Birth defects research. Part B, Developmental and reproductive toxicology最新文献

{"title":"Reproductive and neurobehavioral effects of maternal exposure to piperonyl butoxide (PBO) in F1 -generation mice.","authors":"Toyohito Tanaka, A. Inomata","doi":"10.1002/bdrb.21185","DOIUrl":"https://doi.org/10.1002/bdrb.21185","url":null,"abstract":"Female mice were exposed maternally to piperonyl butoxide (PBO) through diet to provide levels of 0 (control), 0.015, 0.03, and 0.06% during gestation and lactation periods, and selected reproductive and neurobehavioral parameters were measured in F1 generation. There was no adverse effect of PBO on litter size, litter weight, or sex ratio at birth. The average body weights of offspring showed no significant effects of PBO treatment through the lactation period in both sexes except for the low-dose group of females on PND 21. With respect to behavioral developmental parameters, swimming direction of female offspring on PND 7 was significantly accelerated in the low-dose group (p = 0.022). Exploratory behavior examination in male offspring indicated that total distance and movement time shortened significantly in dose-related manners (p = 0.0138 and 0.00231, respectively), average time of rearing lengthened significantly in a dose-related manner (p = 0.00814), and the frequencies of mice with urination was increased significantly in a dose-related manner (p < 0.05). For spontaneous behavior examination, the average time of movement in males and average time of rearing in females showed slightly dose-related effects in the F1 generation. The dose levels of PBO in the present study produced some adverse effects in neurobehavioral parameters in mice.","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82787198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ovarian Stimulators, Intrauterine Insemination, and Assisted Reproductive Technologies Use and the Risk of Major Congenital Malformations—The AtRISK Study","authors":"Sonia Chaabane,&nbsp;Odile Sheehy,&nbsp;Patricia Monnier,&nbsp;François Bissonnette,&nbsp;Jacquetta M. Trasler,&nbsp;William Fraser,&nbsp;Anick Bérard","doi":"10.1002/bdrb.21178","DOIUrl":"10.1002/bdrb.21178","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> OBJECTIVE</h3>\u0000 \u0000 <p>To quantify the risk of major congenital malformations (MCMs) associated with the use of ovarian stimulators alone, intrauterine insemination (IUI), and assisted reproductive technologies (ARTs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We conducted a case–control analysis using a birth cohort, built with the linkage of data obtained by a self-administered questionnaire, medical, pharmaceutic, and birth databases. Cases were pregnancies with at least one live birth with an MCM. Controls were pregnancies that did not result in major or minor congenital malformations. Multiple logistic regression models were used to calculate the odds ratios (ORs) and confidence intervals (CIs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Among the 5021 pregnancies identified, 825 were cases of MCM and 4196 were controls. Compared with spontaneous conception, the use of ART increased the risk of major urogenital malformations (adjusted OR, 3.11; 95% CI, 1.33–7.27). The use of IUI was associated with an increased risk of major musculoskeletal malformations (adjusted OR, 2.02; 95% CI, 1.10–3.71). Among the 471 women who used fertility treatments for conception, the use of ART was associated with an increased risk of any MCM (adjusted OR, 1.66; 95% CI, 1.00–2.79) and urogenital malformations (adjusted OR, 7.18; 95% CI, 1.59–32.53) when compared with ovarian stimulators used alone.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> CONCLUSIONS</h3>\u0000 \u0000 <p>The use of ART and IUI was associated with an increased risk of major musculoskeletal and urogenital malformations. ART was associated with a higher risk of MCM compared to ovarian stimulators used alone. Even the adjustment, a contribution of the underlying subfertility problems cannot completely ruled out given the differences in the severity of subfertility</p>\u0000 </section>\u0000 </div>","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdrb.21178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34572459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gestational and Early Postnatal Exposure to an Environmentally Relevant Mixture of Brominated Flame Retardants: General Toxicity and Skeletal Variations","authors":"Emily W. Y. Tung,&nbsp;Han Yan,&nbsp;Pavine L. C. Lefèvre,&nbsp;Robert G. Berger,&nbsp;Dorothea F. K. Rawn,&nbsp;Dean W. Gaertner,&nbsp;Alice Kawata,&nbsp;Marc Rigden,&nbsp;Bernard Robaire,&nbsp;Barbara F. Hales,&nbsp;Michael G. Wade","doi":"10.1002/bdrb.21180","DOIUrl":"10.1002/bdrb.21180","url":null,"abstract":"<p>Brominated flame retardants (BFRs) are stable environmental contaminants known to exert endocrine-disrupting effects. Developmental exposure to polybrominated diphenyl ethers (PBDEs) is correlated with impaired thyroid hormone signaling, as well as estrogenic and anti-androgenic effects. As previous studies have focused on a single congener or technical mixture, the purpose of the current study was to examine the effects of gestational and early postnatal exposure to an environmentally relevant mixture of BFRs designed to reflect house dust levels of PBDEs and hexabromocyclododecane on postnatal developmental outcomes. Pregnant Sprague-Dawley rats were exposed to the PBDE mixture from preconception to weaning (PND 21) through the diet containing 0, 0.75, 250, and 750 mg mixture/kg diet. BFR exposure induced transient reductions in body weight at PND 35 in male and from PND 30–45 in female offspring (250 and 750 mg/kg). Liver weights (PND 21) and xenobiotic metabolizing enzyme activities (PND 21 and 46) were increased in both male and female offspring exposed to 250 and 750 mg/kg diets. Furthermore, serum T4 levels were reduced at PND 21 in both,male and female offspring (250 and 750 mg/kg). At PND 21, Serum alkaline phosphatase (ALP) was decreased in males exposed to 750 mg/kg dietat, and females exposed to 250 and 750 mg/kg diets. At PND 46 ALP was significantly elevated in males (250 and 750 mg/kg). Variations in the cervical vertebrae and phalanges were observed in pups at PND 4 (250 and 750 mg/kg). Therefore, BFR exposure during gestation through to weaning alters developmental programming in the offspring. The persistence of BFRs in the environment remains a cause for concern with regards to developmental toxicity</p>","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdrb.21180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34565713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Reproductive and Developmental Toxicity Profile of a Glycine Transporter Type 1 (Glyt1) Inhibitor","authors":"Paul Barrow,&nbsp;Neil Parrott,&nbsp;Daniela Alberati,&nbsp;Axel Paehler,&nbsp;Annette Koerner","doi":"10.1002/bdrb.21179","DOIUrl":"10.1002/bdrb.21179","url":null,"abstract":"<p>Bitopertin is a glycine type 1 (GlyT1) inhibitor intended for the treatment of psychiatric disorders. The principle adverse effect in the regulatory reproductive toxicity studies was peri-natal pup death when rat dams were treated during parturition at a dose resulting in five-times the human therapeutic exposure (AUC). Cessation of dosing two days before parturition prevented the pup deaths. Investigatory experiments and pharmacokinetic modelling suggested that the neonatal mortality was related to transplacental passage of bitopertin leading to high systemic levels in the newborn pups. Brain levels of bitopertin in the rat fetus and neonate were two-fold higher than in the mother. As illustrated by knock-out mice models, GlyT1 function is essential for neonatal pup survival in rodents, but is not necessary for normal prenatal morphological development. The glycine transport systems are immature at birth in the rat, but are functionally well-developed in the human newborn. While the relevance to humans of the neonatal mortality seen in rats following late gestational exposure is unknown, bitopertin would not be recommended for use during late pregnancy unless the anticipated benefit for the mother outweighs the potential risk to the newborn.</p>","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdrb.21179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34514746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic Acid and Pitx2 Regulate Early Neural Crest Survival and Migration in Craniofacial and Ocular Development","authors":"Bahaar Chawla,&nbsp;Elisa Schley,&nbsp;Antionette L. Williams,&nbsp;Brenda L. Bohnsack","doi":"10.1002/bdrb.21177","DOIUrl":"10.1002/bdrb.21177","url":null,"abstract":"<p>Congenital eye and craniofacial anomalies are associated with the dysregulation of retinoic acid (RA) levels during embryogenesis. In the present study, we observed that RA and pitx2a cooperatively regulate early cranial neural crest migration from the rhombencephalon to the pharyngeal arches and from the mesencephalon and prosencephalon to the periocular mesenchyme and frontonasal processes. The cranial neural crest tracked toward areas of high RA activity (i.e., developing eye) and circumvented areas of low RA activity (i.e., mesencephalon). Although previous studies have shown that RA increased pitx2a expression at later stages of cranial neural crest development, in these studies we found that RA inhibited pitx2a expression in the early migrating ventral cranial neural crest. Increased RA or decreased Pitx2a expression decreased cell survival and inhibited ventral neural crest migration. Decreased RA or increased pitx2a expression markedly disrupted both dorsal and ventral neural crest migration. The tight control of RA and subsequent regulation of pitx2 were required for precise cranial neural crest survival and migration. These alterations in the neural crest in the periocular mesenchyme and frontonasal processes may reflect the craniofacial dysmorphism and microphthalmia observed in cases of increased (i.e., as resulting from isoretinoin exposure) or decreased (i.e., as may occur in fetal alcohol syndrome) RA signaling during pregnancy</p>","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdrb.21177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34481111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental Toxicity Studies with Pregabalin in Rats: Significance of Alterations in Skull Bone Morphology","authors":"Dennis C. Morse,&nbsp;Judith W. Henck,&nbsp;Steven A. Bailey","doi":"10.1002/bdrb.21175","DOIUrl":"10.1002/bdrb.21175","url":null,"abstract":"<div>\u0000 <p>Pregabalin was administered to pregnant Wistar rats during organogenesis to evaluate potential developmental toxicity. In an embryo-fetal development study, compared with controls, fetuses from pregabalin-treated rats exhibited increased incidence of jugal fused to maxilla (pregabalin 1250 and 2500 mg/kg) and fusion of the nasal sutures (pregabalin 2500 mg/kg). The alterations in skull development occurred in the presence of maternal toxicity (reduced body weight gain) and developmental toxicity (reduced fetal body weight and increased skeletal variations), and were initially classified as malformations. Subsequent investigative studies in pregnant rats treated with pregabalin during organogenesis confirmed the advanced jugal fused to maxilla, and fusion of the nasal sutures at cesarean section (gestation day/postmating day [PMD] 21) in pregabalin-treated groups. In a study designed to evaluate progression of skull development, advanced jugal fused to maxilla and fusion of the nasal sutures was observed on PMD 20–25 and PMD 21–23, respectively (birth occurs approximately on PMD 22). On postnatal day (PND) 21, complete jugal fused to maxilla was observed in the majority of control and 2500 mg/kg offspring. No treatment-related differences in the incidence of skull bone fusions occurred on PND 21, indicating no permanent adverse outcome. Based on the results of the investigative studies, and a review of historical data and scientific literature, the advanced skull bone fusions were reclassified as anatomic variations. Pregabalin was not teratogenic in rats under the conditions of these studies</p>\u0000 </div>","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdrb.21175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34458215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Evaluation of the Impact of PD-1 Pathway Blockade on Reproductive Safety of Therapeutic PD-1 Inhibitors","authors":"Frederique M. Poulet,&nbsp;Jayanthi J. Wolf,&nbsp;Danuta J. Herzyk,&nbsp;Joseph J. DeGeorge","doi":"10.1002/bdrb.21176","DOIUrl":"10.1002/bdrb.21176","url":null,"abstract":"<p>This report discusses the principles of reproductive toxicity risk assessment for biopharmaceuticals blocking the PD-1/programmed cell death ligand 1 (PD-L1) pathway, which have been developed for the treatment of patients with advanced malignancies. The PD-1/PD-L1 pathway is a T-cell co-inhibitory pathway that normally maintains immune tolerance to self. Its role in pregnancy is to maintain immune tolerance to the fetal allograft. In cancer patients, this signaling pathway is hijacked by some neoplasms to avoid immune destruction. PD-1/PD-L1-blocking agents enhance functional activity of the target lymphocytes to eventually cause immune rejection of the tumor. A therapeutic blockade of PD-1/PD-L1 pathway that occurs at full target engagement provides a unique challenge to address the risk to pregnancy because disruption of the same pathway may also reduce or abrogate maternal immune tolerance to the fetal alloantigens inherited through the father. Typically, nonclinical reproductive and developmental toxicity (DART) studies in animals (rats and rabbits) with clinical drug candidates are conducted to identify potential risk in humans and to determine exposure margin for the effects on reproduction as part of the risk assessment. However, for biopharmaceuticals for which the desired mechanism of action cannot be separated from potential deleterious effects to the fetus and when the only relevant toxicology species is nonhuman primate (NHP), the risk to reproduction can be predicted by a mechanism-based assessment using data generated from murine surrogate models as supportive information without conducting DART in NHPs. Such an approach has been used in the evaluation of pregnancy risk of anti-PD-1 agent, pembrolizumab, and has been demonstrated as an important alternative to performing DART studies in NHPs</p>","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdrb.21176","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34446871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Embryo-Fetal Developmental Toxicity Studies with Pregabalin in Mice and Rabbits","authors":"Dennis C. Morse","doi":"10.1002/bdrb.21174","DOIUrl":"10.1002/bdrb.21174","url":null,"abstract":"<div>\u0000 <p>Pregabalin was evaluated for potential developmental toxicity in mice and rabbits. Pregabalin was administered once daily by oral gavage to female albino mice (500, 1250, or 2500 mg/kg) and New Zealand White rabbits (250, 500, or 1250 mg/kg) during organogenesis (gestation day 6 through 15 [mice] or 6 through 20 [rabbits]). Fetuses were evaluated for viability, growth, and morphological development. Pregabalin administration to mice did not induce maternal or developmental toxicity at doses up to 2500 mg/kg, which was associated with a maternal plasma exposure (AUC_0–24) of 3790 μg•hr/ml, ≥30 times the expected human exposure at the maximum recommended daily dose (MRD; 600 mg/day). In rabbits, treatment-related clinical signs occurred at all doses (AUC_0–24 of 1397, 2023, and 4803 μg•hr/ml at 250, 500, and 1250 mg/kg, respectively). Maternal toxicity was evident at all doses and included ataxia, hypoactivity, and cool to touch. In addition, abortion and females euthanized moribund with total resorption occurred at 1250 mg/kg. There were no treatment-related malformations at any dose. At 1250 mg/kg, compared with study and historical controls, the percentage of fetuses with retarded ossification was significantly increased and the mean number of ossification sites was decreased, which correlated with decreased fetal and placental weights, consistent with in utero growth retardation. Therefore, the no-effect dose for developmental toxicity in rabbits was 500 mg/kg, which produced systemic exposure approximately 16-times human exposure at the MRD. These findings indicate that pregabalin, at the highest dose tested, was not teratogenic in mice or rabbits</p>\u0000 </div>","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdrb.21174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89596743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Probability Analysis of Historical Pregnancy and Fetal Data from Dutch Belted and New Zealand White Rabbit Strains from Embryo–Fetal Development Studies","authors":"Lorraine M. Posobiec,&nbsp;Estella M. Cox,&nbsp;Howard M. Solomon,&nbsp;Elise M. Lewis,&nbsp;Kai-fen Wang,&nbsp;Dinesh Stanislaus","doi":"10.1002/bdrb.21173","DOIUrl":"10.1002/bdrb.21173","url":null,"abstract":"<p>Embryo-fetal development (EFD) studies, typically in pregnant rats and rabbits, are conducted prior to enrolling females of reproductive age in clinical trials. Common rabbit strains used are the New Zealand White (NZW) and Dutch Belted (DB). As fetal abnormalities can occur in all groups, including controls, Historical Control Data (HCD) is compiled using data from control groups of EFD studies, and is used along with each study's concurrent control group to help determine whether fetal abnormalities are caused by the test article or are part of background incidences. A probability analysis was conducted on 2014 HCD collected at Charles River Inc., Horsham PA on Covance NZW, Covance DB, and Charles River (CR) NZW rabbits. The analysis was designed to determine the probability of 2 or 3 out of a group of 22 does aborting their litter or of having a fetal abnormality by chance. Results demonstrate that pregnancy parameters and fetal observations differ not only between strains, but between sources of rabbits of the same strain. As a result the probability of these observations occurring by chance in two or three litters was drastically different. Although no one single strain is perfect, this analysis highlights the need to appreciate the inherent differences in pregnancy and fetal abnormalities between strains, and points out that an apparent isolated increased incidence of an observation in one strain will not necessarily be test-article related in another strain. A robust HCD is critical for interpretation of EFD rabbit studies, regardless of the rabbit strain used</p>","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdrb.21173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90528421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetes in the Cohen Rat Intensifies the Fetal Pancreatic Damage Induced by the Diabetogenic High Sucrose Low Copper Diet.","authors":"Z. Ergaz, Meytal Neeman-azulay, Liza Weinstein-Fudim, S. Weksler-Zangen, D. Shoshani-Dror, M. Szyf, A. Ornoy","doi":"10.1002/bdrb.21169","DOIUrl":"https://doi.org/10.1002/bdrb.21169","url":null,"abstract":"Intrauterine hyperglycemic environment could harm the fetus making it more susceptible to develop postnatal glucose intolerance. A possible mechanism is compromise of the fetal pancreatic development. We previously found that a high sucrose low copper diabetogenic diet induces type 2 diabetes in the Cohen diabetic sensitive rats, but not in the Sabra control rats. However, oxidative stress was observed in the placenta and term fetal liver of diabetic and nondiabetic controls. We now investigated whether the fetal pancreas is affected by this diet and whether the effects result from oxidative stress, maternal hyperglycemia, or both. Term fetal pancreases were evaluated for morphology, beta cells, oxidative stress, apoptosis, and DNA methylation. There were no microscopic changes in hematoxylin and eosin stained sections and beta cells immunostaining in the pancreas of fetuses of both strains. Fetuses of the sensitive strain fed diabetogenic diet had significantly higher activity of superoxide dismutase and catalase, elevated levels of low molecular weight antioxidants, and more intense immunostaining for nuclear factor kappa-B and hypoxia inducing factor-1α. Both strains fed diabetogenic diet had increased immunostaining for Bcl-2-like protein and caspase 3 and decreased immunostaining for 5-methylcytosine in their islets and acini. Our data suggest that maternal diabetogenic diet alters apoptotic rate and epigenetic steady states in the term fetal pancreas, unrelated to maternal diabetes. Maternal hyperglycemia further increases pancreatic oxidative stress, aggravating the pancreatic damage. The diet-induced insults to the fetal pancreas may be an important contributor to the high susceptibility to develop diabetes following metabolic intrauterine insults.","PeriodicalId":9120,"journal":{"name":"Birth defects research. Part B, Developmental and reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84595701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}