Associations of prenatal maternal urinary concentrations of triclosan and benzophenone-3 with cognition in 7.5-month-old infants.

BACKGROUND: Endocrine-disrupting chemicals (EDCs) have been linked to adverse health outcomes and prenatal exposure is known to impact infant and child development. However, few studies have assessed early developmental consequences of prenatal exposure to two common phenolic compounds, benzophenone-3 (BP-3) and triclosan (TCS). OBJECTIVE: We evaluated the relationship of prenatal exposure to BP-3 and TCS with infant cognition at 7.5 months via performance on a visual recognition memory (VRM) task. METHODS: Drawing from the Illinois Kids Development Study (IKIDS) cohort, prenatal exposure to BP-3 and TCS was assessed in pools of five urine samples collected from each woman across pregnancy. Cognition was measured in 310 infants using a VRM task assessing information processing speed, attention, and recognition memory through infrared eye-tracking. Generalized linear regression estimated exposure-outcome associations, followed by stratification to investigate modification of associations by infant sex and stimulus set. RESULTS: Sampled mothers were more likely to be white, college educated, and middle or high income relative to the US population. Mean chemical exposures were significantly higher than those of adult women in the NHANES cohort. In models adjusted for income, gestational age at birth, and testing age, prenatal BP-3 exposure was associated with an increase in run duration (average time spent looking at the stimuli before looking away) (ß = 0.0011, CI -0.0001:0.0022), indicating slower information processing speed, while TCS was associated with significantly longer time to familiarization (time to accrue a total of 20 s of looking time to the stimuli) (ß = 0.0686, CI 0.0203:0.1168, p < 0.01), indicating poorer attention. Stratum-specific analyses isolated both effects to male infants who viewed the second of two stimulus sets. CONCLUSION: Higher prenatal exposure to triclosan was associated with poorer attention in infancy, while benzophenone-3 may be associated with slower information processing speed, particularly among males.

A framework for assessing the impact of chemical exposures on neurodevelopment in ECHO: Opportunities and challenges.

The Environmental influences on Child Health Outcomes (ECHO) Program is a research initiative funded by the National Institutes of Health that capitalizes on existing cohort studies to investigate the impact of early life environmental factors on child health and development from infancy through adolescence. In the initial stage of the program, extant data from 70 existing cohort studies are being uploaded to a database that will be publicly available to researchers. This new database will represent an unprecedented opportunity for researchers to combine data across existing cohorts to address associations between prenatal chemical exposures and child neurodevelopment. Data elements collected by ECHO cohorts were determined via a series of surveys administered by the ECHO Data Analysis Center. The most common chemical classes quantified in multiple cohorts include organophosphate pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, environmental phenols (including bisphenol A), phthalates, and metals. For each of these chemicals, at least four ECHO cohorts also collected behavioral data during infancy/early childhood using the Child Behavior Checklist. For these chemicals and this neurodevelopmental assessment (as an example), existing data from multiple ECHO cohorts could be pooled to address research questions requiring larger sample sizes than previously available. In addition to summarizing the data that will be available, the article also describes some of the challenges inherent in combining existing data across cohorts, as well as the gaps that could be filled by the additional data collection in the ECHO Program going forward.

Prenatal exposure to PCBs in Cyp1a2 knock-out mice interferes with F1 fertility, impairs long-term potentiation, reduces acoustic startle and impairs conditioned freezing contextual memory with minimal transgenerational effects.

Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three-coplanar/five-noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2-/- ::Ahrb1 C57BL6/J mice compared with wild-type mice (Ahrb1  = high AHR affinity). Here we exposed gravid Cyp1a2-/- ::Ahrb1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F1 and F3 offspring (not F2 ). PCB-exposed F1 mice exhibited increased open-field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long-term potentiation with no change in spatial learning or memory. F1 mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F3 mice showed few effects. Gene expression changes were primarily in F1 PCB males compared with wild-type males. There were minimal RNA and DNA methylation changes in the hippocampus from F1 to F3 with no clear relevance to the functional effects. F0 PCB exposure during a period of rapid DNA de-/remethylation in a susceptible genotype produced clear F1 effects with little evidence of transgenerational effects in the F3 generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein.

A better approach to in vivo developmental neurotoxicity assessment: Alignment of rodent testing with effects seen in children after neurotoxic exposures.

High throughput screens for developmental neurotoxicity (DN) will facilitate evaluation of chemicals and can be used to prioritize those designated for follow-up. DN is evaluated under different guidelines. Those for drugs generally include peri- and postnatal studies and juvenile toxicity studies. For pesticides and commercial chemicals, when triggered, include developmental neurotoxicity studies (DNT) and extended one-generation reproductive toxicity studies. Raffaele et al. (2010) reviewed 69 pesticide DNT studies and found two of the four behavioral tests underperformed. There are now many epidemiological studies on children showing adverse neurocognitive effects, yet guideline DN studies fail to assess most of the functions affected in children; nor do DN guidelines reflect the advances in brain structure-function relationships from neuroscience. By reducing the number of test ages, removing underperforming tests and replacing them with tests that assess cognitive abilities relevant to children, the value of DN protocols can be improved. Testing for the brain networks that mediate higher cognitive functions need to include assessments of working memory, attention, long-term memory (explicit, implicit, and emotional), and executive functions such as cognitive flexibility. The current DNT focus on what can be measured should be replaced with what should be measured. With the wealth of data available from human studies and neuroscience, the recommendation is made for changes to make DN studies better focused on human-relevant functions using tests of proven validity that assess comparable functions to tests used in children. Such changes will provide regulatory authorities with more relevant data.

Effects of COVID-19 Financial and Social Hardships on Infants' and Toddlers' Development in the ECHO Program.

BACKGROUND: The financial hardships and social isolation experienced during the COVID-19 pandemic have been found to adversely affect children's developmental outcomes. While many studies thus far have focused on school-aged children and the pandemic-related impacts on their academic skills and behavior problems, relatively less is known about pandemic hardships and associations with children's development during their early years. Using a racially and economically diverse sample, we examined whether hardships experienced during the pandemic were associated with children's development with a particular focus on communication and socioemotional development. METHODS: Participants from eight cohorts of the Environmental influences on Child Health Outcomes program provided data on pandemic-related financial and social hardships as well as child developmental outcomes. Financial hardship was defined as at least one parent experiencing job loss or change, and social hardship was defined as families' quarantining from household members or extended family and friends. The development of children under 4 was assessed longitudinally, before and during the pandemic (N = 684), using the Ages and Stages Questionnaire (ASQ). The Generalized Estimating Equations, which accounted for within-child correlation, were used for analysis. RESULTS: Families from minority backgrounds and low socioeconomic status disproportionately experienced pandemic-related hardships. Male children had higher odds of experiencing negative changes in communication and personal social skills from pre- to during-pandemic visits (ORs ranged between 2.24 and 3.03 in analysis with binary ASQ outcomes and ranged from -0.34-0.36 in analyses with ASQ z-scores, ps = 0.000). Pandemic-related hardships in the social and financial areas did not explain within-individual changes in children's developmental outcomes. CONCLUSION: Negative developmental changes from pre- to during-pandemic were found in boys, yet we did not find any associations between increased experience of pandemic-related hardships and children's development. E how pandemic hardships affect development using a larger sample size and with longer follow-up is warranted.

Associations of prenatal exposure to per- and polyfluoroalkyl substances (PFAS) with measures of cognition in 7.5-month-old infants: An exploratory study.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to a wide array of adverse maternal and child health outcomes. However, studies examining PFAS in relation to offspring cognition have been inconclusive. OBJECTIVE: We examined whether prenatal exposure to a mixture of PFAS was related to cognition in 7.5-month-old infants. METHODS: Our analytic sample included participants enrolled in the Chemicals in Our Bodies (CIOB) and Illinois Kids Development Study (IKIDS) cohorts (N = 163). Seven PFAS were measured in 2nd trimester maternal serum samples and were detected in >65% of participants. Infant cognition was measured with a visual recognition memory task using an infrared eye tracker when infants were 7.5 months old. This task included familiarization trials where each infant was shown two identical faces and test trials where each infant was shown the familiar face paired with a novel face. In familiarization, we assessed average run duration (time looking at familiarization stimuli before looking away) as a measure of information processing speed, in addition to time to familiarization (time to reach 20 s of looking at stimuli) and shift rate (the number of times infants looked between stimuli), both as measures of attention. In test trials, we assessed novelty preference (proportion of time looking to the novel face) to measure recognition memory. Linear regression was used to estimate associations of individual PFAS with cognitive outcomes, while Bayesian kernel machine regression (BKMR) was used to estimate mixture effects. RESULTS: In adjusted single-PFAS linear regression models, an interquartile range increase in PFNA, PFOA, PFOS, PFHxS, PFDeA, and PFUdA was associated with an increase in shift rate, reflecting better visual attention. Using BKMR, increasing quartiles of the PFAS mixture was similarly associated with a modest increase in shift rate. There were no significant associations between PFAS exposure and time to reach familiarization (another measure of attention), average run duration (information processing speed), or novelty preference (visual recognition memory). CONCLUSION: In our study population, prenatal PFAS exposure was modestly associated with an increase in shift rate and was not strongly associated with any adverse cognitive outcomes in 7.5-month-old infants.

Prenatal Antidepressant Exposures and Autism Spectrum Disorder or Traits: A Retrospective, Multi-Cohort Study.

Prenatal antidepressant exposure has been associated with increased risk for neurodevelopmental disorders in childhood, including autism spectrum disorder (ASD). The current study utilized multi-cohort data from the Environmental influences on Child Health Outcomes (ECHO) program (N = 3129) to test for this association, and determine whether the association remained after adjusting for maternal prenatal depression and other potential confounders. Antidepressants and a subset of selective serotonin reuptake inhibitors (SSRIs) were examined in relation to binary (e.g., diagnostic) and continuous measures of ASD and ASD related traits (e.g., social difficulties, behavior problems) in children 1.5 to 12 years of age. Child sex was tested as an effect modifier. While prenatal antidepressant exposure was associated with ASD related traits in univariate analyses, these associations were statistically non-significant in models that adjusted for prenatal maternal depression and other maternal and child characteristics. Sex assigned at birth was not an effect modifier for the prenatal antidepressant and child ASD relationship. Overall, we found no association between prenatal antidepressant exposures and ASD diagnoses or traits. Discontinuation of antidepressants in pregnancy does not appear to be warranted on the basis of increased risk for offspring ASD.

Associations of prenatal phthalate exposure with neurobehavioral outcomes in 4.5- and 7.5-month-old infants.

Phthalates are ubiquitous endocrine-disrupting chemicals, and research indicates that prenatal exposure to some phthalates may affect neurodevelopment. In a prospective birth cohort study, five first-morning urine samples collected across pregnancy were pooled and the following phthalate biomarkers assessed: sum of di-(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of diisononyl phthalate metabolites (ΣDINP), sum of dibutyl phthalate metabolites (ΣDBP), sum of anti-androgenic metabolites (ΣAA), monoethyl phthalate (MEP), and sum of all phthalate metabolites (ΣAll). The Ages & Stages Questionnaires® (ASQ), a standardized parent-reported, age-adapted screening tool, measured communication, personal-social, problem solving, and motor domains in infants at 4.5 and 7.5 months (n = 123). Adjusting for maternal age, annual household income, gestational age at birth, infant age at assessment, and sex, repeated-measures generalized linear regression models were used to examine associations between prenatal phthalate urine biomarker concentrations and domain scores (assuming a Poisson distribution). Beta estimates were exponentiated back to the domain scale for ease of interpretation. Mothers were mostly white and college-educated, and most reported an annual household income of ≥$60,000. Associations of phthalate concentrations with ASQ outcomes are presented as follows: (1) anti-androgenic phthalate metabolites (ΣDEHP, ΣDINP, ΣDBP, and ΣAA), (2) MEP, which is not anti-androgenic, and (3) ΣAll. Overall, anti-androgenic phthalates were associated with higher (i.e., better) scores. However, there were exceptions, including the finding that a one-unit increase in ΣDBP was associated with a 12% increase in problem solving scores in 4.5-month-old females (ß = 1.12; 95% CI: 0.99, 1.28; p = 0.067) but a 85% decrease for 7.5-month-old females (ß = 0.54; 95% CI: 0.3, 0.99; p = 0.047). In contrast, MEP was associated with poorer scores on several outcomes. Sex- and timepoint-specific estimates demonstrated a one-unit increase in MEP was associated with: a 52% decrease in personal-social scores in 7.5-month-old males (ß = 0.66; 95% CI: 0.46, 0.95; p = 0.02), a 39% decrease in fine motor scores in 7.5-month-old males (ß = 0.72; 95% CI: 0.52, 0.98; p = 0.035), and a 6% decrease in fine motor scores in 4.5-month-old females (ß = 0.94; 95% CI: 0.88, 0.99; p = 0.03). A one-unit increase in ΣAll was associated with a 4% increase in personal-social scores in 4.5-month-old males (ß = 1.04; 95% CI: 0.99, 1.1; p = 0.08) but a 17% decrease in 7.5-month-old males (ß = 0.85; 95% CI: 0.73, 0.99; p = 0.03). These data suggest age- and sex-specific associations of prenatal phthalates with infant neurobehavior. The current findings should be confirmed by longitudinal studies with larger sample sizes.

Associations of concurrent PCB and PBDE serum concentrations with executive functioning in adolescents.

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental chemicals that have long half-lives. Humans are exposed to PCBs and PBDEs mainly through diet, and relative to other populations, those who consume sport-caught fish generally have elevated body burdens. Numerous studies have found associations between prenatal exposure to these chemicals and neurodevelopmental deficits, but there are few studies assessing the impact of exposure during adolescence, a period of rapid development of executive functions. We assessed executive functions in adolescents at risk for exposure to PCBs and PBDEs through consumption of fish from the Lower Fox River and other contaminated waters in northeastern Wisconsin. Between 2007 and 2012, a sample of 115 12-18-year-old children was recruited from households in the Green Bay, WI area in which at least one parent held a WI fishing license. We assessed associations of total PCBs and total PBDEs, as well as the predominant individual congeners (PBDE 47 and 153; PCB 138/163, 153 and 180) with performance on four tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB): Intradimensional/Extradimensional Set-Shifting (ID/ED) which assesses cognitive flexibility, Delayed Matching to Sample (DMS) which assesses visual recognition memory, Spatial Working Memory (SWM), and Stockings of Cambridge (SOC) which assess planning and working memory. In addition to the exposure and outcome variables, multivariable regression models included the child's age, sex and IQ score as well as a sex by exposure interaction term. All of the children were non-Hispanic whites and most parents were married, employed, and had at least some college. After adjusting for serum lipids, the GM (GSD) for total PCBs (ng/g) was 30.83 (2.46), and the GM (GSD) for the predominant PCB congeners PCB 138/163, PCB 153, and PCB 180 were 4.60 (2.39), 5.43 (2.37), and 1.01 (2.71), respectively. The GM (GSD) for total PBDEs (ng/g) was 26.82 (3.30), and the GM (GSD) for the predominant PBDE congeners PBDE 47 and PBDE 153 were 16.64 (2.94) and 3.95 (3.43), respectively. For both chemicals, the primary finding of the negative binomial regression analyses was that higher blood serum concentrations were associated with poorer cognitive flexibility as measured on the ID/ED task. In particular, the PCB x sex interaction p-value was 0.08, and stratifying by sex demonstrated that males with higher blood serum total PCB concentrations (ß = 2.20, 95% CL: 1.16, 4.16, p = 0.02) took more trials to complete the ID/ED task, while both males and females with higher total PBDE concentrations (ß = 1.74, 95% CL: 1.25, 2.42, p = 0.001) took more total trials to complete the task. Higher serum total PCB concentrations were also associated with more errors on the DMS task (ß = 1.15, 95% CL: 1.00, 1.31, p < 0.05). These findings suggest that exposure to PCBs or PBDEs during adolescence may be associated with impaired cognitive flexibility and that adolescent PCB exposure may be associated with visual recognition memory deficits.

Impact of preweaning stress on long-term neurobehavioral outcomes in Sprague-Dawley rats: Differential effects of barren cage rearing, pup isolation, and the combination.

Two developmental stressors were compared in preweaning rats exposed to either one stressor or both. Stressors were barren cage rearing or maternal separation (pup isolation). 40 gravid Sprague-Dawley CD/IGS rats were randomly assigned to two cage conditions: standard (Std) cage or barren cage (Bar), 20 litters/condition throughout gestation and lactation. After delivery, litters were randomly culled to 4 males and 4 females. The second stressor was maternal separation: Two male/female pairs per litter were isolated from their dam 4 h/day (Iso) and two pairs were not (Norm). Hence, there were 4 conditions: Std-Norm, Std-Iso, Bar-Norm, and Bar-Iso. One pair/litter/stress condition received the following: elevated zero-maze (EZM), open-field, swim channel, Cincinnati water maze, conditioned fear, and open-field with methamphetamine challenge. The second pair/litter/condition received the light-dark test, swim channel, Morris water maze, forced swim, and EZM with diazepam challenge. Barren rearing reduced EZM time-in-open, whereas isolation rearing reduced open-field activity in males and increased it in females. Effects on straight channel swimming were minor. In the Cincinnati water maze test of egocentric learning, isolation rearing increased errors whereas barren cage housing reduced errors in combination with normal rearing. Barren cage with maternal separation (pup isolation) increased Cincinnati water maze escape latency but not errors. Barren cage housing reduced hyperactivity in response to methamphetamine. Isolation rearing increased time in open in the EZM after diazepam challenge. Trends were seen in the Morris water maze. These suggested that barren cage and isolation rearing in combination reduced latency on acquisition on days 1 and 2 in males, whereas females had increased latency on days 2 and 3. Combined exposure to two developmental stressors did not induce additive or synergistic effects, however the data show that these stressors had long-term effects with some evidence that the combination of both caused effects when either stressor alone did not, but synergism was not observed.

Developmental manganese, lead, and barren cage exposure have adverse long-term neurocognitive, behavioral and monoamine effects in Sprague-Dawley rats.

Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES households experience more stress and are more likely to be exposed to environmental neurotoxins such as lead (Pb) and manganese (Mn) than children in higher SES households. Co-exposure to stress, Pb, and Mn during early development may increase the risk of central nervous system dysfunction compared with unexposed children. To investigate the potential interaction of these factors, Sprague-Dawley rats were bred, and litters born in-house were culled on postnatal day (P)1 to 6 males and 6 females. One male and female within each litter were assigned to one of the following groups: 0 (vehicle), 10 mg/kg Pb, 100 mg/kg Mn, or 10 mg/kg Pb + 100 mg/kg Mn (PbMn), water gavage, and handled only from P4-28 with half the litters reared in cages with standard bedding (29 litters) and half with no bedding (Barren; 27 litters). Mn and PbMn groups had decreased anxiety, reduced acoustic startle, initial open-field hypoactivity, increased activity following (+)-methamphetamine, deficits in egocentric learning in the Cincinnati water maze (CWM), and deficits in latent inhibition conditioning. Pb increased anxiety and reduced open-field activity. Barren-reared rats had decreased anxiety, CWM deficits, increased startle, and initial open-field hyperactivity. Mn, PbMn, Pb Barren-reared groups had impaired Morris water maze performance. Pb altered neostriatal serotonin and norepinephrine, Mn increased hippocampal serotonin in males, Mn + Barren-rearing increased neostriatal serotonin, and Barren-rearing decreased neostriatal dopamine in males. At the doses used here, most effects were in the Mn and PbMn groups. Few interactions between Mn, Pb, and rearing stress were found, indicating that the interaction of these three variables is not as impactful as hypothesized.

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

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants known to adversely impact human health. Ortho-substituted PCBs affect the nervous system, including the brain dopaminergic system. The reinforcing effects of psychostimulants are typically modulated via the dopaminergic system, so this study used a preclinical (i.e., rodent) model to evaluate whether developmental contaminant exposure altered intravenous self-administration (IV SA) for the psychostimulant cocaine. Long-Evans rats were perinatally exposed to 6 or 3 mg/kg/day of PCBs throughout gestation and lactation and compared with nonexposed controls. Rats were trained to lever press for a food reinforcer in an operant chamber under a fixed-ratio 5 (FR5) schedule and later underwent jugular catheterization. Food reinforcers were switched for infusions of 250 µg of cocaine, but the response requirement to earn the reinforcer remained. Active lever presses and infusions were higher in males during response acquisition and maintenance. The same sex effect was observed during later sessions which evaluated responding for cocaine doses ranging from 31.25-500 µg. PCB-exposed males (not females) exhibited an increase in cocaine infusions (with a similar trend in active lever presses) during acquisition, but no PCB-related differences were observed during maintenance, examination of the cocaine dose-response relationship, or progressive ratio (PR) sessions. Overall, these results indicated perinatal PCB exposure enhanced early cocaine drug-seeking in this preclinical model of developmental contaminant exposure (particularly the males), but no differences were seen during later cocaine SA sessions. As such, additional questions regarding substance abuse proclivity may be warranted in epidemiological studies evaluating environmental contaminant exposures. (PsycINFO Database Record

Cocaine sensitization in adult Long-Evans rats perinatally exposed to polychlorinated biphenyls.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants known to adversely affect the nervous system and more specifically the dopamine system. Developmental PCB exposure in rats has been shown to produce alterations in dopaminergic signaling that persist into adulthood. The reinforcing properties of psychostimulants are typically modulated via the dopaminergic system, so this project used a behavioral sensitization paradigm to evaluate whether perinatal PCB exposure altered sensitization to the psychostimulant cocaine. Long-Evans rats were perinatally exposed to 0, 3 or 6mg/kg/day of PCBs throughout gestation and lactation. One male and female pup from each litter was retained for behavioral testing. Both horizontal and vertical activity were used to measure cocaine sensitization following repeated injections of 10mg/kg cocaine (IP) on post-natal day (PND) 91-96 and again after a week in the home cage on PND 103. A final locomotor activity session following a challenge injection of 20mg/kg was given on PND 110 to further evaluate the availability of presynaptic dopamine stores. The PCB-exposed rats appeared to be pre-sensitized to cocaine as they exhibited a greater degree of cocaine-induced locomotor activation to the initial injections of cocaine and therefore demonstrated a more rapid onset of cocaine behavioral sensitization compared to non-exposed controls. These results add to the literature detailing how perinatal exposure to dopamine-disrupting contaminants can change the developing brain, thereby producing permanent changes in the neurobehavioral response to psychostimulants later in life.

Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats.

Most antidepressants inhibit monoamine reuptake. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) act on the 5-HT transporter (SERT) whereas norepinephrine-dopamine reuptake inhibitors (NDRIs) act on the norepinephrine and dopamine transporters. Epidemiological reports link SSRI use during pregnancy to an increased prevalence of autism spectrum disorder (ASD). We previously showed that perinatal exposure to the SSRI citalopram (CIT) results in rodent offspring that exhibit a number of behaviors consistent with an ASD-like phenotype. The present study examined the effect of perinatal exposure to CIT (at a lower dose), another SSRI, fluoxetine (FLX), and an NDRI, bupropion (BUP). Gravid Sprague-Dawley rats were subcutaneously injected twice per day (6h apart) with 5mg/kg CIT, 5mg/kg FLX, 15mg/kg BUP, or saline (SAL) from embryonic day (E) 6-21, and directly to the pups from postnatal day (P) 1-20. As adults, one male/female from each litter was given one of a series of tests. Both SSRI-exposed groups showed spatial learning deficits in Morris and radial water mazes, increased marble burying, increased acoustic startle, hypoactivity, and attenuated activity to the stimulating effect of the NMDA-R antagonist MK-801. The BUP-exposed group showed a reduction in elevated zero-maze quadrant entries and increased stimulated open-field activity following (+)-amphetamine challenge. These results reinforce concern about the use of antidepressants during pregnancy and highlight how the two classes of drugs produce different constellations of effects with more effects associated with the SSRIs. Further investigation into how antidepressants alter brain development leading to enduring adverse neurobehavioral effects is warranted.

Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats.

Selective serotonin reuptake inhibitors (SSRIs) block the serotonin (5-HT) reuptake transporter (SERT) and increase synaptic 5-HT. 5-HT is also important in brain development; hence when SSRIs are taken during pregnancy there exists the potential for these drugs to affect CNS ontogeny. Prenatal SSRI exposure has been associated with an increased prevalence of autism spectrum disorder (ASD), and peripheral 5-HT is elevated in some ASD patients. Perinatal SSRI exposure in rodents has been associated with increased depression and anxiety-like behavior, decreased sociability, and impaired learning in the offspring, behaviors often seen in ASD. The present study investigated whether perinatal exposure to citalopram causes persistent neurobehavioral effects. Gravid Sprague-Dawley rats were assigned to two groups and subcutaneously injected twice per day with citalopram (10mg/kg; Cit) or saline (Sal) 6h apart on embryonic day (E)6-21, and then drug was given directly to the pups after delivery from postnatal day (P)1-20. Starting on P60, one male/female from each litter was tested in the Cincinnati water maze (CWM) and open-field before and after MK-801. A second pair from each litter was tested in the Morris water maze (MWM) and open-field before and after (+)-amphetamine. A third pair was tested as follows: elevated zero-maze, open-field, marble burying, prepulse inhibition of acoustic startle, social preference, and forced swim. Cit-exposed rats were impaired in the MWM during acquisition and probe, but not during reversal, shift, or cued trials. Cit-exposed rats also showed increased marble burying, decreased time in the center of the open-field, decreased latency to immobility in forced swim, and increased acoustic startle across prepulse intensities with no effects on CWM. The results are consistent with citalopram inducing several ASD-like effects. The findings add to concerns about use of SSRIs during pregnancy. Further research on different classes of antidepressants, dose-effect relationships, timing of exposure periods, and mechanisms for these effects are needed. It is also important to balance the effects described here against the effects of the disorders for which the drugs are given.

A comparison of presynaptic and postsynaptic dopaminergic agonists on inhibitory control performance in rats perinatally exposed to PCBs.

Polychlorinated Biphenyls (PCBs) are very stable environmental contaminants whose exposure induces a number of health and cognitive concerns. Currently, it is well known that PCB exposure leads to poor performance on inhibitory control tasks. It is also well known that dopamine (DA) depletion within medial prefrontal cortex (mPFC) leads to poor performance on inhibitory control tasks. However, what is not well established is whether or not the inhibitory control problems found following PCB exposure are mediated by DA depletion in mPFC. This study was an investigation into the link between perinatal exposure to PCBs, the effect of this exposure on DA neurotransmission in the mPFC, and inhibitory-control problems during adulthood using a rodent model. The current study served to determine if microinjections of different DA agonists (the presynaptic DA transporter inhibitor and vesicular monoamine transporter agonist bupropion, the postsynaptic DA receptor 2 (DAD2) agonist quinpirole, and the postsynaptic DA receptor 1 (DAD1) agonist SKF81297) directly into the mPFC would differentially improve performance on an inhibitory control task in rats perinatally exposed to an environmentally relevant PCB mixture. Findings suggest several significant sex-based differences on differential reinforcement of low rates (DRL) 15 performance as well as some evidence of differential effectiveness of the DA agonists based on PCB exposure group.