The mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.

In addition to its role in the pathophysiology of numerous psychiatric disorders, increasing evidence points to serotonin (5-HT) as a crucial molecule for the modulation of neurodevelopmental processes. Recent evidence indicates that the placenta is involved in the synthesis of 5-HT from maternally derived tryptophan (TRP). This gives rise to the possibility that genetic and environmental perturbations directly affecting placental TRP metabolism may lead to abnormal brain circuit wiring in the developing embryo, and therefore contribute to the developmental origin of psychiatric disorders. In this review, we discuss how perturbations of the placental TRP metabolic pathway may lead to abnormal brain development and function throughout life. Of particular interest is prenatal exposure to maternal depression and antidepressants, both known to alter fetal development. We review existing evidence on how antidepressants can alter placental physiology in its key function of maintaining fetal homeostasis and have long-term effects on fetal forebrain development.

Human epidemiological and animal-model studies suggest that separate exposure to stress or serotonin-selective reuptake inhibitor (SSRI) antidepressants during pregnancy increases risks for neurodevelopmental disorders in offspring. Yet, little is known about the combined effects of maternal stress and SSRIs with regard to brain development in utero. We found that the placenta is *

While selective-serotonin reuptake inhibitor (SSRI) antidepressants are commonly prescribed in the treatment of depression, their use during pregnancy leads to fetal drug exposures. According to recent reports, such exposures could affect fetal development and long-term offspring health. A central question is how pregnancy-induced physical and physiological changes in mothers, fetuses, and the placenta influence fetal SSRI exposures during gestation. In this study, we examined the effects of gestational stage on the maternal pharmacokinetics and fetal disposition of the SSRI (±)-citalopram (CIT) in a mouse model. We determined the maternal and fetal CIT serum concentration–time profiles following acute maternal administration on gestational days (GD)14 and GD18, as well as the fetal brain drug disposition. The results show that pregnancy affects the pharmacokinetics of CIT and that maternal drug clearance increases as gestation progresses. The data further show that CIT and its primary metabolite desmethylcitalopram (DCIT) readily cross the placenta into the fetal compartment, and fetal exposure to CIT exceeds that of the mother during gestation 2 h after maternal administration. Enzymatic activity assays revealed that fetal drug metabolic capacity develops in late gestation, resulting in elevated circulating and brain concentrations of DCIT at embryonic day (E)18. Fetal exposure to the SSRI CIT in murine pregnancy is therefore influenced by both maternal gestational stage and embryonic development, suggesting potential time-dependent effects on fetal brain development.

Dysfunction of brain serotonin (5-HT) signaling contributes to the pathophysiology of several psychiatric disorders. However, before 5-HT acts as a neurotransmitter/neuromodulator in the adult brain, increasing evidence suggests that it plays crucial roles in the modulation of essential neurodevelopmental processes. It was recently demonstrated that the placenta synthesizes 5-HT from maternally derived tryptophan during pregnancy. Therefore, genetic and environmental perturbations that affect placental tryptophan metabolism could alter neurodevelopmental processes in the developing embryo, and contribute to the developmental origin of psychiatric disorders. Here we discuss how disruptions of the placental tryptophan metabolic pathway may lead to abnormal brain development and function in adult life.

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Fetal exposure to selective serotonin reuptake inhibitors (SSRI) has been associated with increased risk of adverse neurodevelopmental outcomes. In the adult brain, SSRI therapy regulates p11 (s100a10) expression and alters neurogenesis. The protein p11 indirectly regulates 5-HT signaling through 5-HT1B/D receptors. In the fetal brain, signaling through these receptors modulates axonal circuit formation. We determined whether p11 is expressed in the fetal mouse brain, and whether maternal SSRI exposure affects fetal p11 expression and neurogenesis. The SSRI ± citalopram was administered to pregnant mice from gestational day 8 to 17. Results show that p11 is expressed in fetal thalamic neurons and thalamocortical axons. Furthermore, p11 protein expression is significantly decreased in the fetal thalamus after in utero ±citalopram exposure compared to untreated controls, and neurogenesis is significantly decreased in specific fetal brain regions. These findings reveal differential regulation of p11 expression and altered neurogenesis in the fetal brain as a result of maternal SSRI exposure.

Florpyrauxifen-benzyl (FPB) is a new class of auxinic herbicide developed for selective weed control in rice. This study aimed to evaluate the effect of environmental conditions, P450 inhibitors, rice cultivar response, and gene expression on FPB selectivity in rice. Field experiments established in a randomized block design showed that rice plant injury due to two FPB rates (30 and 60 g ai ha−1) was affected by planting time and rice stage at herbicide application. The injury was higher at the earliest planting season and more in younger plants (V2) than larger (V6 and R0). However, no yield reduction was detected. Under greenhouse conditions, two dose-response experiments in a randomized block design showed that spraying malathion (1 kg ha−1) before FPB application did not reduce herbicide selectivity. The addition of two P450 inhibitors (dietholate and piperonyl butoxide, 10 g a.i. seed-kg−1 and 4.2 kg ai ha−1, respectively) decreased the doses to cause 50% of plant injury (ED50) and growth reduction (GR50). However, it seems not to compromise crop selectivity. Pampeira cultivar showed lower ED50 and GR50 than IRGA 424 RI. A growth chamber experiment was conducted in a completely randomized design to evaluate the gene expression of rice plants sprayed with FPB (30 and 60 g ai ha−1). Results showed downregulation of OsWAKL21.2, an esterase probably related to bio-activation of FPB-ester. However, no effect was detected on CYP71A21 monooxygenase and OsGSTL transferase, enzymes probably related to FPB degradation. Further research should focus on understanding FBP bio-activation as the selective mechanism.