An additional proofreader contributes to DNA replication fidelity in mycobacteria.

The removal of mis-incorporated nucleotides by proofreading activity ensures DNA replication fidelity. Whereas the ε-exonuclease DnaQ is a well-established proofreader in the model organism Escherichia coli, it has been shown that proofreading in a majority of bacteria relies on the polymerase and histidinol phosphatase (PHP) domain of replicative polymerase, despite the presence of a DnaQ homolog that is structurally and functionally distinct from E. coli DnaQ. However, the biological functions of this type of noncanonical DnaQ remain unclear. Here, we provide independent evidence that noncanonical DnaQ functions as an additional proofreader for mycobacteria. Using the mutation accumulation assay in combination with whole-genome sequencing, we showed that depletion of DnaQ in Mycolicibacterium smegmatis leads to an increased mutation rate, resulting in AT-biased mutagenesis and increased insertions/deletions in the homopolymer tract. Our results showed that mycobacterial DnaQ binds to the ß clamp and functions synergistically with the PHP domain proofreader to correct replication errors. Furthermore, the loss of dnaQ results in replication fork dysfunction, leading to attenuated growth and increased mutagenesis on subinhibitory fluoroquinolones potentially due to increased vulnerability to fork collapse. By analyzing the sequence polymorphism of dnaQ in clinical isolates of Mycobacterium tuberculosis (Mtb), we demonstrated that a naturally evolved DnaQ variant prevalent in Mtb lineage 4.3 may enable hypermutability and is associated with drug resistance. These results establish a coproofreading model and suggest a division of labor between DnaQ and PHP domain proofreader. This study also provides real-world evidence that a mutator-driven evolutionary pathway may exist during the adaptation of Mtb.

Engineering of Substrate-Binding Domain to Improve Catalytic Activity of Chondroitin B Lyase with Semi-Rational Design.

Dermatan sulfate and chondroitin sulfate are dietary supplements that can be utilized as prophylactics against thrombus formation. Low-molecular-weight dermatan sulfate (LMWDS) is particularly advantageous due to its high absorbability. The enzymatic synthesis of low-molecular-weight dermatan sulfates (LMWDSs) using chondroitin B lyase is a sustainable and environmentally friendly approach to manufacturing. However, the industrial application of chondroitin B lyases is severely hampered by their low catalytic activity. To improve the activity, a semi-rational design strategy of engineering the substrate-binding domain of chondroitin B lyase was performed based on the structure. The binding domain was subjected to screening of critical residues for modification using multiple sequence alignments and molecular docking. A total of thirteen single-point mutants were constructed and analyzed to assess their catalytic characteristics. Out of these, S90T, N103C, H134Y, and R159K exhibited noteworthy enhancements in activity. This study also examined combinatorial mutagenesis and found that the mutant H134Y/R159K exhibited a substantially enhanced catalytic activity of 1266.74 U/mg, which was 3.21-fold that of the wild-type one. Molecular docking revealed that the enhanced activity of the mutant could be attributed to the formation of new hydrogen bonds and hydrophobic interactions with the substrate as well as neighbor residues. The highly active mutant would benefit the utilization of chondroitin B lyase in pharmaceuticals and functional foods.

Meta-analysis of the clinical efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease.

This study aimed to systematically evaluate the efficacy of liraglutide in treating type 2 diabetes mellitus (T2DM) complicated with non-alcoholic fatty liver disease (NAFLD) by comparing liraglutide with placebo or other drugs (mainly insulin). The PubMed, Web of Science, and National Library of Medicine databases were systematically searched from their inception until December 1, 2023. A meta-analysis was performed using Stata 15.1 software. A total of 12 studies with 13 outcome measures were included. The meta-analysis results revealed that liraglutide significantly reduced body mass index (mean difference [MD] = -1.06, 95%CI: -1.41, -0.70, p < 0.001), triglycerides (MD = -0.35, 95%CI: -0.61, -0.09, p = 0.0009), visceral adipose tissue (MD = -21.06, 95%CI: -34.58, -7.55, p = 0.002), and subcutaneous adipose tissue (MD = -20.53, 95%CI: -29.15, -11.90, p < 0.001) levels in patients with T2DM and NAFLD. Of the 11 studies, 2 reported the occurrence of adverse reactions, which were primarily gastrointestinal. Compared with placebo and other drugs (e.g., insulin), liraglutide may improve glucose metabolism, lipid and liver function parameters, and visceral and subcutaneous fat in patients with T2DM and NAFLD, thus constituting an effective treatment for these patients.

The Photodynamic Agent Designed by Involvement of Hydrogen Atom Transfer for Enhancing Photodynamic Therapy.

Although Type-I photodynamic therapy has attracted increasingly growing interest due to its reduced dependence on oxygen, the design of effective Type-I photosensitizers remains a challenge. In this work, we report a design strategy for Type-I photosensitizers by the involvement of hydrogen atom transfer (HAT). As a proof of concept, a HAT-involved Type-I PS, which simultaneously generates superoxide and carbon-centered radicals under light-irradiation, was synthesized. This photosensitizer is comprised of a fluorene-substituted BODIPY unit as an electron acceptor covalently linked with a triphenylamine moiety as an electron donor. Under light-irradiation, photo-induced intramolecular electron transfer occurs to generate the BODIPY anion radical and triphenylamine cation radical. The former transfers electrons to oxygen to generate O2-•, while the latter loses a proton to produce a benzyl carbon-centered radical which is well characterized. The resulting carbon-centered radicals efficiently oxidize NADH by HAT reaction. This photosensitizer demonstrates remarkable photocytotoxicity even under hypoxic conditions, along with outstanding in vivo antitumor efficacy in mouse models bearing HeLa tumors. This work offers a novel strategy for the design of Type-I photosensitizers by involvement of HAT.

Citrus FRIGIDA cooperates with its interaction partner dehydrin to regulate drought tolerance.

Drought is a major environmental stress that severely affects plant growth and crop productivity. FRIGIDA (FRI) is a key regulator of flowering time and drought tolerance in model plants. However, little is known regarding its functions in woody plants, including citrus. Thus, we explored the functional role of the citrus FRI ortholog (CiFRI) under drought. Drought treatment induced CiFRI expression. CiFRI overexpression enhanced drought tolerance in transgenic Arabidopsis and citrus, while CiFRI suppression increased drought susceptibility in citrus. Moreover, transcriptomic profiling under drought conditions suggested that CiFRI overexpression altered the expression of numerous genes involved in the stress response, hormone biosynthesis, and signal transduction. Mechanistic studies revealed that citrus dehydrin likely protects CiFRI from stress-induced degradation, thereby enhancing plant drought tolerance. In addition, a citrus brassinazole-resistant (BZR) transcription factor family member (CiBZR1) directly binds to the CiFRI promoter to activate its expression under drought conditions. CiBZR1 also enhanced drought tolerance in transgenic Arabidopsis and citrus. These findings further our understanding of the molecular mechanisms underlying the CiFRI-mediated drought stress response in citrus.

Enantioselective N-Heterocyclic Carbene Catalyzed α-Oxidative Coupling of Enals with Carboxylic Acids Using an Iodine(III) Reagent.

The enantioselective α-oxidative coupling of enals with carboxylic acids was developed via the umpolung of an NHC-bound enolate with an iodine(III) reagent. The corresponding α-acyloxyl-ß,γ-unsaturated esters were afforded in good yields, with high regio- and enantioselectivities. The key step of the reaction involves the formation of enol iodine(III) intermediate from the enolate with iodosobenzene, which changes the polarity of α-carbon of the enal from nucleophilic to electrophilic, and thus facilitates the subsequent addition of carboxylate.

ε-Benzylation via Cooperative Photoredox and N-Heterocyclic Carbene Catalysis.

The ε-benzylation of γ-alkenyl-γ-oxidized enals via dual photoredox and N-heterocyclic carbene catalysis has been developed, affording the corresponding ε-benzyl-α,ß-γ,δ-bisunsaturated esters in moderate to good yields with exclusive regioselectivities. The reaction is proposed via the generation of benzyl radical under photocatalysis, followed by its addition to an NHC-bound trienolate intermediate.

Synthesis and biological evaluation of BU-4664L derivatives as potential anticancer agents.

BU-4664L is a naturally occurring N-farnesylated dibenzodiazepinone with important biological activities. Herein, we report the synthesis and antitumor evaluation of two series of BU-4664L derivatives bearing different substituent patterns on the dibenzodiazepinone core and with diverse side chains. All of the derivatives displayed micromolar activity against the human prostate cancer PC-3 cells, while lower or no activity against the human lung H460 cells. The most active derivatives were 10a and 16c which exerted antiproliferative activity against PC-3 cells with GI50 values of 5.66 and 5.94 µM, respectively, and thus represent promising lead compounds for further development.

Ascorbic acid and hydrocortisone synergistically inhibit septic organ injury via improving oxidative stress and inhibiting inflammation.

BACKGROUND: The current study aimed to investigate the effect of the combination of ascorbic acid (AscA) and hydrocortisone (Hyd) on septic organ injury and its potential mechanism. METHOD: Sepsis was induced in mice by a single intraperitoneal injection of lipopolysaccharides. RESULTS: AscA and Hyd combined showed more effective protection of the injured liver and kidney in septic mice by decreasing alanine aminotransferase, aspartate aminotransferase, serum urea nitrogen, and serum creatinine and ameliorating pathological manifestations than Hyd or AscA alone. AscA showed a mild inhibitory effect on the secretion of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6)). However, Hyd showed a weak regulatory effect on septic oxidative stress markers (malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)). However, the combination of AscA and Hyd showed a more powerful inhibitory effect on the septic inflammatory response and oxidative stress than Hyd or AscA alone by decreasing TNF-α, IL-1ß, and IL-6 and regulating MDA, SOD, and GSH. In an in vitro study, cotreatment of RAW 264.7 macrophages with Hyd and AscA sharply reduced reactive oxygen species (ROS) generation and synergistically inhibited TNF-α, IL-1ß, and IL-6 secretion, which could be abolished by additional stimulation with the ROS donor 3-nitropropionic acid (3-NP). As expected, cotreatment of macrophages with Hyd and AscA synergistically inhibited the activation of p38 MAPK and p-p65, and the effect could be reversed by additional stimulation with 3-NP. CONCLUSIONS: AscA and Hyd synergistically protect the kidney and liver from injury by inhibiting the inflammatory response and oxidative stress. The powerful inhibitory effects of AscA on oxidative stress contribute to the synergistic anti-inflammatory action.

Cloning, expression, and characterization of an arabitol dehydrogenase and coupled with NADH oxidase for effective production of L-xylulose.

A novel arabitol dehydrogenase (ArDH) gene was cloned from a bacterium named Aspergillus nidulans and expressed heterologously in Escherichia coli. The purified ArDH exhibited the maximal activity in pH 9.5 Tris-HCl buffer at 40 °C, showed Km and Vmax of 1.2 mg/mL and 9.1 U/mg, respectively. The ArDH was used to produce the L-xylulose and coupled with the NADH oxidase (Nox) for the regeneration of NAD+. In further optimization, a high conversion of 84.6% in 8 hours was achieved under the optimal conditions: 20 mM of xylitol, 100 µM NAD+ in pH 9.0 Tris-HCl buffer at 30 °C. The results indicated the coupling system with cofactor regeneration provides a promising approach for L-xylulose production from xylitol.

Outcomes of icotinib combined with concurrent chemoradiotherapy in locally advanced cervical cancer.

Concurrent chemoradiotherapy (CRT) based on cisplatin is recognized as the current standard treatment for locally advanced cervical cancer. The treatment of cervical cancer has reached a plateau in the last 20 years. Previous studies have proven that the epidermal growth factor receptor is correlated with chemo- and radioresistance and treatment failure. Hence, the purpose of this study was to investigate the efficacy and safety of icotinib combined with CRT in the treatment of locally advanced cervical cancer. Eligibility criteria included patients treated in the radiotherapy department of Taizhou Central Hospital of Zhejiang Province for stage IIB to IIIB cervical cancers who had not received anti-tumor treatment before and a performance status of 0 to 2. Patients were given icotinib 125 mg three times a day for 6 weeks, which was one week before the start of radiotherapy (500 centigrays in 28 fractions) and chemotherapy (40 mg/m2 administered weekly for 3-5 cycles). There were 29 patients who completed the I+CRT treatment, and it was tolerated well. The median follow-up time was 50 months and 27 patients (93.10%) achieved complete responses. The 5-year cumulative overall survival rate and disease-free survival rate were 58.4% and 60.9%, respectively. The treatment with I+CRT is safe and effective for locally advanced cervical cancer. As far as we know, this is the first study to report the 5-year survival rate of locally advanced cervical cancer with targeted therapy combined with chemoradiotherapy.

Oxidation of dCTP contributes to antibiotic lethality in stationary-phase mycobacteria.

Growing evidence shows that generation of reactive oxygen species (ROS) derived from antibiotic-induced metabolic perturbation contribute to antibiotic lethality. However, our knowledge of the mechanisms by which antibiotic-induced oxidative stress actually kills cells remains elusive. Here, we show that oxidation of dCTP underlies ROS-mediated antibiotic lethality via induction of DNA double-strand breaks (DSBs). Deletion of mazG-encoded 5-OH-dCTP-specific pyrophosphohydrolase potentiates antibiotic killing of stationary-phase mycobacteria, but did not affect antibiotic efficacy in exponentially growing cultures. Critically, the effect of mazG deletion on potentiating antibiotic killing is associated with antibiotic-induced ROS and accumulation of 5-OH-dCTP. Independent lines of evidence presented here indicate that the increased level of DSBs observed in the ΔmazG mutant is a dead-end event accounting for enhanced antibiotic killing. Moreover, we provided genetic evidence that 5-OH-dCTP is incorporated into genomic DNA via error-prone DNA polymerase DnaE2 and repair of 5-OH-dC lesions via the endonuclease Nth leads to the generation of lethal DSBs. This work provides a mechanistic view of ROS-mediated antibiotic lethality in stationary phase and may have broad implications not only with respect to antibiotic lethality but also to the mechanism of stress-induced mutagenesis in bacteria.

High-Density Genetic Map Construction and Identification of QTLs Controlling Leaf Abscission Trait in Poncirus trifoliata.

A high-density genetic linkage map is essential for genetic and genomic studies including QTL mapping, genome assembly, and comparative genomic analysis. Here, we constructed a citrus high-density linkage map using SSR and SNP markers, which are evenly distributed across the citrus genome. The integrated linkage map contains 4163 markers with an average distance of 1.12 cM. The female and male linkage maps contain 1478 and 2976 markers with genetic lengths of 1093.90 cM and 1227.03 cM, respectively. Meanwhile, a genetic map comparison demonstrates that the linear order of common markers is highly conserved between the clementine mandarin and Poncirus trifoliata. Based on this high-density integrated citrus genetic map and two years of deciduous phenotypic data, two loci conferring leaf abscission phenotypic variation were detected on scaffold 1 (including 36 genes) and scaffold 8 (including 107 genes) using association analysis. Moreover, the expression patterns of 30 candidate genes were investigated under cold stress conditions because cold temperature is closely linked with the deciduous trait. The developed high-density genetic map will facilitate QTL mapping and genomic studies, and the localization of the leaf abscission deciduous trait will be valuable for understanding the mechanism of this deciduous trait and citrus breeding.

[Overview of quality standards of Eucommiae Cortex in China and overseas].

Eucommiae Cortex is an authentic medicinal material with broad growing areas( such as Hunan and Sichuan provinces in China. It is well-known for its efficacy in tonifying liver and kidney,strengthening muscles and bones,and stabilizing fetus. It has also been proven in pharmacology to possess the functions such as lowering blood pressure and lipids. Hence,Eucommiae Cortex has attracted increasing attention. The current quality standards of Eucommiae Cortex vary in different countries or regions. The quality of Eucommiae Cortex products on the market is affected by mix-ups of non-medicinal parts and insufficient growth years. In view of these problems,this paper summarizes the current quality standards and research progress of Eucommiae Cortex in China and overseas,aiming to provide a reference for the establishment of the quality standards of Eucommiae Cortex.

Systematic analysis of the basic/helix-loop-helix (bHLH) transcription factor family in pummelo (Citrus grandis) and identification of the key members involved in the response to iron deficiency.

BACKGROUND: Iron (Fe) deficiency is a common problem in citrus production. As the second largest superfamily of transcription factors (TFs), the basic/helix-loop-helix (bHLH) proteins have been shown to participate in the regulation of Fe homeostasis and a series of other biological and developmental processes in plants. However, this family of members in citrus and their functions in citrus Fe deficiency are still largely unknown. RESULTS: In this study, we identified a total of 128 CgbHLHs from pummelo (Citrus grandis) genome that were classified into 18 subfamilies by phylogenetic comparison with Arabidopsis thaliana bHLH proteins. All of these CgbHLHs were randomly distributed on nine known (125 genes) and one unknown (3 genes) chromosomes, and 12 and 47 of them were identified to be tandem and segmental duplicated genes, respectively. Sequence analysis showed detailed characteristics of their intron-exon structures, bHLH domain and conserved motifs. Gene ontology (GO) analysis suggested that most of CgbHLHs were annotated to the nucleus, DNA-binding transcription factor activity, response to abiotic stimulus, reproduction, post-embryonic development, flower development and photosynthesis. In addition, 27 CgbHLH proteins were predicted to have direct or indirect protein-protein interactions. Based on GO annotation, RNA sequencing data in public database and qRT-PCR results, several of CgbHLHs were identified as the key candidates that respond to iron deficiency. CONCLUSIONS: In total, 128 CgbHLH proteins were identified from pummelo, and their detailed sequence and structure characteristics and putative functions were analyzed. This study provides comprehensive information for further functional elucidation of CgbHLH genes in citrus.

Comprehensive Analysis of Autophagy-Related Genes in Sweet Orange (Citrus sinensis) Highlights Their Roles in Response to Abiotic Stresses.

Autophagy is a highly conserved intracellular degradation pathway that breaks down damaged macromolecules and/or organelles. It is involved in plant development and senescence, as well as in biotic and abiotic stresses. However, the autophagy process and related genes are largely unknown in citrus. In this study, we identified 35 autophagy-related genes (CsATGs-autophagy-related genes (ATGs) of Citrus sinensis, Cs) in a genome-wide manner from sweet orange (Citrus sinensis). Bioinformatic analysis showed that these CsATGs were highly similar to Arabidopsis ATGs in both sequence and phylogeny. All the CsATGs were randomly distributed on nine known (28 genes) and one unknown (7 genes) chromosomes. Ten CsATGs were predicted to be segmental duplications. Expression patterns suggested that most of the CsATG were significantly up- or down-regulated in response to drought; cold; heat; salt; mannitol; and excess manganese, copper, and cadmium stresses. In addition, two ATG18 members, CsATG18a and CsATG18b, were cloned from sweet orange and ectopically expressed in Arabidopsis. The CsATG18a and CsATG18b transgenic plants showed enhanced tolerance to osmotic stress, salt, as well as drought (CsATG18a) or cold (CsATG18b), compared to wild-type plants. These results highlight the essential roles of CsATG genes in abiotic stresses.

Screening and characterization of a novel high-efficiency tumor-homing cell-penetrating peptide from the buffalo cathelicidin family.

Targeted delivery of antitumor drugs is especially important for tumor therapy. Cell-penetrating peptides (CPPs) have been shown to be very effective drug carriers for tumor therapy. However, most CPPs lack tumor cell specificity. Here, we identified a highly efficient CPP, CAT, from the newly identified buffalo-derived cathelicidin family, which exhibits a preferential binding capacity for multiple tumor cell lines and delivers carried drug molecules into cells. CAT showed an approximately threefold to sixfold higher translocation efficiency than some reported cell-penetrating antimicrobial peptides, including the well-known classical CPP TAT. Moreover, the delivery efficiency of CAT was greater in a variety of tested tumor cells than in normal cells, especially for the human hepatoma cell line SMMC-7721, for which delivery was 7 times more efficient than the normal human embryonic lung cell line MRC-5, according to fluorescent labeling experiment results. CAT was conjugated to the Momordica charantia-derived type-I ribosome-inactivating protein MAP 30, and the cytotoxicity of the MAP 30-CAT fusion protein in the tumor cell line SMMC-7721 was significantly enhanced compared with that of the unconjugated MAP 30. The IC50 value of MAP 30-CAT was approximately 83 times lower than the IC50 value of the original MAP 30. Interestingly, the IC50 value of MAP 30 alone for MRC-5 was approximately twofold higher than the value for SMMC-7721, showing a small difference. However, when MAP 30 was conjugated to CAT, the difference in IC50 values between the two cell lines was significantly increased by 38-fold. The results of the flow cytometric detection of apoptosis revealed that the increase in cytotoxicity after CAT conjugation was mainly caused by the increased induction of apoptosis by the fusion protein. These results suggest that CAT, as a novel tumor-homing CPP, has great potential in drug delivery applications in vivo and will be beneficial to the development of tumor therapeutics.

A randomized controlled trial of well-being therapy to promote adaptation and alleviate emotional distress among medical freshmen.

BACKGROUND: Maladjustment and emotional distress are extremely prevalent among first-year medical students in college and are associated with numerous negative consequences for medical freshmen, their families and universities. The current research aimed to detect the efficacy of a well-being therapy in promoting adaptation to college life and alleviating emotional distress among medical freshmen. METHODS: One hundred one participants who met the inclusion criteria were enrolled in a single-blind randomized controlled trial. Well-being therapy was given to the intervention group weekly for 5 weeks (WBT, n = 50). At the same time, students in the placebo control condition (CC, n = 51) were required to record early memory for 5 weeks and at weekly meetings it would be shared voluntarily. Psychological well-being, adaptation, anxiety and depression were recorded at pretest, posttest, and at three-month follow-up. Data from 87 first-year students with complete follow-ups (WBT, n = 39; CC, n = 48) were analyzed over three time periods. RESULTS: Compared with the control group, students undergoing the 5-week well-being therapy reported larger improvements in psychological well-being and adaptation, and greater alleviation in symptoms of anxiety and depression from pretest to posttest to follow-up. CONCLUSIONS: Well-being intervention may provide first-year medical students with skills to efficiently manage maladjustment and emotional distress. It seems that medical freshmen would benefit a lot when such an intervention programme could be incorporated into the general medical education. TRIAL REGISTRATION NUMBER: ChiCTR-ROC-17012636. Registered 11 September 2017 (Retrospectively registered) at Chinese Clinical Trial Registry.

Thyroid autoantibodies in pregnancy are associated with hypertensive disorders of pregnancy: Ma'anshan Birth Cohort Study.

OBJECTIVE: Hypertensive disorders of pregnancy (HDP) have been associated with adverse health outcomes for both mothers and children. Previous studies examining associations of maternal thyroid autoantibodies with HDP indicate conflicting results. The objective of this study was to examine associations of maternal thyroid autoantibody positivity in the first and the second trimesters with the risk of HDP. DESIGN, PARTICIPANTS AND MEASUREMENTS: In the Ma'anshan Birth Cohort study, a population-based prospective study in China, a total of 3474 pregnant women were enrolled between May 2013 and September 2014. Thyroid autoantibodies, including antithyroperoxidase autoantibody (TPOAb) and antithyroglobulin autoantibody (TgAb), as well as thyroid function tests, were measured in both the first and the second trimesters in 2893 pregnant women. Multivariate logistic regression analyses were conducted to calculate the odds ratio (OR) and 95% confidence interval (CI) for the associations between thyroid autoantibodies and HDP. RESULTS: Multivariate logistic regression analyses showed that TPOAb positivity in the first trimester was associated with a 1.80 (95% CI = 1.17-2.78) increased odds of HDP after adjustment for confounders, which was mainly due to an increased risk of gestational hypertension (OR = 1.93, 95% CI = 1.17-3.18). In addition, TgAb positivity in the first trimester was associated with a higher risk of HDP (OR = 1.78, 95% CI = 1.16-2.73) after adjustment for confounders, which was mainly due to an increased risk of gestational hypertension (OR = 1.89, 95% CI = 1.15-3.11). These associations were also seen among euthyroid women. Women with positive TPOAb in the second trimester seemed to have a higher risk of gestational hypertension (OR = 1.87, 95% CI = 1.02-3.43) after adjustment for confounders. However, among euthyroid women, TPOAb positivity in the second trimester was not associated with HDP. The TgAb status in the second trimester was not associated with HDP. CONCLUSIONS: Our results show that TPOAb positivity and TgAb positivity in the first trimester are associated with an increased risk of HDP. These data demonstrate that these associations are even seen among euthyroid women.

Prenatal phthalate exposure and placental size and shape at birth: A birth cohort study.

OBJECTIVE: There is concern over the potential placental effects of prenatal phthalate exposure, and the potential adverse effects of prenatal phthalate exposure require further study; however, few data are available in humans. We investigated the associations between phthalate exposure in each trimester and both placental size and shape at birth. METHODS: We measured the urinary concentrations of phthalate metabolites among 2725 pregnant women in the Ma'anshan Birth Cohort. Before collecting urine samples from each of the three trimesters, the pregnant women were interviewed via questionnaires. Placental information was obtained from hospital records. We estimated the sex-specific associations between urinary phthalate concentrations in each trimester and both placental size and shape at birth using adjusted multiple regression. A linear mixed model was used for the repeated measures analysis with subject-specific random intercepts and slopes for gestational age at sample collection to test the effect of phthalate levels on placental size and shape and to estimate the effect sizes. RESULTS: Overall, placental breadth increased by 0.148cm (95% CI: 0.078, 0.218) with each 1 ln-concentration increase in MBP in the first trimester. The difference between placental length and breadth (length-breadth) decreased by 0.086cm (95% CI: -0.159, -0.012) and 0.149cm (95% CI: -0.221, -0.076) with each 1 ln-concentration increase in MMP and MBP, respectively, in the first trimester. In the second trimester, placental thickness increased by 0.017cm (95% CI: 0.006, 0.027), 0.020cm (95% CI: 0.004, 0.036), 0.028cm (95% CI: 0.007, 0.048), and 0.035cm (95% CI: 0.018, 0.053) with each 1 ln-concentration increase in MMP, MBP, MEOHP, and MEHHP, respectively. In the third trimester, placental thickness increased by 0.037cm (95% CI: 0.019, 0.056) and 0.019cm (95% CI: 0, 0.037) with each 1 ln-concentration increase in MBP and MEHP, respectively. Multiple linear regression for each offspring sex indicated that prenatal phthalate exposure increased placental thickness in both the first and second trimesters in males, whereas the corresponding relationship was close to null in females. Linear mixed models (LMMs) yielded similar results. CONCLUSION: Our results suggest the presence of associations between prenatal phthalate exposure and placental size and shape. Exposure to certain phthalates may cause the placenta to become thicker and more circular. Associations appeared stronger for the subsample representing male offspring than those for the subsample representing female offspring. Given the few studies on this topic, additional research is warranted.