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Humans are exposed to phthalates, a class of endocrine-disrupting chemicals used in food packaging/processing, PVC plastics, and personal care products. Gestational exposure may lead to adverse neurodevelopmental outcomes. In a rat model, perinatal exposure to an environmentally relevant mixture and dose of phthalates leads to increased developmental apoptosis in the medial prefrontal cortex (mPFC) and a subsequent reduction in neurons and in cognitive flexibility measured in adults of both sexes (Sellinger et al., 2021b; Kougias et al., 2018b). However, whether these effects generalize to other cognitive regions, like the hippocampus, is less well understood as existing studies used single phthalates at large doses, unrepresentative of human exposure. In the current study, patterns of naturally occurring cell death were first established in the dorsal and ventral hippocampal subfields (CA3 and CA1). Both dorsal and ventral CA3 reached high levels of cell death on P2 while levels in dorsal and ventral CA1 peaked on P5 in both sexes. Exposure to a phthalate mixture (0.2 and 1 mg/kg/day) throughout gestation through postnatal day 10 resulted in subtle age- and region-specific decreases in developmental cell death, however there were no significant changes in adult neuron number or associated behaviors: the Morris water maze and social recognition. Therefore, perinatal exposure to a low dose mixture of phthalates does not result in the dramatic structural and behavioral changes seen with high doses of single phthalates. This study also adds to our understanding of the distinct neurodevelopmental effects of phthalates on different brain regions.

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Bisphenol A (BPA) is an endocrine disruptor found in polycarbonate plastics and exposure in humans is nearly ubiquitous and it has widespread effects on cognitive, emotional, and reproductive behaviors in both humans and animal models. In our laboratory we previously found that perinatal BPA exposure results in a higher number of neurons in the adult male rat prefrontal cortex (PFC) and less play in adolescents of both sexes. Here we examine changes in the rate of postnatal apoptosis in the rat prefrontal cortex and its timing with brief BPA exposure. Because an increased number of neurons in the PFC is a characteristic of a subtype of autism spectrum disorder, we tested social preference following brief BPA exposure and also expression of a small group of genes. Males and females were exposed to BPA from postnatal days (P) 6 through 8 or from P10 through 12. Both exposures significantly decreased indicators of cell death in the developing medial prefrontal cortex in male subjects only. Additionally, males exposed to BPA from P6 - 8 showed decreased social preference and decreased cortical expression of Shank3 and Homer1, two synaptic scaffolding genes that have been implicated in social deficits. There were no significant effects of BPA in the female subjects. These results draw attention to the negative consequences following brief exposure to BPA during early development.

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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.

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In female rats, pubertal onset is associated with maturation of the medial prefrontal cortex (mPFC) and mPFC-mediated behaviours. These behavioural and anatomical changes are likely a result of the effects of oestrogens at the nuclear oestrogen receptor (ER)ß, which is expressed at higher levels than the ERα isoform in the adult mPFC. Researchers have previously quantified ERß protein and Esr2 RNA in rodents during early postnatal development and adulthood, although an adolescent-specific trajectory of this receptor in the mPFC has not been documented. Given that Esr2 expression can fluctuate in the presence or absence of oestrogens, puberty and the subsequent rise in gonadal hormones could influence levels of ERß in the adolescent brain. To further explore this, we used RNAscope® technology to quantify the amount of Esr2 mRNA in pre-pubertal adolescent, recently post-pubertal adolescent and adult female rats. We show that Esr2 expression decreases significantly in the mPFC, striatum and motor cortex between pre-pubertal adolescence and adulthood. In the mPFC, this decrease occurs rapidly at pubertal onset, with no significant decrease in Esr2 levels between the recently post-pubertal and adult cohort. By contrast, the striatum and motor cortex had no significant differences in the amount of Esr2 mRNA between pre- and post-pubertal females. Insofar as the amount of Esr2 expression is proportional to functional ERß, these results suggest ERß decreases in a region-specific pattern in response to pubertal onset and highlight a role for this receptor in the maturational events that occur in the female rat mPFC at puberty.

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Apoptosis, programmed cell death, is a critical component of neurodevelopment occurring in temporal, spatial, and at times, sex-specific, patterns across the cortex during the early postnatal period. During this time, the brain is particularly susceptible to environmental influences that are often used in animal models of neurodevelopmental disorders. In the present study, the timing of peak cell death was assessed by the presence of pyknotic cells in the male and female rat medial prefrontal cortex (mPFC), a cortical region that in humans, is often involved in developmental disorders. One male and one female rat per litter were sacrificed at the following ages: postnatal day (P)2, 4, 6, 8, 10, 12, 14, 16, 18, and 25. The mPFC was Nissl-stained, the densities of pyknotic cells and live neurons were stereologically collected, and the number of pyknotic cells per 100 live neurons, pyknotic cell density, and neuron density were analyzed. Males and females showed a significant peak in the ratio of pyknotic to live neurons on P8, and in females, this elevation persisted through P12. Likewise, the density of pyknotic cells peaked on P8 in both sexes and persisted through P12 in females. The timing of cell death within the rat mPFC will inform study design in experiments that employ early environmental manipulations that might disrupt this process.

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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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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.SIGNIFICANCE STATEMENT Humans globally are exposed on a daily basis to a variety of phthalates, which are endocrine-disrupting chemicals. The effects of phthalate exposure on the developing brain, especially on cognitively relevant regions, such as the mPFC, are not known. Here, we use a rat model of human prenatal exposure to an environmentally relevant mixture of phthalates and find that there is an appreciable reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. These results may have serious implications for humans given that the mPFC is involved in executive functions and is implicated in the pathology of many neuropsychiatric disorders.

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This study investigated the effects of religious education on student religious identity over and above parent religiosity by examining student perceptions of two aspects of teacher functioning: teacher caring and teacher as role-model. We posited that effects of these variables on students' religious identity are mediated by student perceptions that the school provides a non-alienating religious atmosphere and meaningful religious studies. Participants were 2691 male and female students (grades 9-12) in 152 classes of 25 schools from the Jewish public-religious sector in Israel. Results indicate that in addition to their parents' religiosity, adolescents' perceptions of their teachers as role models and their religious studies as meaningful are important variables affecting their religious identity. Moreover, this research suggests that religious identity formation processes flourish in an educational environment which students perceive as accommodating religious exploration.

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This paper deals with the theoretical construct of "identity configuration." It portrays the different possible ways in which individuals configure the relationship among potentially conflicting identifications in the process of identity formation. In order to explicate these configurations, I analyzed narratives of identity development retold by individuals describing personal identity conflicts that arise within a larger context of sociocultural conflict. Thirty Jewish modern orthodox young adults were interviewed regarding a potentially conflictual identity issue (i.e. their religious and sexual development). Their deliberations, as described in the interviews, were examined, and four different configurations were identified: a configuration based on choice and suppression; an assimilative and synthesizing configuration; a confederacy of identifications; and a configuration based on the thrill of dissonance. The different configurations are illustrated through exemplars, and the possible implications of the concept of "configuration" for identity theory are discussed.

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From January 1st, 1983 to March 31st, 1988, 66 children with GER were tested with barium esophagogram, esophageal pH monitoring and esophagoscopy. A medical therapy was given to 49 children and 46 had a clinical improvement; 13 were operated. Early diagnosis is very important to prevent complications: in fact our data show that older children have the worst complications, while infants with GER and severe esophageal pH monitoring have only I-II grade esophagitis.

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