NBTS28Gene expression in developing brain is altered by modestreductions in circulating levels of thyroid hormone

Mary Gilbert, Kevin Crofton, Gail Nelson, Geremy KnappUS Environmental Protection Agency, Research Triangle Park, NC,United States

Disruption of thyroid hormone (TH) homeostasis is a knowneffect of environmental contaminants. Although animal models ofdevelopmental TH deficiency can predict the impact of severe insultsto the thyroid system, the effects of moderate TH insufficiencies havenot been adequately addressed. This research investigated dose–response relationships of TH insufficiency on TH action in developingbrain. Three methods to perturb the thyroid axis were employed:propylthiouracil (PTU), dietary iodine deficiency, and perchlorate.PTU inhibits TH synthesis; iodine is an essential element for THsynthesis; and perchlorate is an environmental contaminant thatblocks iodine uptake. These treatments were delivered via drinkingwater or food, producing graded levels of TH reduction duringgestation and lactation. TH-responsive genes were examined incortex of offspring on PN14. A set of 8 genes that were significantlyaltered in a gene array analysis by PTU was selected based on themagnitude of change, significance to brain development, and link tothyroid function. Gene-expression was determined using qRT-PCRand used as an estimate of TH action, i.e., an indication of adequatelevels of TH in critical target tissues. Dose-dependent reductions inexpression of a number of genes were observed that were similaracross different modes of thyroid-axis perturbation. Significantreductions were also observed at doses that produced mild reduc-tions in circulating TH in dams or offspring. These findings suggestthat autoregulatory mechanisms of the thyroid axis may beinsufficient to maintain required tissue levels of TH in the developingbrain. (Does not necessarily reflect EPA policy.)

doi:10.1016/j.ntt.2010.04.029

NBTS29Outcome in mice exposed in utero to chlorpyrifos

Thomas M. Burbacher, Toby B. Cole, Jenna Fisher, Sarah Park,Sungwoo Hong, William C. Griffith, Elaine M. FaustmanDepartment of Environmental and Occupational Health Sciences, Schoolof Public Health, University of Washington, Seattle, WA, USA

Pregnant C57Bl/6J mice were injected subcutaneously daily fromGD6 to GD17 with chlorpyrifos (dissolved in DMSO) at 0, 2, 4, or12 mg/kg/day. Control mice received DMSO alone. Experiments wereconducted in three cohorts as part of a larger study that examinedother endpoints of toxicity (global gene expression and acetylcholi-nesterase activity in dams and fetuses). On postnatal day 4 afterparturition, litters were culled to six mice (3 males and 3 females).One male and one female from each litter were assigned randomly to“neurobehavioral assessment group A” and one male and one femalewere assigned to “neurobehavioral assessment group B”, with theremaining two mice used for measurement of brain acetylcholines-terase activity. At weaning, mice were transferred to the neurobeha-vioral testing facility and housed two per cage for the duration oftesting. No overt signs of cholinergic toxicity, such as tremors ordifficulty breathing, were observed in pregnant females or offspring.Postnatal weight gain was significantly reduced in chlorpyrifos-exposed offspring. Chlorpyrifos exposure delayed reflex righting butaccelerated negative geotaxis behavior. A gender specific effect ofchlorpyrifos exposure was observed on cued fear conditioning. Male

offspring exposed to chlorpyrifos exhibited lower response rates (%freezing) to the cue (tone) than controls. Chlorpyrifos exposureaffected Morris maze acquisition, retention and reversal. Most effectswere observed at the 12 mg/kg/day dosage. The results indicate thatchlorpyrifos affects a wide range of developmental processes.(Supported by CHC grants 5-P01-ES009601 NIEHS/NIH and RD-83170901-0 EPA and CEEH grant 5 P30 ES07033 NIEHS.)

doi:10.1016/j.ntt.2010.04.030

NBTS30Effects of methylphenidate on motivation in children withattention-deficit/hyperactivity disorder

John Chelonisa,b, Teresa Johnsonb, Sherry Fergusona,b, Brian Kubacakb,Mark Edwardsb, Merle Paulea,baNational Center for Toxicological Research-FDA, Jefferson, AR,United StatesbUniversity of Arkansas forMedical Sciences/Arkansas Children's Hospital,Little Rock, AR, United States

This research examined the effects of methylphenidate (MPH) onmotivation in children who were prescribed MPH for the treatment ofADHD using a progressive ratio (PR) task. Twenty-three children 7 to12 years of age completed two test sessions, one on medication andone off. During each session, children pressed a lever to earn nickelreinforcers, where the first press resulted in a reinforcer and tenadditional presses were required for each subsequent reinforcer.Children on MPH made significantly more responses during thanwhen off medication. This MPH-associated response increase wasreflected in a significant decrease in the inter-response times (IRT).Further, MPH administration resulted in a significant decrease in thevariability of IRTs. In contrast, the MPH administration had nosignificant effects on the means and variability of post-reinforcementpause durations. These results suggest that MPH increased motiva-tion in children being treated for ADHD. However, the inability ofMPH to significantly reduce post-reinforcement pauses while sim-ultaneously decreasing IRTs suggests that while MPH may increasemotivation to perform an ongoing task, it may have little effect on theinitiation of a task.

doi:10.1016/j.ntt.2010.04.031

NBTS31Effect of lifetime exposure to acrylamide on motor nerveconduction velocity in rats at one year of age

Joan Gareya, Zbigniew Biniendab, Merle PaulebaSRC, Inc, Arlington, VA, United StatesbNCTR/FDA, Jefferson, AR, United States

The ability of acrylamide (ACR) to alter motor nerve conductionvelocity (CV) in rats was addressed as part of a lifetime ACR exposurestudy. Reduction in CV among treated animals is considered a sensitivemethod for detecting the presence of ACR-induced neuropathy in theabsence of clearly identifiable locomotor dysfunction. We previouslyestablished a method of measuring CV in which changes in CV wereobserved in rats dosed (i.p.) with 30 mg/kg bw ACR daily over twoweeks; i.e., a statistically significantly lower CV was observed in ACR-treated rats compared with control rats. In the current study, Fischer344 rats were treated with ACR from gestational day 6 (dams weregavaged with 0, 0.1, 0.3, 1.0 or 5.0 mg/kg bw/day) through parturition.

NBTS 2010 Abstract504