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Abstract

Hormones influence neurodevelopment which can result in vulnerability to endocrine disruptors such as phthalates during both the perinatal period and adolescence. Using a rat model, we have previously shown that perinatal exposure to an environmentally relevant phthalate mixture at low doses results in cognitive flexibility deficits in adults and a reduction in neuron and synapse number within the medial prefrontal cortex. Here, we further examined the behavioral effects of exposure to an environmentally relevant mixture of phthalates at low doses during either perinatal development or adolescence. Using the elevated plus maze, adult females, not males, exposed to phthalates during adolescence showed indications of reduced anxiety-like behavior while perinatal exposed animals were unaffected. There was no effect of adolescent phthalate exposure on cognitive flexibility using the attentional set shift paradigm in either sex, unlike the impairments we have previously reported following perinatal exposure (Kougias et al., 2018b). Finally, there was no effect of phthalate exposure during either time frame on sensorimotor gating measured using prepulse inhibition. Environmentally relevant phthalate exposure during the perinatal period or during adolescence did not induce widespread changes in the adult behaviors measured here.

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... Eight studies (five on rats, three on mice) investigated the effects of prenatal/postnatal or prepubertal/pubertal exposure to DEHP or a phthalate mixture on anxiety-like behavior of F1 offspring, using mainly the elevated plus maze alone or in combination with the open-field (Table 2). Among these studies, seven analyzed these effects on cyclic females [69,[71][72][73][74][75][76] and one in postpartum females [67]. Four out of seven studies found increased anxiety-state levels in PND30-35 mice exposed to 5 or 40 µg/kg/d of DEHP [69], in PND42 and adult females at the diestrus or estrus stage exposed to DEHP above 10 mg/kg/d [74,75], and in adult females of unknown estrous stage exposed to DEHP from 1 mg/kg/d [73]. ...
... In these studies, increased anxiety-related behavior was associated with impaired HPA axis as evidenced by higher ACTH and lower corticosterone levels together with elevated hypothalamic amounts of GR [73], and lower amounts of hippocampal and striatal ERβ and dopamine receptor 2 [75], with no changes in circulating levels of estradiol [74,75]. The remaining three of seven studies reported no effects in pubertal (PND30, PND42 and PND45) or adult females of unknown estrous stage, which were exposed prenatally or postnatally to DEHP at 30 mg/kg/d [71] or 200 mg/kg/d [76] or to a phthalate mixture at 0.2 or 1 mg/kg/d [72]. Whether this discrepancy is due to differences in the female estrous stage or to other experimental conditions needs further investigation. ...
... 1 Composition of the mixture in [72]: 35% DEP, 21% DEHP, 15% DBP, 15% DiNP, 8% DiBP, 5% BBP. 2 Detailed test protocols are reported in Table S3. ...
Article
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Phthalates have been widely studied for their reprotoxic effects in male rodents and in particular on testosterone production, for which reference doses were established. The female rodent brain can also represent a target for exposure to these environmental endocrine disruptors. Indeed, a large range of behaviors including reproductive behaviors, mood-related behaviors, and learning and memory are regulated by sex steroid hormones. Here we review the experimental studies addressing the effects and mechanisms of phthalate exposure on these behaviors in female rodents, paying particular attention to the experimental conditions (period of exposure, doses, estrous stage of analyses etc.). The objective of this review is to provide a clear picture of the consistent effects that can occur in female rodents and the gaps that still need to be filled in terms of effects and mode(s) of action for a better risk assessment for human health.
... Previous studies (Kougias et al., 2018a, b;Sellinger et al., 2020;Zhou et al., 2017) have used a mixture of phthalates derived from concentrations of phthalate metabolites in the urine of pregnant women in Champaign, Illinois (Strakovsky and Schantz, personal communication; Pacyga et al., 2021). This mixture is composed of six phthalates: 35% diethyl phthalate (DEP), 21% di(2-ethylhexyl) phthalate (DEHP), 15% dibutyl phthalate (DBP), 15% diisononyl phthalate (DiNP), 8% diisobutyl phthalate (DiBP) and 5% benzyl butyl phthalate (BBP) (all purchased from Sigma-Alrdrich, St. Louis, MO). ...
Article
Phthalates are a class of endocrine disruptors found in a variety of consumer goods, and offspring can be exposed to these compounds during gestation and lactation. Our laboratory has found that perinatal exposure to an environmentally relevant mixture of phthalates resulted in a decrease in cognitive flexibility and in neuron number in the adult rat medial prefrontal cortex (mPFC). Here, we examine effects of phthalate treatment on prenatal cellular proliferation and perinatal apoptosis in the mPFC. To examine the phthalate effects on cellular proliferation, dams consumed 0, 1, or 5 mg/kg of the phthalate mixture daily from embryonic day 2 (E2) through the day of birth (P0), and on E16 and E17, they were injected with BrdU. The mPFC of offspring was analyzed on P5 and showed a decrease in labelled cells in the phthalate exposed groups. To examine whether changes in BrdU density observed on P5 were due to altered cell survival, cell death was measured on E18, P0, and P5 using a TUNEL assay in a separate cohort of prenatally exposed offspring. There was an increase in TUNEL labelled cells at E18 in the phthalate exposed groups. In the final experiment, dams consumed the phthalate mixture from E2 through P10, at which time mPFC tissue was stained with TUNEL. Phthalate treated subjects showed a higher density of apoptotic cells at P10. These results indicate both pre- and postnatal phthalate exposure increases apoptosis in the male and female rat mPFC. While the impact of phthalates on proliferation cannot be ruled out, these data do not allow for definitive conclusions.
... Supplementary Fig. 4). It is worth noting that the 6-8 week animals used in this study represent mid-late adolescent males [48][49][50][51] . Heightened emotional responses to negative events during adolescence are well documented, and adolescent rats have been demonstrated to show dramatically reduced extinction of fear-induced freezing behaviour compared to adults 52 . ...
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Polyunsaturated free fatty acids (FFAs) such as arachidonic acid, released by phospholipase activity on membrane phospholipids, have long been considered beneficial for learning and memory and are known modulators of neurotransmission and synaptic plasticity. However, the precise nature of other FFA and phospholipid changes in specific areas of the brain during learning is unknown. Here, using a targeted lipidomics approach to characterise FFAs and phospholipids across the rat brain, we demonstrated that the highest concentrations of these analytes were found in areas of the brain classically involved in fear learning and memory, such as the amygdala. Auditory fear conditioning led to an increase in saturated (particularly myristic and palmitic acids) and to a lesser extent unsaturated FFAs (predominantly arachidonic acid) in the amygdala and prefrontal cortex. Both fear conditioning and changes in FFA required activation of NMDA receptors. These results suggest a role for saturated FFAs in memory acquisition.
... These findings are in accordance with the results of another, earlier study(Xu et al. 2015), in which anxiety-like behavior was increased in pubertal mice regardless of sex, and in adults, when females were affected. On the other hand,Lee et al. (2016) andSellinger et al. (2020) did not observe anxiety-like behavior in rodents after prenatal and early postnatal exposure to phthalates. Depression-like behavior was found to be induced in pubertal and adult mice after prenatal and postnatal phthalate exposure(Xu et al. 2015).In transgenerational studies, no effect of DEHP lineage on anxiety-like behavior in F3 juvenile male or female mice was observed(Quinnies et al. 2015;. ...
Article
Phthalates are chemical substances that are widely used to provide flexibility and durability to plastic materials. They leach from products in which they are mixed and reach living organisms. Results from experimental studies suggest that exposure to phthalates can have a negative impact on an individual's neuronal system and behavior. In this regard, exposure during early ontogenesis seems to be particularly dangerous due to the extensive growth and development of body structures and functions. Disruption during this critical time can result in alterations of behavior and the emergence of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Various animal models have been used to elucidate the pathogenesis of this disease. They are fundamental for research, and although the translation of results to humans is difficult, new animal models are being developed. The aim of this review is to summarize laboratory rodent studies in which early developmental phthalate exposure resulted in brain alterations and autistic-like behavioral traits. We also discuss the possibility of using early developmental phthalate exposure in rodents to create a new animal model of autism.
... Findings support a trend toward decreased T levels in BPA-treated rats. Data are represented as mean ± SEM. male rats that had been orally exposed daily to a 1 mg phthalates/kg mixture as adolescents (PND 27-50), supporting no significant impact of adolescent phtalates exposure on anxiety-like behavior in male rats (Sellinger et al., 2020). Notably, however, adolescent exposure to BPA inhibited hops-induced open arm entries in co-exposed rats. ...
Article
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The adolescence period, marked by sexual and brain maturation, has shown sensitivity to various environmental disruptors. Exposure to the xenoestrogen bisphenol A (BPA) is known to alter physiological and behavioral responses although its role at this critical period remains largely unknown. Recent research further suggests biochemical and genomic effects of BPA to be mitigated by various natural compounds, while effects on behavior have not been examined. This study aimed to characterize (1) the effects of dietary BPA during adolescence on endogenous corticosterone (CORT) secretion, emotional behavior, and testosterone (T) in adulthood, and (2) the impact of combined exposure to BPA with hop extracts (Hop), a phytoestrogen with anxiolytic properties. To do so, four groups of male Wistar rats [postnatal day (PND) 28] were administered corn oil (control), BPA (40 mg/kg), hops (40 mg/kg), or BPA-hops by oral gavage for 21 days (PND 28–48). Blood droplets collected on PND 28, 48, and 71 served to measure CORT and T changes. As adults, rats were tested in the elevated plus maze (EPM), the social interaction test, and the forced swim test. Our findings demonstrated elevated anxiety and a trend toward depressive-like behaviors in BPA- compared to hops-exposed rats. However, BPA intake had no impact on basal CORT levels, or adulthood T secretion and sociability. Of note, BPA's anxiogenic effect manifested through decreased EPM open arm entries was abolished by hops co-supplementation. Together, our observations suggest the adolescence period to be less sensitive to deleterious effects of BPA than what has been reported upon gestational and perinatal exposure.
... Animal studies have shown similar findings where prenatal/postnatal DEHP exposure is reported to cause behavioral dysregulation in offspring (Quinnies et al., 2017;Xu et al., 2015). Further, exposure of mice or rats to DEHP/mixture of phthalates at juvenile stage is also reported to influence anxiety-like, social, emotional, and cognitive behavioral patterns at adulthood (Sellinger et al., 2020;Wang et al., 2016). ...
Article
Epigenetic modifications are known to play a crucial role in the behavioral modifications through regulation of gene expression. Environmental factors are known to regulate genetic transcription through DNA methylation which is one of the mechanisms of epigenetic modification. Di-2-ethylhexyl phthalate (DEHP) is one of the most abundant phthalate plasticizers in day-to-day products. Prenatal/postnatal DEHP administration has been reported to cause inflammation as well as behavioral dysregulation, however it is not known if exposure to DEHP during juvenile stage affects peripheral/neuronal inflammation and autism-like symptoms in BTBR mice at adulthood. This study investigated effect of DEHP exposure during juvenile period on DNA methylation (global DNA methylation/DNMT1 expression) and inflammation (IL-17A, IL-6, MCP-1, TNF-α) in CD4 + T cells/CD11c + DCs and cortex, and autism-like symptoms (three-chambered sociability test, self-grooming and marble burying test) in asocial BTBR and social C57 mice at adulthood. Our data reveal that BTBR mice exposed to DEHP during juvenile period have hypomethylated DNA/DNMT1 expression in CD11c + DCs and cortex as compared to vehicle-exposed BTBR mice. It was associated with upregulated inflammation in periphery [plasma IL-6/IL-17A, CD11c + DCs (IL-6/MCP-1/TNF-α), and CD4+ T cells (IL-17A)] and cortex (IL-6, MCP-1, TNF-α), and aggravation in autism-like symptoms in DEHP-treated BTBR mice. These data propose that exposure of DEHP during juvenile period may affect autism-like behavior and inflammation in BTBR mice at adulthood through epigenetic regulation. Therefore, underlying genetic predisposition may play a crucial role in worsening of autistic symptoms in ASD subjects in adulthood if they are exposed to environmental pollutants such as DEHP during juvenile period.
... Perinatal exposure of rats to a phthalate mixture did not show significant effects on the elevated plus maze. However, when the exposure occurred during adolescence, females showed a reduction in anxiety-like behaviors (Sellinger et al., 2020). ...
Article
Sex is a fundamental biological characteristic that influences many aspects of an organism’s phenotype, including neurobiological functions and behavior as a result of species-specific evolutionary pressures. Sex differences have strong implications for vulnerability to disease and susceptibility to environmental perturbations. Endocrine disrupting chemicals (EDCs) have the potential to interfere with sex hormones functioning and influence development in a sex specific manner. Here we present an updated descriptive review of findings from animal models and human studies regarding the current evidence for altered sex-differences in behavioral development in response to early exposure to EDCs, with a focus on bisphenol A and phthalates. Overall, we show that animal and human studies have a good degree of consistency and that there is strong evidence demonstrating that EDCs exposure during critical periods of development affect sex differences in emotional and cognitive behaviors. Results are more heterogeneous when social, sexual and parental behaviors are considered. In order to pinpoint sex differences in environmentally-driven disease vulnerabilities, researchers need to consider sex-biased developmental effects of EDCs.
... For all subjects sacrificed after puberty, the average age of pubertal onset was 34.9 days in females and 42.33 days in males. This is consistent with previous findings from our laboratory (Kougias et al. 2018;Sellinger et al. 2020). Among the pre-and post-pubertal siblings, the average age at sacrifice was 34.55 days with a range of 32-37 for females and 43 days with a range of 41-45 in males. ...
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The prefrontal cortex (PFC) is a late developing region of the cortex, and its protracted maturation during adolescence may confer a period of plasticity. Closure of critical, or sensitive, periods in sensory cortices coincides with perineuronal net (PNN) expression, leading to enhanced inhibitory function and synaptic stabilization. PNN density has been found to increase across adolescence in the male rat medial PFC (mPFC). Here, we examined both male and female rats at four time points spanning adolescent development to stereologically quantify the number and intensity of PNNs in the mPFC. Additionally, because puberty coincides with broad behavioral and neuroanatomical changes, we collected tissue from age-matched pre- and post-pubertal siblings within a litter. Results indicate that both males and females show an increase in the total number and intensity of mPFC PNNs between postnatal day (P) 30 and P60. As we have previously found, white matter under the mPFC also increased at the same time. Male puberty did not affect PNNs, while female pubertal onset led to an abrupt decrease in the total number of PNNs that persisted through mid-adolescence before increasing at P60. Despite the change in PNN number, the intensity of female PNNs was not affected by puberty. Thus, though males and females show increases in mPFC PNNs during adolescence, the pubertal decrease in the number of PNNs in female rats may indicate a difference in the pattern of maximal plasticity between the sexes during adolescence.
... Despite individual differences in pubertal onset and tempo, girls reach puberty, on average, 18 months earlier than boys. This sex difference is also seen in rat models, as we have consistently shown that female Long Evans rats reach pubertal onset 7-10 days earlier than males (Kougias et al., 2018;Sellinger et al., 2020;Willing and Juraska, 2015). In our laboratory, the average age of pubertal onset in Long Evans rats is P35 in females and between P42 and P45 in males (Fig. 1). ...
Chapter
This chapter reviews the remodeling of the prefrontal cortex during adolescence, which occurs in both humans and rats. Other neural regions involved in cognitive behavior are also affected, but the majority of evidence at this time comes from the prefrontal cortex where synapses, dendrites, and neurons are pruned while myelination of the underlying white matter increases. There are studies that indicate at least some of these changes are triggered by the hormones of puberty. The most definitive of these are in rats where the ovarian hormones have been implicated. The neural remodeling during adolescence also influences cognitive behavior, again with some evidence for puberty initiating the change. Future studies examining cognitive behavior during adolescence should account for pubertal status and for the sex difference in the age of pubertal onset, since this may be at least as important chronological age.
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This study aimed to verify whether chronic exposure to nonylphenol (NP) induces anxiety behavior in rats and explored NP's regulatory effect on the BDNF/TrkB/CREB signal network in vitro. Anxiety-like behavior was asses by elevated plus-maze light-dark box tests. The residence time in the dark area increased with NP dose (0.4, 4, 40 mg/kg) and exposure time (3 and 6 months) (P < 0.05). The hippocampal neurons in the medium dose (M-NP, 4 mg/kg) and high dose (H-NP, 40 mg/kg) groups showed disorderly arrangement, cell swelling, and nuclear pyknosis/necrosis. The protein/mRNA expressions of BDNF/TrkB/CREB in the H-NP group decreased, and the decrease was more significant at 6 months (P < 0.05). Both, NP exposure and BDNF knockdown, increase the number of apoptotic cells (P <0.001). NP downregulated the proteins/mRNA expressions of BDNF/TrkB/CREB, and the trend was consistent with the BDNF silence group. Chronic exposure to NP could induce anxiety-like behavior in rats and reduce the expression of key proteins/genes in the BDNF/TrkB/CREB signaling network.
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Early life exposure to endocrine-disrupting chemicals (EDCs) is considered a potential risk factor for aberrant brain development and the emergence of behavioral deficits. The purpose of this review is to summarize the toxic effects of bisphenol-A (BPA) and phthalate exposure during pre-, -post- or perinatal life on different types of behaviour in male and female rodents. Despite results not being always consistent, most probably due to methodological issues, it is highly probable that early life exposure to BPA or/and phthalates, affects various aspects of behaviour in the offspring. Adverse effects include: Increased levels of anxiety, altered exploratory behaviour, reduced social interaction or increased aggression and deficits in spatial or recognition learning and memory. These effects have been observed with a wide range of doses, in some cases even below the currently employed Tolerable Daily Intake dose for either BPA or phthalates.
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The human prefrontal cortex, important for executive functions, loses gray matter throughout the adolescent period. In rats, our laboratory demonstrated that a loss of neurons between adolescence and adulthood partially underlies the loss of volume, and this loss is greater in females than males. Here, we examine whether being deprived of gonadal hormones before puberty through adulthood influences the number of neurons in the medial prefrontal cortex (mPFC). Prior to puberty, the testes or ovaries were removed in male and female rats. In adulthood, the number of neurons and glia in the mPFC were quantified using unbiased stereology, and the volume of the frontal white matter was measured. Prepubertal ovariectomy resulted in a higher number of neurons and glia and a larger volume of white matter compared to sham control littermates. Castrated males were not different from sham males on any measure. Thus ovarian hormones secreted after puberty influence the cellular composition of the medial prefrontal cortex. © 2015 Wiley Periodicals, Inc. Dev Psychobiol. © 2015 Wiley Periodicals, Inc.
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Some phthalates are developmental and reproductive toxicants in animals. Exposure to phthalates is considered to be potentially harmful to human health as well. Based on a comprehensive literature research, we present an overview of the sources of human phthalate exposure and results of exposure assessments with special focus on human biomonitoring data. Among the general population, there is widespread exposure to a number of phthalates. Foodstuff is the major source of phthalate exposure, particularly for the long-chain phthalates such as di(2-ethylhexyl) phthalate. For short-chain phthalates such as di-n-butyl-phthalate, additional pathways are of relevance. In general, children are exposed to higher phthalate doses than adults. Especially, high exposures can occur through some medications or medical devices. By comparing exposure data with existing limit values, one can also assess the risks associated with exposure to phthalates. Within the general population, some individuals exceed tolerable daily intake values for one or more phthalates. In high exposure groups, (intensive medical care, medications) tolerable daily intake transgressions can be substantial. Recent findings from animal studies suggest that a cumulative risk assessment for phthalates is warranted, and a cumulative exposure assessment to phthalates via human biomonitoring is a major step into this direction.
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The present study stems from our previous observations that the brains of adult estrogen receptor beta knockout (ERbeta-/-) mice show regional neuronal hypocellularity especially in the cerebral cortex. We now show that ERbeta is necessary for late embryonic development of the brain and is involved in both neuronal migration and apoptosis. At embryonic day (E)18.5, ERbeta-/- mouse brains were smaller than those of the wild-type (WT) littermates, and there were fewer neurons in the cortex. There were no differences in size or cellularity at E14.5. When proliferating cells were labeled with 5'-bromodeoxyuridine (BrdUrd) on E12.5, a time when cortical neurogenesis in mice begins, and examined on E14.5, there was no difference between WT and ERbeta-/- mice in the number of labeled cells in the cortex. However, when BrdUrd was administered between E14.5 and E16.5, a time when postmitotic neurons migrate to layers of the cortex, there were fewer BrdUrd-labeled cells in the superficial cortical layers by E18.5 and postnatal day 14 in mice lacking ERbeta. At E18.5, there were more apoptotic cells in the ventricular zone of mice lacking ERbeta. In addition, the processes of the cortical radial glia, which are essential for guiding the migrating neurons, were fragmented. These findings suggest that by influencing migration and neuronal survival, ERbeta has an important role in brain development.
Article
Background: Studies suggest that exposure to endocrine disrupting chemicals (EDCs), including phthalates, phenols, and parabens may influence childhood behavior, but the relationship during adolescence has not been assessed. Objective: We investigated the association between urinary biomarker concentrations of potential EDCs, including some phthalate and bisphenol A replacement chemicals, and behavior in adolescents. Methods: Participants were from the New Bedford Cohort (NBC), a prospective birth cohort of residents near the New Bedford Harbor Superfund site in Massachusetts. We measured urinary concentrations of 16 phthalate metabolites or replacements, 8 phenols, and 4 parabens in 205 NBC adolescents and estimated associations between select EDCs and adolescent behavior assessed with the Behavior Assessment System for Children, Second Edition -Teacher Rating Scale (BASC-2). Of note, up to 32 of the 205 in our assessment had missing outcome information imputed. Results: Increased urinary concentrations of the sum of 11 antiandrogenic phthalate metabolites were associated with an increase in maladaptive behaviors (Externalizing Behavior, Behavioral Symptoms Index, and Developmental Social Disorders or DSD), and a decrease in Adaptive Skills. For example, a doubling of urinary concentrations of antiandrogenic phthalate metabolites was associated with an increased risk of Externalizing Behavior (RR=1.04; 95% CI: 1.01-1.08). While associations were generally stronger in males, sex differences were not statistically significant. Urine concentrations of phenols and parabens were not associated with adverse behavior. Conclusion: Our findings support the importance of exposure to antiandrogenic phthalates during adolescence as a potential correlate of maladaptive behaviors including Externalizing Behavior, DSD behaviors, and decrements in Adaptive Skills.
Article
The growth and organization of the developing brain are known to be influenced by hormones, but little is known about whether disruption of hormones affects cortical regions, such as mPFC. This region is particularly important given its involvement in executive functions and implication in the pathology of many neuropsychiatric disorders. Here, we examine the long-term effects of perinatal exposure to endocrine-disrupting compounds, the phthalates, on the mPFC and associated behavior. This investigation is pertinent as humans are ubiquitously exposed to phthalates through a variety of consumer products and phthalates can readily cross the placenta and be delivered to offspring via lactation. Pregnant dams orally consumed an environmentally relevant mixture of phthalates at 0, 200, or 1000 μg/kg/d through pregnancy and for 10 d while lactating. As adults, offspring were tested in an attentional set-shifting task, which assesses cognitive flexibility. Brains were also examined in adulthood for stereological quantification of the number of neurons, glia, and synapses within the mPFC. We found that, independent of sex, perinatal phthalate exposure at either dose resulted in a reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. Interestingly, the number of synapses was correlated with cognitive flexibility, such that rats with fewer synapses were less cognitively flexible than those with more synapses. These results demonstrate that perinatal phthalate exposure can have long-term effects on the cortex and behavior of both male and female rats.
Article
The endocrine disruptor di-(2-ethylhexyl) phthalate (DEHP) is used in a variety of consumer products made with polyvinyl chloride and also in the manufacture of medical devices. DEHP disrupts reproductive tract development in an antiandrogenic manner and also may induce neurobehavioral changes. The aim of this study was to investigate the effects of chronic postnatal exposure to DEHP (30 mg/kg body weight/day, orally from birth to day 60) on the neuroendocrine regulation of the gonadal axis and its impact on the anxiety-like behavior in adult male rats, as well as the probable participation of the GABAergic system in these effects. DEHP produced a significant increase in plasmatic luteinizing hormone and follicle stimulating hormone, as well as significant testosterone decrease, accompanied with a decrease in hypothalamic gamma-aminobutyric acid (GABA) concentration. On the other hand, DEHP increased the anxiety-like behavior in the elevated plus maze test, evidenced by a significant decrease in the percentages of time spent in the open arms and the frequency in the open arm entries and a significant increase in the percentage of time spent in closed arms. Neuroendocrine and behavioral effects were reversed by GABA agonists, muscimol (2 mg/kg i.p. ) and baclofen (10 mg/kg i.p.). In conclusion, chronic DEHP postnatal exposure induced a disruption in the neuroendocrine regulation of the testicular axis in young adult male rats, and this effect was correlated with an anxiety-like behavior. Since GABA agonists reversed these effects, the results suggest that GABA could participate in the modulation of reproductive and behavioral DEHP effects.
Article
Phthalates are a family of synthetic chemicals that are used in producing a variety of consumer products. Di-(2-ethylhexyl) phthalate (DEHP) is an widely used phthalate and poses a public health concern. Prenatal exposure to DEHP has been shown to induce premature reproductive senescence in animal studies. In this study, we tested the hypothesis that prenatal exposure to DEHP impairs neurobehavior and recognition memory in her male offspring and we investigated one possible mechanism—oxidative damage in the hippocampus. Pregnant CD-1 female mice were orally administered 200μg, 500mg, or 750mg/kg/day DEHP or vehicle from gestational day 11 until birth. The neurobehavioral impact of the prenatal DEHP exposure was assessed at the ages of 16 to 22 months. Elevated plus maze and open field tests were used to measure anxiety levels. Y-maze and novel object recognition tests were employed to measure memory function. The oxidative damage in the hippocampus was measured by the levels of oxidative DNA damage and by SLIM microscopic counting of hippocampal neurons. Adult male mice that were prenatally exposed to DEHP exhibited anxious behaviors and impaired spatial and short-term recognition memory. The number of hippocampal pyramidal neurons was significantly decreased in the DEHP mice. Furthermore, DEHP mice expressed remarkably high levels of cyclooxygenase-2, 8-hydroxyguanine, and thymidine glycol in their hippocampal neurons. DEHP mice also had lower circulating testosterone concentrations and displayed a weaker immunoreactivity than the control mice to androgen receptor expression in the brain. This study found that prenatal exposure to DEHP caused elevated anxiety behavior and impaired recognition memory. These behavioral changes may originate from neurodegeneration caused by oxidative damage and inflammation in the hippocampus. Decreased circulating testosterone concentrations and decreased expression of androgen receptor in the brain also may be factors contributing to the impaired neurobehavior in the DEHP mice.
Article
Humans are ubiquitously exposed to many phthalates, a class of endocrine-disrupting chemicals commonly used in many consumer goods, and diet, especially fatty foods, is presumed to be a major source of exposure. Here, we use a rat model of human prenatal exposure to investigate the potential interactive effects of an environmentally relevant mixture of phthalates and a maternal high-fat diet (HFD). From gestation through postnatal day (P)10, dams consumed the mixture of phthalates (0, 200, or 1000 μg/kg/day) and were fed a control or HFD. In males, perinatal exposure to the mixture of phthalates decreased prepubertal body weight and, in a dose-specific manner, periadolescent social play behavior. A dose-specific effect from phthalates with HFD was also seen in increased time alone in females during social play. HFD resulted in dams consuming more calories, having greater gestational weight gain, and licking and nursing their pups more, such that an early postnatal HFD generally increased pup body weight. There also was a tendency for increased oxidative stress markers at P10 within the medial prefrontal cortex of males exposed to the relatively high dose of phthalates and HFD. Effects on gene expression were inconsistent at P10 and P90 in both the medial prefrontal cortex and hypothalamus. Overall, this study demonstrates that phthalates and a maternal HFD only rarely interacted, except in oxidative stress markers in males. Additionally, perinatal exposure to an environmentally relevant mixture of phthalates can have a modest, but lasting, impact on social behaviors in both males and females.
Article
Objective: The central auditory pathway is known to continue its development during the postnatal critical periods and is shaped by experience and sensory inputs. Phthalate, a known neurotoxic material, has been reported to be associated with attention deficits in children, impacting many infant neurobehaviors. The objective of this study was to investigate the potential effects of neonatal phthalate exposure on the development of auditory temporal processing. Methods: Neonatal Sprague-Dawley rats were randomly assigned into two groups: The phthalate group (n = 6), and the control group (n = 6). Phthalate was given once per day from postnatal day 8 (P8) to P28. Upon completion, at P28, the Auditory Brainstem Response (ABR) and Gap Prepulse Inhibition of Acoustic Startle response (GPIAS) at each gap duration (2, 5, 10, 20, 50 and 80 ms) were measured, and gap detection threshold (GDT) was calculated. These outcomes were compared between the two groups. Results: Hearing thresholds by ABR showed no significant differences at all frequencies between the two groups. Regarding GPIAS, no significant difference was observed, except at a gap duration of 20 ms (p = 0.037). The mean GDT of the phthalate group (44.0 ms) was higher than that of the control group (20.0 ms), but without statistical significance (p = 0.065). Moreover, the phthalate group tended to demonstrate more of a scattered distribution in the GDT group than the in the control group. Conclusion: Neonatal phthalate exposure may disrupt the development of auditory temporal processing in rats.
Article
Adolescence is a transitional period of physical and behavioral development between childhood and adulthood. Puberty is a distinct period of sexual maturation that occurs during adolescence. Since the advent of magnetic resonance imaging (MRI), human studies have largely examined neurodevelopment in the context of age. A breadth of animal findings suggest that sex hormones continue to influence the brain beyond the prenatal period, with both organizational and activational effects occurring during puberty. Given the animal evidence, human MRI research has also set out to determine how puberty may influence otherwise known patterns of age-related neurodevelopment. Here we review structural-based MRI studies and show that pubertal maturation is a key variable to consider in elucidating sex- and individual- based differences in patterns of human brain development. We also highlight the continuing challenges faced, as well as future considerations, for this vital avenue of research.
Article
Endocrine-disrupting chemicals (EDCs) might increase the risk of childhood diseases by disrupting hormone-mediated processes that are critical for growth and development during gestation, infancy and childhood. The fetus, infant and child might have enhanced sensitivity to environmental stressors such as EDCs due to their rapid development and increased exposure to some EDCs as a consequence of development-specific behaviour, anatomy and physiology. In this Review, I discuss epidemiological studies examining the relationship between early-life exposure to bisphenol A (BPA), phthalates, triclosan and perfluoroalkyl substances (PFAS) with childhood neurobehavioural disorders and obesity. The available epidemiological evidence suggest that prenatal exposure to several of these ubiquitous EDCs is associated with adverse neurobehaviour (BPA and phthalates) and excess adiposity or increased risk of obesity and/or overweight (PFAS). Quantifying the effects of EDC mixtures, improving EDC exposure assessment, reducing bias from confounding, identifying periods of heightened vulnerability and elucidating the presence and nature of sexually dimorphic EDC effects would enable stronger inferences to be made from epidemiological studies than currently possible. Ultimately, improved estimates of the causal effects of EDC exposures on child health could help identify susceptible subpopulations and lead to public health interventions to reduce these exposures.
Article
Background: The PrePulse Inhibition (PPI) of the acoustic startle reflex is a neurobehavioral test frequently used in neurodevelopmental studies. Most PPI studies have used rodent models of schizophrenia; however, the currently used data analysis method does not take into account the variability present in autistic preclinical models. New method: We propose a new data modelling approach for PPI data obtained from animals exposed to valproic acid or endocrine disruptors, using mixed modeling; and a new calculation of inhibition of the acoustic startle, which takes into account the habituation phenomenon. Results: Habituation, or possibly exhaustion, occurred in all groups. The classic method of calculation of inhibition analysed with ANOVA indicated no group or sex effect for the overall inhibition of startle. In contrast, when analysed using mixed models, group and sex effects were observed. In addition, using the new method of calculation, both statistical analyses showed a sex effect, with females having decreased global inhibition but no group effect. ANOVA generated more false positive results for PPI in relation to prepulse intensities. Comparison with existing method: The current classic method of analysis of PPI test is a calculation of inhibition based on average startle amplitude throughout the test session and a statistical ANOVA analysis. This method does not take into account habituation/exhaustion and within-subject and -group variability. Conclusions: The results of this study demonstrate that use of ANOVA analysis leads to misinterpretation of PPI data in autistic preclinical models and we propose a new data analysis adapted to these models.
Article
Background: Exposure to bisphenol-A (BPA) and phthalates is highly prevalent. Prior studies have not assessed associations between urinary levels of BPA and phthalate metabolites and body composition. Methods: National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2006 on adults aged ≥20 were analyzed by linear regression for associations between urinary BPA, monoethyl phthalate, monobutyl phthalate (MBP), monoethylhexyl phthalate (MEHP), and monobenzyl phthalate (MBzP) and lean mass, fat mass, and percent body fat. Results: BPA and phthalate metabolites were not independently associated with fat mass or percent body fat. Significant inverse associations were observed with lean mass, with the strongest association observed for BPA in men (mean lean mass 1.39 kg lower for quartile 4 vs. quartile 1, p trend = 0.02). Conclusions: BPA and some phthalates could have important, negative effects on muscle and may affect conditions related to deficits in lean mass, though additional research is needed.
Article
Every year millions of tons of plastic are produced around the world and humans are increasingly exposed to them. This constant exposure to plastics has raised some concerns against human health, particularly when it comes to phthalates. These compounds have endocrine-disrupting properties, as they have the ability to bind molecular targets in the body and interfere with hormonal function and quantity. The main use of phthalates is to give flexibility to polyvinyl chloride (PVC) polymers. Phthalates are found in a variety of industrial and consumer products, and as they are not covalently bound to the plastic, phthalates contaminate the environment from which human exposure occurs. Studies in human and animal populations suggest a correlation between phthalate exposure and adverse health outcomes, particularly at the reproductive and cardiovascular systems, however there is much less information about the phthalate toxicity of the later. Thus, the main purpose of this review is to present the studies relating the effects already stated of phthalates on the cardiovascular and reproductive systems, and also present the link between these two systems.
Article
Dibutyl phthalate (DBP) is widely used as plasticizer in numerous kinds of products such as plastic packaging in food industries. There is high risk of DBP exposure for human; it can easily migrate into the human bodies through food plastic packaging and be a potential hazard for human health. In this study the neurobehavioral effects of oral DBP for 14 days (6.25, 12.5, 25, 50, 100 and 200 mg/kg) were investigated in mice, using open field, Y-maze, elevated plus maze, passive avoidance test, rotarod and grip strength test. The results showed that DBP could reduce total distance movement, impair memory function and induce anxiety in mice. Histological analysis (haematoxylin-eosin staining) also showed significant nuclei size reduction and condensation in dentate gyrus cells of the DBP treated mice. In conclusion oral DBP administration for 14 days may cause some neurobehavioral adverse effects in mice.
Article
Adolescence is a unique period of development, marked by maturation of the prefrontal cortex (PFC), a region important for executive functioning. During this time, the human PFC decreases in overall volume and thickness. Likewise in adolescent rodents, losses of neurons, dendrites, dendritic spines and neurotransmitter receptors have been documented within the medial prefrontal cortex (mPFC), sometimes with sex and layer specificity. However, changes in the number of synapses during this time have not been examined. In the present study, we stereologically quantified the number of synaptophysin-immunoreactive boutons in the male and female rat mPFC across multiple time points from the juvenile period through adulthood (postnatal days (P) 25, 35, 45, 60 and 90). In females, there was a significant decrease in synaptophysin boutons between P35 and P45, coinciding with the onset of puberty. In males, there was no significant main effect of age on synaptophysin boutons; however, in both males and females, pubertal onset was associated with significant synaptic losses. These results suggest that puberty is a critical period for synaptic pruning within the rat mPFC, potentially contributing to maturation of adolescent executive function. This article is protected by copyright. All rights reserved.
Article
DEHP, one of the most commonly phthalates used in plastics and many other products, is an environmental endocrine disruptor (EED). Puberty is another critical period for the brain development besides the neonatal period and is sensitive to EEDs. Social behavior is organized during puberty, so the present study is to investigate whether pubertal exposure to DEHP influenced social behavior of adult female mice. The results showed that pubertal exposure to DEHP for 2 weeks did not change the serum level of 17β-estradiol and the weight of uterus of adult females, but decreased the number of grid crossings and the frequency of rearing, and increased grooming in open field. DEHP reduced the open arm entries and the time spent in open arms in the elevated plus maze. DEHP reduced mutual sniffing and grooming between unfamiliar conspecifics in social play task and reduced the right chamber (containing unfamiliar female mouse) entries and the frequency of sniffing unfamiliar female mouse. DEHP at 1 mg kg(-1) d(-1) reduced the time spent in right chamber. Furthermore, Western blot analyses showed that DEHP decreased the levels of estrogen receptor β (ERβ), dopamine receptor D2, and the phosphorylation of ERKs in striatum. These results suggest that pubertal exposure to DEHP impaired social investigation and sociability and influenced anxiety-like state of adult female mice. The decreased activity of ERK1/2, and the down-regulated D2 and ERβ in striatum may be associated with the DEHP-induced changes of emotional and social behavior in mice.
Article
Emerging evidence from observational studies suggests that prenatal exposure to phthalates affects neurodevelopment in children. To conduct a systematic review of the existing literature on the association between urinary phthalate concentrations and children's neurodevelopment. We searched electronic bibliographic databases (MEDLINE, PubMed, EMBASE, PsycINFO, CINAHL, Global Health, CAB abstracts, and ERIC) (1910 to February 21st, 2014); reference lists of included articles, and conference abstracts (American Psychiatric Association, American Academy of Neurology, and Pediatric Academic Societies). Two independent reviewers screened abstracts and extracted data. We included original studies reporting on the association between prenatal or childhood urinary phthalate metabolites, and cognitive and behavioral outcomes (e.g., IQ scores, BASC-2 scores or equivalent) in children 0-12 years of age. Of 2804 abstracts screened, 11 original articles met our criteria for inclusion. A systematic review of the literature supports the contention that prenatal exposure phthalates is associated with adverse cognitive and behavioral outcomes in children, including lower IQ, and problems with attention, hyperactivity, and poorer social communication. Further research characterizing the associations between specific phthalate metabolites and children's neurodevelopmental outcomes is needed to support the development of mitigation strategies and enhance the development of appropriate health policy. Copyright © 2015 Elsevier Inc. All rights reserved.
Article
Adolescence is a critical period for brain maturation characterized by the reorganization of interacting neural networks. In particular the prefrontal cortex, a region involved in executive function, undergoes synaptic and neuronal pruning during this time in both humans and rats. Our laboratory has previously shown that rats lose neurons in the medial prefrontal cortex (mPFC) and there is an increase in white matter under the frontal cortex between adolescence and adulthood. Female rats lose more neurons during this period, and ovarian hormones may play a role as ovariectomy before adolescence prevents neuronal loss. However, little is known regarding the timing of neuroanatomical changes that occur between early adolescence and adulthood. In the present study, we quantified the number of neurons and glia in the male and female mPFC at multiple time points from preadolescence through adulthood (postnatal days 25, 35, 45, 60 and 90). Females, but not males, lost a significant number of neurons in the mPFC between days 35 and 45, coinciding with the onset of puberty. Counts of GABA immunoreactive cell bodies indicated that the neurons lost were not primarily GABAergic. These results suggest that in females, pubertal hormones may exert temporally specific changes in PFC anatomy. As expected, both males and females gained white matter under the prefrontal cortex throughout adolescence, though these gains in females were diminished after day 35, but not in males. The differences in cell loss in males and females may lead to differential vulnerability to external influences and dysfunctions of the prefrontal cortex that manifest in adolescence. Copyright © 2015. Published by Elsevier Ltd.
Article
Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disrupter. Currently, little is known about neurodevelopmental toxicity of DEHP in wildlife and humans. The present study investigated the effects of DEHP, focusing on the changes in the behavior of offspring mice at the ages of 6 and 12 w, respectively, following utero and lactational exposure to DEHP (10, 50, and 200 mg/kg/d) from gestation day 7 through postnatal day 21. The results of open field tasks showed that DEHP increased the grooming of males at age 6 w and females at age 12 w but decreased the frequency of rearing of 6-w-old females and the number of grid crossings of 12-w-old females. In the Morris water maze task, 50 and 200 mg/kg/d DEHP significantly prolonged the time of searching the hidden platform in water maze and reduced the time staying in the target quadrant during a probe trial of 6-w-old male mice, but not of 6-w-old females nor 12-w-old mice of both sexes, suggesting an impaired spatial learning and memory among younger males after perinatal exposure to DEHP. Western blot analyses further showed that DEHP at 50 and 200 mg/kg/d decreased the levels of the N-methyl-D-aspartic acid (NMDA) receptor subunits NR1 and NR2B in the hippocampus of 6-w-old males. These results suggest that uterine and lactational exposure to low doses of DEHP sex-specifically impacted behaviors, including locomotion activity and spatial memory, via the concomitant inhibition of the NMDA receptor of the hippocampus in offspring mice. Copyright © 2015. Published by Elsevier Inc.
Article
Evidence is gradually accumulating that sex steroids play a significant role in modulating post-natal neuronal maturation and neural circuit formation. Sexual dimorphism of morphological parameters has also been demonstrated in certain brain areas where receptors for sex steroids are abundant. In this review, the morphological correlates of sexual differentiation in the rat brain will be discussed.
Article
Di-2-ethylhexyl phthalate (DEHP) is the most widely used phthalate to convey flexibility and transparency to plastic products made of polyvinyl chloride. It has been recognized as endocrine disruptor and associated with reproductive toxic effects. We examined the effects of perinatal exposure to DEHP on anxiety-like behavior, using the Elevated Plus Maze (EPM) test, in male and female rats at different stages of sexual development. Anxiety-like behavior was expressed as a) frequency of open arm entries over the total arm entries (% FEO); b) time spent in them compared with total time the animal stayed in the EPM (% TSO) and c) time spent in closed arms (TSC). Because DEHP has anti-androgenic action we also tested control and exposed immature male rats pretreated with testosterone. We found sex differences in behavior induced by DEHP; while male rats of 45 and 60days of age showed a significant decrease in FEO and TSO percentages, as well as an increase in TSC, no changes were observed in anxiety-like behavior in perinatal DEHP exposed females at these ages of sexual maturation. In 60- day- old male rats, DEHP exposure produced a significant decrease in serum testosterone levels. Testosterone replacement was able to antagonize the adverse effects of DEHP exposure on LH, activating the negative feed-back mechanism of this steroid on reproductive axis, as well as increasing FEO and TSO percentages to similar values observed in control group. These findings suggest that the anti-androgenic action of this chemical could be one possible mechanism underlie anxiogenic-like behavior produced by perinatal DEHP exposure in 60- day- old male rats.
Article
focuses on late developmental events [those occurring during the second trimester of gestation and continuing into the postnatal period]—synaptogenesis and synapse elimination—in human cerebral cortex [in fetuses–70 yr olds], and stresses functional correlates where these can be determined (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
Article
We have previously shown that males have more neurons than females in the primary visual cortex, and neonatal androgens play an important role in this difference. Also, we have found that females experience more cell death during development in this region than in males. Therefore, we hypothesized that the neonatal hormone environment directly influences the amount of cell death. In the present experiment, female rats were implanted with dihydrotestosterone (DHT) or estradiol at postnatal day 1. These animals, along with control males and females, were sacrificed on postnatal days 6, 11 and 25. Using unbiased stereology to quantify neuronal and pyknotic cell density, we observed that females implanted with DHT had a similar pattern and proportion of cells dying as control males. Additionally, developmental cell death in females implanted with estradiol was not significantly different than control females. Thus, neonatal androgens have an inhibitory effect on developmental cell death in the rat primary visual cortex.
Article
Neural sensorimotor gating mechanisms prevent the interruption of ongoing information processing routines by ensuing stimuli to permit mental integration and adaptive behavior. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is now being investigated using murine models to exploit transgenic and “knockout” technology. The present studies were undertaken to evaluate potential murine strain differences in the effects of serotonergic drugs on PPI and habituation. Two strains used most often as a genetic background for transgenic or knockout manipulations, C57BL/6 and 129Sv, and the outbred ICR strain were used. We assessed the effects of the 5-HT1A/1B agonist 5-methoxy-3(1,2,3,6)tetrahydropyridin-4-yl-1H-indole (RU24969), the 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), the 5-HT2A/2C agonist (±)2,5-dimethoxy-4-methylamphetamine (DOM), and the serotonin releaser (+)3,4-methylenedioxy-N-methylamphetamine (MDMA) on PPI and habituation of acoustic startle in the three strains. C57BL/6 mice exhibited lower baseline PPI levels than 129Sv and ICR mice, and 129Sv mice habituated less than C57BL/6 and ICR mice. MDMA decreased PPI in C57BL/6 and ICR, but not 129Sv mice, and RU24969 disrupted habituation in C57BL/6 and 129Sv, but not ICR mice. Lastly, RU24969 decreased and 8-OH-DPAT increased PPI across all strains, although qualitative differences were observed. Thus, both baseline and serotonergic drug-induced effects on murine PPI and habituation are strain-dependent.
Article
Dibutyl phthalate (DBP), an important representative of endocrine disrupting chemical, is suspected of affecting the cognitive function of humans and animals. In this study, effects of DBP on maze performance in male rats were evaluated by spatial learning tasks; the effects of DBP on the expression of brain-derived neurotrophic factor (BDNF) were also analyzed in both mRNA and mature protein levels in the hippocampus, with intent to investigate the possible mechanism underlying the behavioral findings. Pregnant Wistar rats were treated orally by gavage with 0, 25, 75, 225 and 675mgDBP/kgBW/day from gestational day (GD) 6 to postnatal day (PND) 21, and then the weaned offspring continued receiving the same treatment till PND 28. We found that male pups treated with high-dose DBP showed enhancement in spatial acquisition in a Morris water maze during PNDs 30-33, and displayed better retention of spatial memory in a probe trial after a reverse trail during PNDs 60-62. Real-time PCR and western blotting analysis of the hippocampus from DBP-treated male rats on PND 21 revealed an increase in BDNF expression, compared to the vehicle-matched control. BDNF variant III, a transcription promoted by active CREB (i.e. p-CREB), as well as the immunocontent of p-CREB, was scarcely altered by the treatment. Our results suggest that developmental treatment with high-dose DBP improves spatial memory in male rats, and this effect may be related to an increase in BDNF expression in the hippocampus in a p-CREB independent route.
Article
Transformations in affective and social behaviors, many of which involve amygdalar circuits, are hallmarks of adolescence in many mammalian species. In this study, using the rat as a model, we provide the first evidence that afferents of the basal amygdala (BA) undergo significant structural remodeling during adolescence. We used quantitative tract-tracing and gene expression profiling methods to characterize changes in the medial prefrontal cortical (mPFC) inputs to the BA across ages analogous to the late juvenile period [postnatal day (P) 25], late adolescence (P45), and adulthood (P90) in the rat. As assessed after deposition of Fluorogold into the BA, the number of BA-projecting neurons in the mPFC remained stable between P25 and P45 but decreased by about 50% between P45 and P90. Anterograde tract tracing with biotin dextran amine deposits centered in the ventral prelimbic cortex revealed that, during this period, the density of mPFC-derived axon terminals in the BA also decrease significantly, an effect particularly evident in the dorsal basolateral nucleus. Within the BA, there were also highly significant changes in gene expression indicative of neurite or synaptic plasticity, most notably in the Ras/GTPase superfamily, and in pathways that regulate cytoskeletal dynamics and steroid synthesis/lipid metabolism. These data provide convergent evidence that mPFC inputs to the BA are pruned during late adolescence or early adulthood. Moreover, the structural remodeling within these afferents may be accompanied by significant changes in neurite plasticity within the BA.
Article
Phthalate esters are ubiquitous environmental contaminants that in general display low-toxicity. Overall, the reproductive effects of these compounds are well characterized in adult's animals, with gonadal injury observed after high dose exposure. However, results of recent transgeneration studies indicate that the reproductive system of developing animals is particularly vulnerable to certain phthalates. The phenotypic alterations observed in male offspring rats exposed during the perinatal period have remarkable similarities with common human reproductive disorders, including cryptorchidism, hypospadias and low-sperm counts. Recent results also indicate that high phthalate doses can adversely affect adult and developing female rats. However, the main question involving phthalates is whether the current level of human exposure is sufficient to adversely affect male and/or female reproductive health. Here, we review the reproductive toxicity data of phthalates in adult and developing animals as well as possible modes of action. In addition, we briefly discuss the relevance of animal studies to humans in light of recent epidemiological data and experimental research with low (human relevant) doses. Finally, we point out some critical issues that should be addressed in order to clarify the implications of phthalates for human reproduction.
Article
This chapter focuses on the development of the rat prefrontal cortex (PFC). It also describes the size and development of connections with the thalamus, spinal cord and, other cortical areas. It also explores whether or not the prefrontal cortex has a later or prolonged development in comparison with other cortical areas. The pre- and postnatal development of the rat cerebral cortex is also reviewed in the chapter. The cortical areas that attain an adult-like myelinization pattern prior to birth all belong to sensoric/motoric areas. The development of the cortical layers, ingrowth of thalamic and dopaminergic fibers, follow a scheme of development that is comparable to that of other cortical areas. Only the volumetric development seems to point to a delayed maturation of the prefrontal areas, especially the orbital PFC. Reciprocal projection from the prefrontal cortex to the mediodorsal thalamus is largely formed during the second week of postnatal life. A way to monitor the development of the PFC is to measure its increase in size during the first postnatal months.
Article
Five daily oral doses of di(2-ethylhexyl) phthalate (DEHP) (2 g/kg) given to rats on Days 2-6, 6-10, or 14-18 of lactation caused significant decreases in body weight and increases in hepatic peroxisomal enzymes palmitoyl CoA oxidase and carnitine acetyltransferase in the dams and their suckling pups. Plasma cholesterol and triglyceride levels were decreased in the lactating dams. Decreased food consumption, as indicated by pair-fed rats, accounted for the decreased body weight in the pups but not the increases in enzyme activities. To determine whether DEHP and mono(2-ethylhexyl) phthalate (MEHP) were transferred through the milk, milk and plasma were collected from lactating rats 6 hr after the third dose of DEHP. The milk contained 216 +/- 23 micrograms/ml DEHP and 25 +/- 6 micrograms/ml MEHP (mean +/- SE), while the plasma contained less than 0.5 micrograms/ml DEHP and 75 +/- 12 micrograms/ml MEHP. The high milk/plasma ratio for DEHP (greater than 200) indicates efficient extraction of DEHP from the plasma into the milk. DEHP dosing during lactation also caused a decrease in mammary gland weight and a decrease in mammary gland RNA content which reflects synthetic activity. The water content of the milk was reduced, which probably accounted for the increase in lipid in the milk. Milk lactose was decreased in DEHP-treated and pair-fed rats, consistent with the decrease in milk production. The results show that exposure to high doses of DEHP during lactation in rats can result in changes in milk quality and quantity and can lead to DEHP and MEHP exposure in the suckling rat pups.
Article
The effect of a transitory increase in plasma FSH and LH levels during the prepubertal period on puberty has been investigated. Twenty-day-old rats had been bilaterally ovariectomized and 24 hr later they received two ovaries of infantile rats beneath the kidney capsule. These rats exhibited precocious puberty. Animals into which two additional ovaries had been transplanted first and the next day their own ovaries removed showed puberty at the same time as controls. Additional investigations provided evidence that the ovariectomized and ovary implanted rats plasma FSH and LH levels were in the control range four days after implantation. The findings support the assumption that the hypothalamic lesion-induced precocious puberty is due rather to a transitory enhanced release of gonadotropin releasing hormone by the lesion than to the destruction of sex-steroid sensitive structures inhibiting the release of gonadotropic hormones in prepubertal rats.
Article
The formation of synaptic contacts in human cerebral cortex was compared in two cortical regions: auditory cortex (Heschl's gyrus) and prefrontal cortex (middle frontal gyrus). Synapse formation in both cortical regions begins in the fetus, before conceptual age 27 weeks. Synaptic density increases more rapidly in auditory cortex, where the maximum is reached near postnatal age 3 months. Maximum synaptic density in middle frontal gyrus is not reached until after age 15 months. Synaptogenesis occurs concurrently with dendritic and axonal growth and with myelination of the subcortical white matter. A phase of net synapse elimination occurs late in childhood, earlier in auditory cortex, where it has ended by age 12 years, than in prefrontal cortex, where it extends to midadolescence. Synaptogenesis and synapse elimination in humans appear to be heterochronous in different cortical regions and, in that respect, appears to differ from the rhesus monkey, where they are concurrent. In other respects, including overproduction of synaptic contacts in infancy, persistence of high levels of synaptic density to late childhood or adolescence, the absolute values of maximum and adult synaptic density, and layer specific differences, findings in the human resemble those in rhesus monkeys.
Article
Structural magnetic resonance imaging (MRI) data have provided much evidence in support of our current view that schizophrenia is a brain disorder with altered brain structure, and consequently involving more than a simple disturbance in neurotransmission. This review surveys 118 peer-reviewed studies with control group from 1987 to May 1998. Most studies (81%) do not find abnormalities of whole brain/intracranial contents, while lateral ventricle enlargement is reported in 77%, and third ventricle enlargement in 67%. The temporal lobe was the brain parenchymal region with the most consistently documented abnormalities. Volume decreases were found in 62% of 37 studies of whole temporal lobe, and in 81% of 16 studies of the superior temporal gyrus (and in 100% with gray matter separately evaluated). Fully 77% of the 30 studies of the medial temporal lobe reported volume reduction in one or more of its constituent structures (hippocampus, amygdala, parahippocampal gyrus). Despite evidence for frontal lobe functional abnormalities, structural MRI investigations less consistently found abnormalities, with 55% describing volume reduction. It may be that frontal lobe volume changes are small, and near the threshold for MRI detection. The parietal and occipital lobes were much less studied; about half of the studies showed positive findings. Most studies of cortical gray matter (86%) found volume reductions were not diffuse, but more pronounced in certain areas. About two thirds of the studies of subcortical structures of thalamus, corpus callosum and basal ganglia (which tend to increase volume with typical neuroleptics), show positive findings, as do almost all (91%) studies of cavum septi pellucidi (CSP). Most data were consistent with a developmental model, but growing evidence was compatible also with progressive, neurodegenerative features, suggesting a "two-hit" model of schizophrenia, for which a cellular hypothesis is discussed. The relationship of clinical symptoms to MRI findings is reviewed, as is the growing evidence suggesting structural abnormalities differ in affective (bipolar) psychosis and schizophrenia.
Article
Startle is a fast response to sudden, intense stimuli and probably protects the organism from injury by a predator or by a blow. The acoustic startle response (ASR) of mammals is mediated by a relatively simple neuronal circuit located in the lower brainstem. Neurons of the caudal pontine reticular nucleus (PnC) are key elements of this primary ASR pathway. The ASR in humans and animals has a non-zero baseline, that is, the response magnitude can be increased or decreased by a variety of pathological conditions and experimental manipulations. Therefore, the ASR has been used as a behavioral tool to assess the neuronal basis of behavioral plasticity and to model neuropathological dysfunctions of sensorimotor information processing. Cross-species examples for the increase of the ASR magnitude are sensitization, fear-potentiation and drug-induced enhancement. Examples for the reduction of the ASR magnitude are habituation, prepulse inhibition, drug-induced inhibition and the attenuation by positive affect. This review describes the neuronal basis underlying the mediation of the ASR, as well as the neuronal and neurochemical substrates of different phenomena of enhancement and attenuation of the ASR. It also attempts to elucidate the biological background of these forms of behavioral plasticity. Special emphasis is put on the potential relevance of ASR modulations for the understanding of human psychiatric and neurological diseases.
Article
The pathophysiological characteristics of schizophrenia appear to involve altered synaptic connectivity in the dorsolateral prefrontal cortex. Given the central role that layer 3 pyramidal neurons play in corticocortical and thalamocortical connectivity, we hypothesized that the excitatory inputs to these neurons are altered in subjects with schizophrenia. To test this hypothesis, we determined the density of dendritic spines, markers of excitatory inputs, on the basilar dendrites of Golgi-impregnated pyramidal neurons in the superficial and deep portions of layer 3 in the dorsolateral prefrontal cortex (area 46) and in layer 3 of the primary visual cortex (area 17) of 15 schizophrenic subjects, 15 normal control subjects, and 15 nonschizophrenic subjects with a psychiatric illness (referred to as psychiatric subjects). There was a significant effect of diagnosis on spine density only for deep layer 3 pyramidal neurons in area 46 (P = .006). In the schizophrenic subjects, spine density on these neurons was decreased by 23% and 16% compared with the normal control (P = .004) and psychiatric (P = .08) subjects, respectively. In contrast, spine density on neurons in superficial layer 3 in area 46 (P = .09) or in area 17 (P = .08) did not significantly differ across the 3 subject groups. Furthermore, spine density on deep layer 3 neurons in area 46 did not significantly (P = .81) differ between psychiatric subjects treated with antipsychotic agents and normal controls. This region- and disease-specific decrease in dendritic spine density on dorsolateral prefrontal cortex layer 3 pyramidal cells is consistent with the hypothesis that the number of cortical and/or thalamic excitatory inputs to these neurons is altered in subjects with schizophrenia.
Article
In this article, we consider whether studies in rats can provide useful information regarding the debate about the functions of the primate prefrontal cortex. At a superficial level, comparison of regional specializations within the prefrontal cortices of different species suggests functional correspondence. Unfortunately, the nature of functional specialization in primate prefrontal cortex is controversial, and data supporting the idea of homology between specific areas of rat and primate prefrontal cortex are weak. Nevertheless, we argue here that studies of the computational functions within the relatively undifferentiated prefrontal cortex of rats can shed light on processing in primate prefrontal cortex.
Article
Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation.
Article
We analyzed 85 urine samples of the general German population for human specific metabolites of phthalates. By that we avoided contamination with the parent phthalates being omnipresent in the environment and for the first time could deduce each individual's internal exposure to phthalates without contamination. Determined were the secondary metabolites mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP) and mono(2-ethyl-5-oxo-hexyl)phthalate (5oxo-MEHP) of di(2-ethylhexyl)phthalate (DEHP) and the primary monoester metabolites of DEHP, di-noctylphthalate (DnOP), di-n-butylphthalate (DnBP), butylbenzylphthalate (BBzP) and diethylphthalate (DEP). Based on these internal exposure values we calculated the daily intake of the parent phthalates using urinary metabolite excretion factors. For DEHP we determined a median intake of 13.8 micrograms/kg body weight/day and an intake at the 95th percentile of 52.1 micrograms/kg body weight/day. The tolerable daily intake (TDI) value settled by the EU Scientific Committee for Toxicity, Ecotoxicity and the Environment (CSTEE) is 37 micrograms/kg body weight/day. Twelve percent of the subjects (10 out of 85 samples) within our collective of the general population are exceeding this value. Thirty-one percent of the subjects (26 out of 85 samples) had values higher than the reference dose (RfD) of 20 micrograms/kg body weight/day of the U.S. Environmental Protection Agency (EPA). For DnBP, BBzP, DEP and DnOP intake values at the 95th percentile were 16.2, 2.5, 22.1 and 0.42 micrograms/kg body weight/day respectively. Our results unequivocally prove that the general German population is exposed to DEHP to a much higher extent than previously believed. This is of greatest importance for public health since DEHP is not only the most important phthalate with respect to its production, use, occurrence and omnipresence but also the phthalate with the greatest endocrine disrupting potency. DEHP is strongly suspected to be a developmental and reproductive toxicant. We are not aware of any other environmental contaminant for which the TDI and RfD are exceeded to such an extent within the general population. The transgressions of the TDI and RfD for DEHP are accompanied by considerable ubiquitous exposures to DnBP and BbzP, two phthalates under scrutiny for similar toxicological mechanisms.
Article
Prepulse inhibition (PPI) is the normal suppression of the startle reflex when an intense startling stimulus is preceded by a barely detectable prepulse. Habituation of the acoustic startle reflex is decrement in response when the same stimulus is presented repeatedly. These factors have been proposed as neurophysiologic measures of sensorimotor gating or filtering and discussed as trait-linked markers for information-processing deficits in schizophrenia-spectrum disorders. The aim of this study was to examine whether first-episode schizophrenia patients also exhibit deficits in PPI and habituation. Never-medicated male schizophrenic and schizophreniform patients in their first psychotic episode (n=24) were compared with age-matched healthy men (n=21) in an acoustic startle paradigm assessing PPI (30-, 60-, 120-, 240-, and 2000-msec interstimulus intervals) and habituation. Compared with control subjects, first-episode patients exhibited significant deficits in both PPI in the 60-msec prepulse condition and startle habituation. Patients also exhibited less facilitation in the 2000-msec prepulse condition. In combination with other studies, these findings indicate that PPI and habituation may be sensitive intermediate phenotypic markers for information-processing deficits in schizophrenic patients.
Article
The lack of a single anatomical or functional definition of 'prefrontal cortex' has led to different and, in some respects, controversial views on the existence of a prefrontal cortex in non-primate mammals, in particular in rats. Until the classic paper by Rose and Woolsey [Res. Publ. Assoc. Nerv. Ment. Dis. 27 (1948) 210], the general idea was that a prefrontal cortex is unique to primate species. Rose and Woolsey's 'prefrontal cortex' definition was based upon a single anatomical criterion, i.e. the cortical projection area of the mediodorsal thalamic nucleus. Single criteria, however, do not appear to be sufficient for defining the prefrontal cortex. Therefore, other anatomical and functional characteristics are currently used to identify the prefrontal cortex in different species. Yet, recently the debate about the nature of the prefrontal cortex in non-primate species has been resumed. In the present paper we will compare the structural and functional characteristics of the prefrontal cortex of nonhuman primates and rats. We will argue that rats have a functionally divided prefrontal cortex that includes not only features of the medial and orbital areas in primates, but also some features of the primate dorsolateral prefrontal cortex.