Primary production of the kelp Lessonia corrugata varies with season and water motion: Implications for coastal carbon cycling.

Kelp forests provide vital ecosystem services such as carbon storage and cycling, and understanding primary production dynamics regarding seasonal and spatial variations is essential. We conducted surveys at three sites in southeast Tasmania, Australia, that had different levels of water motion, across four seasons to determine seasonal primary production and carbon storage as living biomass for kelp beds of Lessonia corrugata (Order Laminariales). We quantified blade growth, erosion rates, and the variation in population density and estimated both the net biomass accumulation (NBA) per square meter and the carbon standing stock. We observed a significant difference in blade growth and erosion rates between seasons and sites. Spring had the highest growth rate (0.02 g C · blade-1 · d-1 ) and NBA (1.62 g C · m-2 · d-1 ), while summer had the highest blade erosion (0.01 g C · blade-1 · d-1 ), with a negative NBA (-1.18 g C · m-2 · d-1 ). Sites exhibiting lower blade erosion rates demonstrated notably greater NBA than sites with elevated erosion rates. The sites with the highest water motion had the slowest erosion rates. Moreover, the most wave-exposed site had the densest populations, resulting in the highest NBA and a greater standing stock. Our results reveal a strong seasonal and water motion influence on carbon dynamics in L. corrugata populations. This knowledge is important for understanding the dynamics of the carbon cycle in coastal regions.

Thermal performance curves identify seasonal and site-specific variation in the development of Ecklonia radiata (Phaeophyceae) gametophytes and sporophytes.

Rapid ocean warming is affecting kelp forests globally. While the sporophyte life stage has been well studied for many species, the microscopic life stages of laminarian kelps have been understudied, particularly regarding spatial and temporal variations in thermal tolerance and their interaction. We investigated the thermal tolerance of growth, survival, development, and fertilization of Ecklonia radiata gametophytes, derived from zoospores sampled from two sites in Tasmania, Australia, throughout a year, over a temperature gradient (3-30°C). For growth we found a relatively stable thermal optimum at ~20.5°C and stable thermal maxima (25.3-27.7°C). The magnitude of growth was highly variable and depended on season and site, with no consistent spatial pattern for growth and gametophyte size. Survival also had a relatively stable thermal optimum of ~17°C, 3°C below the optimum for growth. Gametophytes grew to single cells between 5 and 25°C, but sporophytes were only observed between 10 and 20°C, indicating reproductive failure outside this range. The results reveal complex effects of source population and season of collection on gametophyte performance in E. radiata, with implications when comparing results from material collected at different localities and times. In Tasmania, gametophytes grow considerably below the estimated thermal maxima and thermal optima that are currently only reached during summer heatwaves, whereas optima for survival (~17°C) are frequently reached and surpassed during heatwaves, which may affect the persistence and recruitment of E. radiata in a warmer climate.

AKAP150-anchored PKA regulation of synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the lateral habenula.

Numerous studies of hippocampal synaptic function in learning and memory have established the functional significance of the scaffolding A-kinase anchoring protein 150 (AKAP150) in kinase and phosphatase regulation of synaptic receptor and ion channel trafficking/function and hence synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a critical role in brain's processing of rewarding/aversive experiences. Here we focused on an unexplored role of AKAP150 in the lateral habenula (LHb), a diencephalic brain region that integrates and relays negative reward signals from forebrain striatal and limbic structures to midbrain monoaminergic centers. LHb aberrant activity (specifically hyperactivity) is also linked to depression. Using whole cell patch clamp recordings in LHb of male wildtype (WT) and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), we found that the genetic disruption of PKA anchoring to AKAP150 significantly reduced AMPA receptor (AMPAR)-mediated glutamatergic transmission and prevented the induction of presynaptic endocannabinoid (eCB)-mediated long-term depression (LTD) in LHb neurons. Moreover, ΔPKA mutation potentiated GABAA receptor (GABAAR)-mediated inhibitory transmission postsynaptically while increasing LHb intrinsic neuronal excitability through suppression of medium afterhyperpolarizations (mAHPs). Given that LHb is a highly stress-responsive brain region, we further tested the effects of corticotropin releasing factor (CRF) stress neuromodulator on synaptic transmission and intrinsic excitability of LHb neurons in WT and ΔPKA mice. As in our earlier study in rat LHb, CRF significantly suppressed GABAergic transmission onto LHb neurons and increased intrinsic excitability by diminishing small-conductance potassium (SK) channel-mediated mAHPs. ΔPKA mutation-induced suppression of mAHPs also blunted the synaptic and neuroexcitatory actions of CRF in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPAR and GABAAR synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPAR and potassium channel trafficking and eCB signaling within the LHb.

Caregiver's cognitive traits are associated with pup fitness in a cooperatively breeding mammal.

Studies across diverse taxa have revealed the importance of early life environment and parenting on characteristics later in life. While some have shown how early life experiences can impact cognitive abilities, very few have turned this around and looked at how the cognitive skills of parents or other carers during early life affect the fitness of young. In this study, we investigate how the characteristics of carers may affect proxies of fitness of pups in the cooperatively breeding banded mongoose (Mungos mungo). We gave adult mongooses a spatial memory test and compared the results to the success of the pups those individuals cared for. Our results show a tradeoff between speed and accuracy in the spatial memory task, with those individuals which were faster to move between cups in the test arena making more erroneous re-visits to cups that they had already checked for food. Furthermore, the accuracy of their carer predicted future survival, but not weight gain of the pups and the effect was contrary to expected, with pups that were cared for by less accurate individuals being more likely to survive to adulthood. Our research also provides evidence that while younger carers were less accurate during the test, the age of the carer did not have an impact on the chance of raising young that live to sexual maturity. Our findings suggest that banded mongoose carers' cognitive traits have fitness consequences for the young they care for, affecting the chance that these young live to maturity.

The social formation of fitness: lifetime consequences of prenatal nutrition and postnatal care in a wild mammal population.

Research in medicine and evolutionary biology suggests that the sequencing of parental investment has a crucial impact on offspring life history and health. Here, we take advantage of the synchronous birth system of wild banded mongooses to test experimentally the lifetime consequences to offspring of receiving extra investment prenatally versus postnatally. We provided extra food to half of the breeding females in each group during pregnancy, leaving the other half as matched controls. This manipulation resulted in two categories of experimental offspring in synchronously born litters: (i) 'prenatal boost' offspring whose mothers had been fed during pregnancy, and (ii) 'postnatal boost' offspring whose mothers were not fed during pregnancy but who received extra alloparental care in the postnatal period. Prenatal boost offspring lived substantially longer as adults, but postnatal boost offspring had higher lifetime reproductive success (LRS) and higher glucocorticoid levels across the lifespan. Both types of experimental offspring had higher LRS than offspring from unmanipulated litters. We found no difference between the two experimental categories of offspring in adult weight, age at first reproduction, oxidative stress or telomere lengths. These findings are rare experimental evidence that prenatal and postnatal investments have distinct effects in moulding individual life history and fitness in wild mammals. This article is part of the theme issue 'Evolutionary ecology of inequality'.

Electronic field effect detection of SARS-CoV-2 N-protein before the onset of symptoms.

As part of the efforts to contain the pandemic, researchers around the world have raced to develop testing platforms to detect the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the Coronavirus disease 2019 (COVID-19). Within the different detection platforms studied, the field effect transistor (FET) is a promising device due to its high sensitivity and fast detection capabilities. In this work, a graphene-based FET which uses a boron and nitrogen co-doped graphene oxide gel (BN-GO gel) transducer functionalized with nucleoprotein antibodies, has been investigated for the detection of SARS-CoV-2 nucleocapsid (N)-protein in buffer. This biosensor was able to detect the viral protein in less than 4 min, with a limit of detection (LOD) as low as 10 ag/mL and a wide linear detection range stretching over 11 orders of magnitude from 10 ag/mL-1 µg/mL. This represents the lowest LOD and widest detection range of any COVID-19 sensor and thus can potentially enable the detection of infected individuals before they become contagious. In addition to its potential use in the COVID-19 pandemic, our device serves as a proof-of-concept of the ability of functionalized BN-GO gel FETs to be used for ultrasensitive yet robust biosensors.

A veil of ignorance can promote fairness in a mammal society.

Rawls argued that fairness in human societies can be achieved if decisions about the distribution of societal rewards are made from behind a veil of ignorance, which obscures the personal gains that result. Whether ignorance promotes fairness in animal societies, that is, the distribution of resources to reduce inequality, is unknown. Here we show experimentally that cooperatively breeding banded mongooses, acting from behind a veil of ignorance over kinship, allocate postnatal care in a way that reduces inequality among offspring, in the manner predicted by a Rawlsian model of cooperation. In this society synchronized reproduction leaves adults in a group ignorant of the individual parentage of their communal young. We provisioned half of the mothers in each mongoose group during pregnancy, leaving the other half as matched controls, thus increasing inequality among mothers and increasing the amount of variation in offspring birth weight in communal litters. After birth, fed mothers provided extra care to the offspring of unfed mothers, not their own young, which levelled up initial size inequalities among the offspring and equalized their survival to adulthood. Our findings suggest that a classic idea of moral philosophy also applies to the evolution of cooperation in biological systems.

30-Day postoperative COVID-19 outcomes in 398 patients from regional hospitals utilising a designated COVID-19 minimal surgical site pathway.

INTRODUCTION: Postoperative pulmonary complications and mortality rates during the COVID-19 pandemic have been higher than expected, leading to mass cancellation of elective operating in the UK. To minimise this, the Guy's and St Thomas' Hospital NHS Foundation Trust elective surgery hub and the executive team at London Bridge Hospital (LBH) created an elective operating framework at LBH, a COVID-19 minimal site, in which patients self-isolated for two weeks and proceeded with surgery only following a negative preoperative SARS-CoV-2 polymerase chain reaction swab. The aim was to determine the rates of rates of postoperative COVID-19 infection. METHODS: The collaboration involved three large hospital trusts, covering the geographic area of south-east London. All patients were referred to LBH for elective surgery. Patients were followed up by telephone interview at four weeks postoperatively. RESULTS: Three hundred and ninety-eight patients from 13 surgical specialties were included in the analysis. The median age was 60 (IQR 29-71) years. Sixty-three per cent (252/398) were female. In total, 78.4% of patients had an American Society of Anesthesiologists grade of 1-2 and the average BMI was 27.2 (IQR 23.7-31.8) kg/m2. Some 83.6% (336/402) were 'major' operations. The rate of COVID-19-related death in our cohort was 0.25% (1/398). Overall, there was a 1.26% (5/398) 30-day postoperative all-cause mortality rate. Seven patients (1.76%) reported COVID-19 symptoms, but none attended the emergency department or were readmitted to hospital as a result. CONCLUSION: The risk of contracting COVID-19 in our elective operating framework was very low. We demonstrate that high-volume major surgery is safe, even at the peak of the pandemic, if patients are screened appropriately preoperatively.

An ultrasensitive heart-failure BNP biosensor using B/N co-doped graphene oxide gel FET.

Heart failure (HF) is the number one cause of death in the world. B-type natriuretic peptide (BNP) is a recognized biomarker for HF and can be used for early detection. Field effect transistor (FET) biosensors have the ability to sense BNP in much shorter times than conventional clinical studies. The lowest limit of detection (LOD) of state-of-the-art HF FET biosensors is 100 fM and detection ranges are short, being less than 4 orders of magnitude. In this work, a B/N co-doped graphene oxide (GO) gel (BN-GO) was used as the channel material in an FET biosensor targeting BNP. The sensor was able to sense BNP in as little as 2 min, with an LOD as low as 10 aM and a wide linear detection range of 10 aM-1 µM, stretching over 11 orders of magnitude. The biosensor showed great selectivity and minimal response towards K+ and OH- ions and the human epidermal growth factor receptor (HER2) protein. This biosensor serves as a proof-of-concept of the ability of BN-GO gel FETs to be used for ultrasensitive biosensors.

Synergistic performance of triggered drug release and photothermal therapy of MCF7 cells based on laser activated PEGylated GO + DOX.

Graphene oxide is used as a singular 2D nano-carrier in cancer therapy. Here, graphene oxide is used as a hybrid chemo-drug graphene oxide (GO) + doxorubicin (DOX), mainly due to its unique chemical and optical properties. The laser triggers GO + DOX for selective drug delivery to optimize the drug release. The characterization of GO is investigated in terms of laser properties at 808 nm. Furthermore, the laser activates GO + DOX compounds to treat MCF7 cancerous cells. The drug release strongly depends on the temperature rise that mainly effects on the viability of the cancerous cells of interest. DOX simultaneously acts as a chemo-drug and as an optical fluorescent agent, whereas GO performs as an efficient photothermal nano-carrier. In fact, the GO-DOX hybrid drug demonstrates multifunctional during malignant cell treatment. We have shown that the laser heating of GO enhances the release percentage up to a treatment yield of 90%. This arises from the synergistic nature of DOX and GO compounds in simultaneous chemo/photo thermal therapy. Furthermore, the fluorescence property of DOX is used to assess the GO uptake using confocal microscope imaging.

Ascher's syndrome: a rare cause of lip swelling.

Ascher's syndrome is a rare, benign entity with just over 100 reported cases. The condition is characterised by a 'double' upper lip, blepharochalasis and non-toxic thyroid enlargement. It presents before the age of 20 years in the majority of cases and shows no racial or gender differences. While the exact cause is unknown, hormonal dysfunction and autosomal dominant inheritance have been suggested as possible aetiological factors. We present two cases of Ascher's syndrome referred for investigation of lip swelling.

Synthesis and biological assessment of a ruthenium(II) cyclopentadienyl complex in breast cancer cells and on the development of zebrafish embryos.

Ruthenium-based complexes currently attract great attention as they hold promise to replace platinum-based drugs as a first line cancer treatment. Whereas ruthenium arene complexes are some of the most studied species for their potential anticancer properties, other types of ruthenium complexes have been overlooked for this purpose. Here, we report the synthesis and characterization of Ru(II) cyclopentadienyl (Cp), Ru(II) cyclooctadienyl (COD) and Ru(III) complexes bearing anastrozole or letrozole ligands, third-generation aromatase inhibitors currently used for the treatment of estrogen receptor positive (ER +) breast cancer. Among these complexes, Ru(II)Cp 2 was the only one that displayed a high stability in DMSO and in cell culture media and consequently, the only complex for which the in vitro and in vivo biological activities were investigated. Unlike anastrozole alone, complex 2 was considerably cytotoxic in vitro (IC50 values < 1 µM) in human ER + breast cancer (T47D and MCF7), triple negative breast cancer (TNBC) (MBA-MB-231), and in adrenocortical carcinoma (H295R) cells. Theoretical (docking simulation) and experimental (aromatase catalytic activity) studies suggested that an interaction between 2 and the aromatase enzyme was not likely to occur and that the bulkiness of the PPh3 ligands could be an important factor preventing the complex to reach the active site of the enzyme. Exposure of zebrafish embryos to complex 2 at concentrations around its in vitro cytotoxicity IC50 value (0.1-1 µM) did not lead to noticeable signs of toxicity over 96 h, making it a suitable candidate for further in vivo investigations. This study confirms the potential of Ru(II)Cp complexes for breast cancer therapy, more specifically against TNBCs that are usually not responsive to currently used chemotherapeutic agents.

Organoruthenium(II) Complexes Bearing an Aromatase Inhibitor: Synthesis, Characterization, in Vitro Biological Activity and in Vivo Toxicity in Zebrafish Embryos.

Third-generation aromatase inhibitors such as anastrozole (ATZ) and letrozole (LTZ) are widely used to treat estrogen receptor-positive ER+ breast cancers in postmenopausal women. Investigating their ability to coordinate metals could lead to the emergence of a new category of anticancer drug candidates with a broader spectrum of pharmacological activities. In this study, a series of ruthenium (II) arene complexes bearing the aromatase inhibitor anastrozole was synthesized and characterized. Among these complexes, [Ru(η 6 -C6H6)(PPh3)(η 1 -ATZ)Cl]BPh4 (3) was found to be the most stable in cell culture media, to lead to the highest cellular uptake and in vitro cytotoxicity in two ER+ human breast cancer cell lines (MCF7 and T47D), and to induce a decrease in aromatase activity in H295R cells. Exposure of zebrafish embryos to complex 3 (12.5 µM) did not lead to noticeable signs of toxicity over 96 h, making it a suitable candidate for further in vivo investigations.

Serotonin and serotonin reuptake inhibitors alter placental aromatase.

Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.

Evaluating the effects on steroidogenesis of estragole and trans-anethole in a feto-placental co-culture model.

In this study, we determined whether estragole and its isomer trans-anethole interfered with feto-placental steroidogenesis in a human co-culture model composed of fetal-like adrenocortical (H295R) and placental trophoblast-like (BeWo) cells. Estragole and trans-anethole are considered the biologically active compounds within basil and fennel seed essential oils, respectively. After a 24 h exposure of the co-culture to 2.5, 5.2 and 25 µM estragole or trans-anethole, hormone concentrations of estradiol, estrone, dehydroepiandrosterone, androstenedione, progesterone and estriol were significantly increased. Using RT-qPCR, estragole and trans-anethole were shown to significantly alter the expression of several key steroidogenic enzymes, such as those involved in cholesterol transport and steroid hormone biosynthesis, including StAR, CYP11A1, HSD3B1/2, SULT2A1, and HSD17B1, -4, and -5. Furthermore, we provided mechanistic insight into the ability of estragole and trans-anethole to stimulate promoter-specific expression of CYP19 through activation of the PKA pathway in H295R cells and the PKC pathway in BeWo cells, in both cases associated with increased cAMP levels. Moreover, we show new evidence suggesting a role for progesterone in regulating steroid hormone biosynthesis through regulation of the StAR gene.

Serotonin-estrogen interactions: What can we learn from pregnancy?

We have reviewed the scientific literature related to four diseases in which to serotonin (5-HT) is involved in the etiology, herein named 5-HT-linked diseases, and whose prevalence is influenced by estrogenic status: depression, migraine, irritable bowel syndrome and eating disorders. These diseases all have in common a sex-dimorphic prevalence, with women more frequently affected than men. The co-occurrence between these 5-HT-linked diseases suggests that they have common physiopathological mechanisms. In most 5-HT-linked diseases (except for anorexia nervosa and irritable bowel syndrome), a decrease in the serotonergic tone is observed and estrogens are thought to contribute to the improvement of symptoms by stimulating the serotonergic system. Human pregnancy is characterized by a unique 5-HT and estrogen synthesis by the placenta. Pregnancy-specific disorders, such as hyperemesis gravidarum, gestational diabetes mellitus and pre-eclampsia, are associated with a hyperserotonergic state and decreased estrogen levels. Fetal programming of 5-HT-linked diseases is a complex phenomenon that involves notably fetal-sex differences, which suggest the implication of sex steroids. From a mechanistic point of view, we hypothesize that estrogens regulate the serotonergic system, resulting in a protective effect against 5-HT-linked diseases, but that, in turn, 5-HT affects estrogen synthesis in an attempt to retrieve homeostasis. These two processes (5-HT and estrogen biosynthesis) are crucial for successful pregnancy outcomes, and thus, a disruption of this 5-HT-estrogen relationship may explain pregnancy-specific pathologies or pregnancy complications associated with 5-HT-linked diseases.

Effects of selective serotonin-reuptake inhibitors (SSRIs) in JEG-3 and HIPEC cell models of the extravillous trophoblast.

INTRODUCTION: Between 2 and 10% of pregnant women are treated with selective serotonin-reuptake inhibitors (SSRIs) for depression. The extravillous trophoblasts (evTBs), which migrate and invade maternal tissues, are crucial for embryo implantation and remodeling of maternal spiral arteries. Poor migration/invasion of evTBs can cause serious pregnancy complications, yet the effects of SSRIs on these processes has never been studied. To determine the effects of five SSRIs (fluoxetine, norfluoxetine, citalopram, sertraline and venlafaxine) on migration/invasion, we used JEG-3 and HIPEC cells as evTB models. METHODS: Cells were treated with increasing concentrations (0.03-10 µM) of SSRIs. Cell proliferation was monitored using an impedance-based system and cell cycle by flow cytometry. Migration was determined using a scratch test, and metalloproteinase (MMP) activities, by zymography. Invasion markers were determined by RT-qPCR. RESULTS: Fluoxetine and sertraline (10 µM) significantly decreased cell proliferation by 94% and by 100%, respectively, in JEG-3 cells, and by 58.6% and 100%, respectively, in HIPEC cells. Norfluoxetine increased MMP-9 activity in JEG-3 cells by 2.0% at 0.03 µM and by 43.9% at 3 µM, but decreased MMP-9 activity in HIPEC cells by 63.7% at 3 µM. Sertraline at 0.03 µM increased mRNA level of TIMP-1 in JEG-3 cells by 36% and that of ADAM-10 by 85% and 115% at 0.3 and 3 µM, respectively. In HIPEC cells, venlafaxine at 0.03 and 0.3 µM, increased ADAM-10 mRNA levels by 156% and 167%, respectively. DISCUSSION: This study shows that SSRIs may affect evTBs homeostasis at therapeutic levels and provides guidance for future research.

Autophagy inhibition improves the chemotherapeutic efficacy of cruciferous vegetable-derived diindolymethane in a murine prostate cancer xenograft model.

Prostate cancer is the second leading cause of cancer-related deaths in men in North America and there is an urgent need for development of more effective therapeutic treatments against this disease. We have recently shown that diindolylmethane (DIM) and several of its halogenated derivatives (ring-DIMs) induce death and protective autophagy in human prostate cancer cells. However, the in vivo efficacy of ring-DIMs and the use of autophagy inhibitors as adjuvant therapy have not yet been studied in vivo. The objective of this study was to determine these effects on tumor growth in nude CD-1 mice bearing bioluminescent androgen-independent PC-3 human prostate cancer cells. We found that chloroquine (CQ) significantly sensitized PC-3 cells to death in the presence of sub-toxic concentrations of DIM or 4,4'-Br2DIM in vitro. Moreover, a combination of DIM (10 mg/kg) and CQ (60 mg/kg), 3× per week, significantly decreased PC-3 tumor growth in vivo after 3 and 4 weeks of treatment. Furthermore, 4,4'-Br2DIM at 10 mg/kg (3× per week) significantly inhibited tumour growth after 4 weeks of treatment. Tissues microarray analysis showed that DIM alone or combined with CQ induced apoptosis marker TUNEL; the combination also significantly inhibited the cell proliferation marker Ki67. In conclusion, we have confirmed that DIM and 4,4'-Br2DIM are effective agents against prostate cancer in vivo and shown that inhibition of autophagy with CQ enhances the anticancer efficacy of DIM. Our results suggest that including selective autophagy inhibitors as adjuvants may improve the efficacy of existing and novel drug therapies against prostate cancer.

Effects of selective serotonin-reuptake inhibitors (SSRIs) on human villous trophoblasts syncytialization.

Selective serotonin-reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants during pregnancy. The human placenta is a highly specialized organ supporting normal growth and development of the fetus. Therefore, this study aims to analyze the effects of SSRIs on villous cytotrophoblasts cells, using BeWo cells and human placental trophoblast cells in primary culture. The SSRIs fluoxetine and its metabolite norfluoxetine, sertraline and venlafaxine did not affect BeWo cell proliferation and viability, nor the percentage of M30-positive (apoptotic) primary trophoblast cells. None of the SSRIs affected basal or forskolin-stimulated BeWo cell fusion, whereas sertraline and venlafaxine increased the fusion of primary villous trophoblasts. Sertraline and venlafaxine also modified human chorionic gonadotropin beta (ß-hCG) secretion by BeWo cells, whereas none of the SSRIs affected ß-hCG secretion in primary trophoblasts. Norfluoxetine increased CGB (chorionic gonadotropin beta) and GJA1 (gap junction protein alpha 1) levels of gene expression (biomarkers of syncytialization) in BeWo cells, whereas in primary trophoblasts none of the SSRIs tested affected the expression of these genes. This study shows that SSRIs affect villous trophoblast syncytialization in a structure- and concentration-dependent manner and suggests that certain SSRIs may compromise placental health. In addition, it highlights the importance of using primary trophoblast cells instead of "trophoblast -like" cell lines to assess the effects of medications on human villous trophoblast function.