender and differences in rearing are assessed. Differences between this nonhuman primate version of the open field and that typically used with rodents are discussed, including reasons for differences in the variability of behavior between monkeys and rodents and a comparison of coefficients of detection (as an index of the power of the test to detect group differences). Overall, the use of the nonhuman primate version of the open field in behavioral toxicology and teratology is feasible and may fill a significant niche not presently well represented.

Effects of arecoline and scopolamine on open field behavior of adult monkeys treated with lead during the first year postpartum

Nursery-reared rhesus monkeys were treated with no or moderate levels of lead during the first year postpartum. Previously, the lead-treated monkeys exhibited behaviors in the nonhuman primate version of the open field (10) resembling those caused by hippocampal lesions. The current study investigated the mechanism(s) underlying these lead-related effects using a cholinergic agonist (arecoline) and antagonist (scopolamine) as pharmacological probes that were administered prior to open field testing at 5 and 6 years of age, respectively. Arecoline decreased locomotion and number of sectors entered. Scopolamine decreased defecation frequency. Neither drug interacted with prior lead treatment, indicating limited cholinergic involvement in the expression of these alterations. The lead-treated subjects continued to exhibit alterations as previously reported (10); specifically, a longer latency to enter the open field, increased frequency and duration of environmental exploration and, at 5 years of age, decreased duration of inactivity in the open field. These effects were seen four and five years after lead treatment ended and nearly three and four years after blood lead levels had declined to less than or equal to 5 micrograms/dL. Although latency to enter and duration of inactivity seem to be approaching control levels, the increased exploration does not.

Lack of effect of chronic developmental lead treatment on biogenic amines and metabolites in monkey cerebrospinal fluid

Concentrations of 3,4 dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were assayed in the cerebrospinal fluid (CSF) of control and chronically lead-treated nursery-reared rhesus monkeys sampled periodically from infancy through adulthood. Blood lead levels peaked at 62 micrograms/dl at 1.5 months of age, averaged 45 micrograms/dl for the remainder of the first year postpartum, and were maintained at 14 micrograms/dl from 20-58 months of age. Cisternal CSF samples were collected monthly from 5-35 months of age and every 1-4 months from 36-58 months of age. Biogenic amine and metabolite concentrations were assayed by high-performance liquid chromatography with electrochemical detection. Overall concentrations of DOPAC, HVA, NE, MHPG, and 5-HIAA were not significantly different in the control and lead-treated groups nor were there any significant interactions between lead treatment and age for any measure. DOPAC, HVA, and 5-HIAA concentrations decreased gradually with age, whereas MHPG concentration decreased sharply between 35 and 40 months of age. NE concentration remained stable across development.