Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer.

Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.

A Mechanism for microRNA Arm Switching Regulated by Uridylation.

Strand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may change depending on cellular contexts, the molecular mechanism and physiological significance of such alternative strand selection (or "arm switching") remain elusive. Here we find miR-324 to be one of the strongly regulated miRNAs by arm switching and identify the terminal uridylyl transferases TUT4 and TUT7 to be the key regulators. Uridylation of pre-miR-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus from which the 3' strand (3p) is selected instead of the 5' strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated, whereas the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential.

An open repository of real-time COVID-19 indicators.

The COVID-19 pandemic presented enormous data challenges in the United States. Policy makers, epidemiological modelers, and health researchers all require up-to-date data on the pandemic and relevant public behavior, ideally at fine spatial and temporal resolution. The COVIDcast API is our attempt to fill this need: Operational since April 2020, it provides open access to both traditional public health surveillance signals (cases, deaths, and hospitalizations) and many auxiliary indicators of COVID-19 activity, such as signals extracted from deidentified medical claims data, massive online surveys, cell phone mobility data, and internet search trends. These are available at a fine geographic resolution (mostly at the county level) and are updated daily. The COVIDcast API also tracks all revisions to historical data, allowing modelers to account for the frequent revisions and backfill that are common for many public health data sources. All of the data are available in a common format through the API and accompanying R and Python software packages. This paper describes the data sources and signals, and provides examples demonstrating that the auxiliary signals in the COVIDcast API present information relevant to tracking COVID activity, augmenting traditional public health reporting and empowering research and decision-making.

Nucleic Acid-Based Approaches to Tackle KRAS Mutant Cancers.

Activating mutations in KRAS are highly relevant to various cancers, driving persistent efforts toward the development of drugs that can effectively inhibit KRAS activity. Previously, KRAS was considered 'undruggable'; however, the recent advances in our understanding of RNA and nucleic acid chemistry and delivery formulations have sparked a paradigm shift in the approach to KRAS inhibition. We are currently witnessing a large wave of next-generation drugs for KRAS mutant cancers-nucleic acid-based therapeutics. In this review, we discuss the current progress in targeting KRAS mutant tumors and outline significant developments in nucleic acid-based strategies. We delve into their mechanisms of action, address existing challenges, and offer insights into the current clinical trial status of these approaches. We aim to provide a thorough understanding of the potential of nucleic acid-based strategies in the field of KRAS mutant cancer therapeutics.

Interactive effect of the empirical lifestyle index for insulin resistance with the common genetic susceptibility locus rs2423279 for colorectal cancer.

The aim of this study is to examine the empirical insulinemic potential consisting of dietary and lifestyle factors and the interactive effect with the common genetic susceptibility locus rs2423279 on the risk of colorectal cancer (CRC). This case-control study was conducted with 923 CRC patients and 1846 controls. The empirical measures for assessing the insulinemic potential, namely, the empirical dietary index for hyperinsulinemia (EDIH), for insulin resistance (EDIR), the empirical lifestyle index for hyperinsulinemia (ELIH), and for insulin resistance (ELIR), were calculated based on semiquantitative food frequency questionnaire and lifestyle questionnaire. A genetic variant of rs2423279 was genotyped. The CRC patients were more likely to score in the highest quartile for the ELIH (OR 2·90, Q4 v. Q1, 95 % CI (2·01, 4·19), Pfor trend < 0·001), EDIR (OR 3·32, Q4 v. Q1, 95 % CI (2·32, 4·74), P < 0·001) and ELIR (OR 2·79, Q4 v. Q1, 95 % CI (1·96, 3·97), P < 0·001) than the controls. The significant effect between the ELIR, which assesses dietary and lifestyle patterns related to insulin resistance, and C allele carriers of rs2423279 was stronger than that for homozygous T allele carriers (OR 2·50, 95 % CI (1·78, 3·51), Pfor interaction = 0·034). The empirical insulinemic potential for insulin resistance might have interactive effects with the rs2423279 polymorphism on the risk of CRC. The results of this study suggest the basis of the metabolic impact of the insulin response on colorectal carcinogenesis.

Dietary methyl donor nutrients, DNA mismatch repair polymorphisms, and risk of colorectal cancer based on microsatellite instability status.

PURPOSE: Colorectal cancer (CRC) is a heterogeneous disease caused by complex interplay among the diet, the environment, and genetics involving numerous molecules and pathological pathways. This study aimed to determine whether methyl donor nutrients are associated with CRC and how these associations are altered by DNA mismatch repair (MMR) genes. METHODS: In total, 626 cases and 838 age- and sex-matched controls were recruited for this case-control study. A validated food frequency questionnaire was used to assess seven methyl donor nutrients (vitamin B2, niacin, B6, folate, B12, methionine, and choline). MMR polymorphisms were genotyped using an Illumina MEGA-Expanded Array. For the 626 patients, the microsatellite instability status and immunohistochemical expression of MMR proteins were analyzed. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among the methyl donor nutrients, B2, niacin, B6, folate, and methionine were inversely associated with CRC risk, while a high intake of choline increased CRC. Regarding MMR genes, three hMSH3 polymorphisms (rs32952 A > C, rs41097 A > G, and rs245404 C > G) reduced CRC risk. Regarding gene-diet interactions, a stronger interaction effect was observed in G allele carriers of hMSH3 rs41097 with high niacin intake than in AA carriers with low niacin intake (OR, 95% CI = 0.49, 0.33-0.72, P for interaction = 0.02) in subgroups of patients with distal colon cancer (P for interaction = 0.008) and MMR proficiency with microsatellite stability (P for interaction = 0.021). CONCLUSIONS: Methyl donor nutrients may affect CRC risk leading to a balance in the MMR machinery.

XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer.

The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS-mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS-mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo. The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5-Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS-mutant lung cancers, and can be overcome with the co-administration of a YAP1-TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation.

Bias-minimized quantification of microRNA reveals widespread alternative processing and 3' end modification.

MicroRNAs (miRNAs) modulate diverse biological and pathological processes via post-transcriptional gene silencing. High-throughput small RNA sequencing (sRNA-seq) has been widely adopted to investigate the functions and regulatory mechanisms of miRNAs. However, accurate quantification of miRNAs has been limited owing to the severe ligation bias in conventional sRNA-seq methods. Here, we quantify miRNAs and their variants (known as isomiRs) by an improved sRNA-seq protocol, termed AQ-seq (accurate quantification by sequencing), that utilizes adapters with terminal degenerate sequences and a high concentration of polyethylene glycol (PEG), which minimize the ligation bias during library preparation. Measurement using AQ-seq allows us to correct the previously misannotated 5' end usage and strand preference in public databases. Importantly, the analysis of 5' terminal heterogeneity reveals widespread alternative processing events which have been underestimated. We also identify highly uridylated miRNAs originating from the 3p strands, indicating regulations mediated by terminal uridylyl transferases at the pre-miRNA stage. Taken together, our study reveals the complexity of the miRNA isoform landscape, allowing us to refine miRNA annotation and to advance our understanding of miRNA regulation. Furthermore, AQ-seq can be adopted to improve other ligation-based sequencing methods including crosslinking-immunoprecipitation-sequencing (CLIP-seq) and ribosome profiling (Ribo-seq).

Formate rescues neural tube defects caused by mutations in Slc25a32.

Periconceptional folic acid (FA) supplementation significantly reduces the prevalence of neural tube defects (NTDs). Unfortunately, some NTDs are FA resistant, and as such, NTDs remain a global public health concern. Previous studies have identified SLC25A32 as a mitochondrial folate transporter (MFT), which is capable of transferring tetrahydrofolate (THF) from cellular cytoplasm to the mitochondria in vitro. Herein, we show that gene trap inactivation of Slc25a32 (Mft) in mice induces NTDs that are folate (5-methyltetrahydrofolate, 5-mTHF) resistant yet are preventable by formate supplementation. Slc25a32gt/gt embryos die in utero with 100% penetrant cranial NTDs. 5-mTHF supplementation failed to promote normal neural tube closure (NTC) in mutant embryos, while formate supplementation enabled the majority (78%) of knockout embryos to complete NTC. A parallel genetic study in human subjects with NTDs identified biallelic loss of function SLC25A32 variants in a cranial NTD case. These data demonstrate that the loss of functional Slc25a32 results in cranial NTDs in mice and has also been observed in a human NTD patient.

Arabidopsis cargo receptor NBR1 mediates selective autophagy of defective proteins.

Aggrephagy, a type of selective autophagy that sequesters protein aggregates for degradation in the vacuole, is an important protein quality control mechanism, particularly during cell stress. In mammalian cells, aggrephagy and several other forms of selective autophagy are mediated by dedicated cargo receptors such as NEIGHBOR OF BRCA1 (NBR1). Although plant NBR1 homologs have been linked to selective autophagy during biotic stress, it remains unclear how they impact selective autophagy under non-stressed and abiotic stress conditions. Through microscopic and biochemical analysis of nbr1 mutants expressing autophagy markers and an aggregation-prone reporter, we tested the connection between NBR1 and aggrephagy in Arabidopsis. Although NBR1 is not essential for general autophagy, or for the selective clearance of peroxisomes, mitochondria, or the ER, we found that NBR1 is required for the heat-induced formation of autophagic vesicles. Moreover, cytoplasmic puncta containing aggregation-prone proteins, which were rarely observed in wild-type plants, were found to accumulate in nbr1 mutants under both control and heat stress conditions. Given that NBR1 co-localizes with these cytoplasmic puncta, we propose that Arabidopsis NBR1 is a plant aggrephagy receptor essential for maintaining proteostasis under both heat stress and non-stress conditions.

Associations among dietary seaweed intake, c-MYC rs6983267 polymorphism, and risk of colorectal cancer in a Korean population: a case-control study.

PURPOSE: The effects of seaweed compounds have been studied in relation to colorectal cancer (CRC) based on their ability to modulate carcinogen metabolism in vivo and in vitro. However, no epidemiological studies on the interaction between edible seaweed and genetic variants relevant to CRC have been reported. This study examined the associations among dietary seaweed intake (gim, miyeok, and dashima), single-nucleotide polymorphisms (SNPs; rs6983267, rs7014346, and rs719725), and CRC risk in a Korean population. METHODS: The participants comprised 923 CRC patients and 1846 controls who visited the National Cancer Center Korea. We used a Semiquantitative Food Frequency Questionnaire and genotyped SNPs using genomic DNA samples. RESULTS: The intake of total seaweed, miyeok, and dashima showed a significant inverse association with CRC risk after adjusting for potential confounding factors (total seaweed odds ratio (OR) [95% CI] = 0.65 [0.50-0.85], P for trend < 0.001; miyeok = 0.82 [0.62-1.09], P for trend < 0.05; dashima = 0.58 [0.44-0.76], P for trend < 0.001, highest vs. lowest tertile). We confirmed that the homozygous T/T allele of rs6983267 c-MYC indicated an interaction between dietary seaweed intake and both overall CRC and rectal cancer (CRC OR [95% CI] = 0.52 [0.34-0.81], P for interaction = 0.015; rectal cancer = 0.45 [0.25-0.79], P for interaction = 0.007, T/T carriers with high total seaweed intake vs. T/T carriers with low total seaweed intake). CONCLUSIONS: This study provides evidence of the effect of dietary seaweed intake on CRC risk with respect to c-MYC gene variants.

Autophagy-related proteins are required for degradation of peroxisomes in Arabidopsis hypocotyls during seedling growth.

Plant peroxisomes play a pivotal role during postgerminative growth by breaking down fatty acids to provide fixed carbons for seedlings before the onset of photosynthesis. The enzyme composition of peroxisomes changes during the transition of the seedling from a heterotrophic to an autotrophic state; however, the mechanisms for the degradation of obsolete peroxisomal proteins remain elusive. One candidate mechanism is autophagy, a bulk degradation pathway targeting cytoplasmic constituents to the lytic vacuole. We present evidence supporting the autophagy of peroxisomes in Arabidopsis thaliana hypocotyls during seedling growth. Mutants defective in autophagy appeared to accumulate excess peroxisomes in hypocotyl cells. When degradation in the vacuole was pharmacologically compromised, both autophagic bodies and peroxisomal markers were detected in the wild-type vacuole but not in that of the autophagy-incompetent mutants. On the basis of the genetic and cell biological data we obtained, we propose that autophagy is important for the maintenance of peroxisome number and cell remodeling in Arabidopsis hypocotyls.

Computational detection and suppression of sequence-specific off-target phenotypes from whole genome RNAi screens.

A challenge for large-scale siRNA loss-of-function studies is the biological pleiotropy resulting from multiple modes of action of siRNA reagents. A major confounding feature of these reagents is the microRNA-like translational quelling resulting from short regions of oligonucleotide complementarity to many different messenger RNAs. We developed a computational approach, deconvolution analysis of RNAi screening data, for automated quantitation of off-target effects in RNAi screening data sets. Substantial reduction of off-target rates was experimentally validated in five distinct biological screens across different genome-wide siRNA libraries. A public-access graphical-user-interface has been constructed to facilitate application of this algorithm.

Consumption of dietary fiber and APOA5 genetic variants in metabolic syndrome: baseline data from the Korean Medicine Daejeon Citizen Cohort Study.

BACKGROUND: Consumption of dietary fiber has been suggested as an important aspect of a healthy diet to reduce the risk of metabolic syndrome (MetS), including cardiovascular disease. The role of fiber intake in MetS might differ by individual genetic susceptibility. APOA5 encodes a regulator of plasma triglyceride levels, which impacts the related mechanisms of MetS. This study investigated the association between dietary fiber and the risk of MetS, assessing their associations according to APOA5 genetic variants. METHODS: A total of 1985 participants aged 30-55 years were included from a cross-sectional study based on the Korean Medicine Daejeon Citizen Cohort study at baseline (2017-2019). Dietary fiber intake was measured using a semiquantitative food frequency questionnaire. The APOA5 polymorphisms (rs2266788 A > G, rs662799 A > G, and rs651821 T > C) were genotyped using the Asia Precision Medicine Research Array. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: A higher consumption of dietary fiber was associated with a lower prevalence of MetS (P = 0.025). Among the components of MetS, an inverse association with dietary fiber was observed in increased waist circumference (OR, 95% CI = 0.60, 0.41-0.88, P for trend = 0.009) and elevated triglycerides (OR, 95% CI = 0.69, 0.50-0.96, P for trend = 0.012). Regarding the interaction with APOA5 genetic variants, a stronger association with dietary fiber intake was shown in G allele carriers of rs662799 than in A/A carriers (OR, 95% CI = 2.34, 1.59-3.44, P for interaction = 0.024) and in C allele carriers of rs651821 than in T/T carriers (OR, 95% CI = 2.35, 1.59-3.46, P for interaction = 0.027). CONCLUSIONS: The findings of this study suggest that the benefits of dietary fiber on the risk of MetS could be modified by genetic variants of the APOA5 gene, providing a more effective strategy for preventing MetS.

The breast cancer susceptibility gene BRCA2 is required for the maintenance of telomere homeostasis.

Inactivating mutations in the breast cancer susceptibility gene BRCA2 cause gross chromosomal rearrangements. Chromosome structural instability in the absence of BRCA2 is thought to result from defective homology-directed DNA repair. Here, we show that BRCA2 links the fidelity of telomere maintenance with genetic integrity. Absence of BRCA2 resulted in signs of dysfunctional telomeres, such as telomere shortening, erosions, and end fusions in proliferating mouse fibroblasts. BRCA2 localized to the telomeres in S phase in an ATR-dependent manner, and its absence resulted in the accumulation of common fragile sites, particularly at the G-rich lagging strand, and increased the telomere sister chromatid exchange in unchallenged cells. The incidence of common fragile sites and telomere sister chromatid exchange increased markedly after treatment with replication inhibitors. Congruently, telomere-induced foci were frequently observed in the absence of Brca2, denoting activation of the DNA damage response and abnormal chromosome end joining. These telomere end fusions constituted a significant portion of chromosome aberrations in Brca2-deficient cells. Our results suggest that BRCA2 is required for telomere homeostasis and may be particularly important for the replication of G-rich telomeric lagging strands.

BubR1 acetylation at prometaphase is required for modulating APC/C activity and timing of mitosis.

Regulation of BubR1 is central to the control of APC/C activity. We have found that BubR1 forms a complex with PCAF and is acetylated at lysine 250. Using mass spectrometry and acetylated BubR1-specific antibodies, we have confirmed that BubR1 acetylation occurs at prometaphase. Importantly, BubR1 acetylation was required for checkpoint function, through the inhibition of ubiquitin-dependent BubR1 degradation. BubR1 degradation began before the onset of anaphase. It was noted that the pre-anaphase degradation was regulated by BubR1 acetylation. Degradation of an acetylation-mimetic form, BubR1-K250Q, was inhibited and chromosome segregation in cells expressing BubR1-K250Q was markedly delayed. By contrast, the acetylation-deficient mutant, BubR1-K250R, was unstable, and mitosis was accelerated in BubR1-K250R-expressing cells. Furthermore, we found that APC/C-Cdc20 was responsible for BubR1 degradation during mitosis. On the basis of our collective results, we propose that the acetylation status of BubR1 is a molecular switch that converts BubR1 from an inhibitor to a substrate of the APC/C complex, thus providing an efficient way to modulate APC/C activity and mitotic timing.

Gastric cancer risk is reduced by a predominance of antioxidant factors in the oxidative balance: a hospital-based case-control study in Korea.

OBJECTIVES: Gastric carcinogenesis is linked to oxidative stress from both exogenous and endogenous exposures. This study aimed to determine the association between the risk of gastric cancer and the oxidative balance score (OBS), which comprises antioxidant and pro-oxidant factors, including diet and lifestyle. METHODS: For this hospital-based case-control study, 808 controls and 404 patients with gastric cancer who had clinical records indicating Helicobacter pylori infection and the histological subtype of cancer were recruited. The OBS was determined based on diet and lifestyle factors obtained from a 106-item semiquantitative food frequency questionnaire and a constructed questionnaire. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A higher OBS was associated with a reduced gastric cancer risk (OR, 0.49; 95% CI

Antioxidant-Rich Diet, GSTP1 rs1871042 Polymorphism, and Gastric Cancer Risk in a Hospital-Based Case-Control Study.

BACKGROUND: Chronic gastritis along with Helicobacter pylori (H. pylori) infection has been implicated in inflammatory response-related genes linked to the causation of gastric cancer. Glutathione S-transferase Pi (GSTP1) plays a role in regulating oxidative stress and detoxification against carcinogenesis. In this study, we aimed to determine whether an antioxidant-rich diet is associated with gastric cancer risk and identify how this association could be altered by GSTP1 genetic variants. METHODS: This study included 1,245 participants (415 cases and 830 controls) matched for age and sex. The dietary antioxidant capacity was estimated based on the oxygen radical absorbance capacity (ORAC) incorporated with a semiquantitative food frequency questionnaire. Five single nucleotide polymorphisms (SNPs) of GSTP1 (rs1695, rs749174, rs1871042, rs4891, and rs947895) were selected among the exome array genotype data. RESULTS: High dietary ORAC was inversely associated with gastric cancer (hydrophilic ORAC OR T3 vs . T1, 95% CI = 0.57, 0.39-0.82, P = 0.004; lipophilic ORAC = 0.66, 0.45-0.95, P = 0.021; total phenolics = 0.57, 0.39-0.83, P = 0.005). The polymorphism rs1871042 increased the risk of gastric cancer (OR, 95% CI = 1.55, 1.10-2.16, P = 0.01, CT+TT vs. CC). A remarkably reduced risk of gastric cancer was observed among those who had a high dietary ORAC according to rs1871042 polymorphism (hydrophilic ORAC OR T3 vs . T1, 95% CI = 0.36, 0.17-0.78, P for trend = 0.013; lipophilic ORAC = 0.58, 0.37-0.93, P for trend = 0.021; total phenolics = 0.38, 0.17-0.83, P for trend = 0.019). CONCLUSIONS: Our findings indicate that dietary ORAC intake may be inversely associated with the risk of gastric cancer altered by genetic variants of GSTP1, providing new intervention strategies for gastric cancer patients.

The teratogenic effects of sertraline in mice.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs), which include paroxetine (Paxil), sertraline (Zoloft), fluoxetine (Prozac), citalopram (Celexa), and escitalopram (Lexapro), are the most common antidepressants prescribed to pregnant women. There is considerable debate in the literature regarding the developmental toxicities of SSRIs individually, and as a class. METHODS: It is considered unethical to perform developmental toxicity studies on pregnant women, but rodent and nonrodent species provide laboratory-controlled experimental models to examine the toxicity of SSRI exposure during pregnancy. The Embryo-Fetal Developmental Toxicity Study was conducted with sertraline in mice, Crl:CD1 (lCR), during the period of organogenesis. RESULTS: Increased resorption rates, lower fetal weight, and increased percentage of fetuses with visceral and skeletal abnormalities were found in the intermediate and high sertraline dose groups. In addition to incomplete ossification of treated animals, eleven sertraline exposed fetuses, two in group 2 (5 mg/kg), five in group 3 (25 mg/kg), and four in group 4 (60 mg/kg), had cleft palate (CP). This malformation was not observed in any controls. Only the highest dose of sertraline was found to be maternally toxic, as evidenced by significantly lower weight gain during pregnancy. CONCLUSION: These data indicate that in utero exposure to sertraline at 25 and 60 mg/kg was embryotoxic, teratogenic, and fetotoxic in mice. The incidence of CP observed in groups 3 and 4 (2.99% and 2.5%, respectively) were higher than the maximum range value noted in historical controls and indicate sertraline is a teratogen in ICR mice.