Amotivation is a central feature of psychosis that can lead to underperformance on a variety of tasks, including neurocognitive testing; however, there is some evidence that neurocognitive impairments resulting from low effort can be ameliorated with the use of monetary reinforcement. While cross-sectional data has also shown that amotivation is associated with social cognitive performance, limited research has examined the directionality of this relationship, and whether monetary reinforcement can similarly reduce these impairments. In the present study, 35 patients with early psychosis and 35 community controls were randomized to either a reward condition in which they received monetary reinforcement for every correct response on a theory of mind (ToM) task, or a non-reward condition in which no feedback was provided. A significant group by condition interaction emerged after adjusting for premorbid intelligence and global neurocognition, F(1, 63) = 7.76, p = .007. Post-hoc analyses revealed that performance on the ToM task was similar across conditions for controls, whereas early psychosis patients in the reward condition had clinically and statistically significant differences in ToM performance compared to patients in the non-reward condition. These results suggest that social cognitive task performance may underrepresent actual ability in the early stages of psychosis. Future research is needed to discriminate the relative effects of monetary reinforcement, corrective feedback, and/or a combination of these factors to better understand performance differences between conditions, which appeared to be unique to early psychosis patients.

Prenatal chemical exposure has frequently been associated with reduced fetal growth although results have been inconsistent. Most studies associate single pollutant exposure to this health outcome, even though this does not reflect real life situations as humans are exposed to many pollutants during their life time. The objective of this study is to investigate the association between prenatal exposure to a mixture of persistent environmental chemicals and birth weight using multipollutant models.We combined exposure biomarker data measured in cord blood samples of 1579 women from four Flemish birth cohorts collected over a 10 years’ time period. The common set of available and detectable exposure measures in these cohorts are three polychlorinated biphenyls (PCB) congeners (138, 153 and 180), hexachlorobenzene (HCB), dichlorodiphenyldichloroethylene (p,p’-DDE) and the metals cadmium and lead. Multiple linear regression (MLR), Bayesian Information Criterion (BIC), penalized regression using minimax concave penalty (MCP) and Bayesian Adaptive Sampling (BAS) were applied to assess the influence of multiple pollutants in a single analysis on birth weight, adjusted for a priori selected covariates.In the pooled dataset, a median (P25-P75) birth weight and gestational age of 3420 (3140–3700) grams and 39 (39–40) weeks was observed respectively. The median contaminant levels in cord blood were: 15.8, 26.5, 18.0, 16.9 and 91.5 ng/g lipid for PCB 138, PCB 153, PCB 180, HCB and p,p’-DDE, respectively, 0.075 µg/L for cadmium and 9.7 µg/L for lead. According to the applied statistical methods for multipollutant assessment, p,p’-DDE and PCB 180 were most consistently associated with birth weight. In addition, PCB 153 was selected when applying MCP and BAS. An inverse association with birth weight was found for the PCB congeners, while an increased birth weight was observed for elevated levels of p,p’-DDE.Assessing the health risk of combinations of exposure biomarkers reflects better real-world situations and thereby allows more effective risk assessment. Our results add to the existing evidence based on detrimental effects of PCBs on birth weight and indicate a possible increase in birth weight due to p,p’-DDE (while correcting for PCBs).

Perfluorohexanoic acid (PFHxA), one of the short-chain perfluoroalkyl acids (PFAAs), is considered as a substitute of perfluorooctane sulfonate (PFOS). This emerging organic pollutant is persistent and highly bioavailable to humans, raising concerns about its potential health risks. There are currently few researches on the toxicity of PFHxA. Liver has been suggested to be the main target of PFHxA toxicity, and the mechanism remains unclear. Herein, we investigated the transcriptomic, proteomic, and metabolomic landscape in PFHxA-exposed mice. Using these approaches, we identified several valuable biological processes involved in the process of liver injury, comprising fatty acid biosynthesis and degradation pathways, which might be induced by peroxisome proliferator-activated receptor (PPAR) signaling pathway. These processes further promoted oxidative stress and induced liver injury. Meanwhile, abnormalities in purine metabolism and glutathione metabolism were observed during the liver injury induced by PFHxA, indicating the production of oxidative stress. Finally, our present multi-omics studies provided new insights into the mechanisms involved in PFHxA-induced liver injury.

Lipophilia, acidity, limited protein binding and low molecular mass enhance the transfer of contaminants into the mother’s milk. The intake of contaminants occurs primarily via contaminated foods that cannot necessarily be avoided. Theoretically, absorption via the skin and respiratory tree can also lead to measurable plasma concentrations, and thereby to exposure of the infant via the mother’s milk.Unlike medications, the lengthy persistence in nature of some toxicologically important industrial and environmental contaminants, combined with limited photochemical or bacteriological decomposition and accumulation in the food chain, play a significant role. There is virtually no way these compounds can be detoxified or decomposed in the human body. Elimination via the urine, the stool and the sweat is minimal.Access to screening data on 1,800 chemicals, ToxCast data was made available by the Environmental Protection Agency (EPA) in April 2014. (http://www.epa.gov/ncct/challenges.html). The data were gathered through advanced techniques, including robotics and high-throughput screening. Only a fraction of the chemicals in use have been adequately assessed for potential risk. This information will be useful for prioritizing chemicals for potential risk as well as predicting which chemical exposures could lead to adverse health effects. The mammary gland is capable of regulating concentrations of essential elements such as copper, iron and zinc in milk. This protects the infant from deficiency and excess of these elements. Despite advances in analytical techniques for trace elements in human milk, there remain major challenges. Variation in maternal diet, environment and stage of lactation influence results across studies.

Health concerns have been raised because perfluorooctanoic acid ( PFOA) is commonly found in the environment and can be detected in humans. In rodents, PFOA is a carcinogen and a developmental toxicant. PFOA is a peroxisome proliferator-activated receptor alpha (PPAR alpha) activator; however, PFOA is capable of inducing heptomegaly in the PPAR alpha-null mouse. To study the mechanism associated with PFOA toxicity, wild-type and PPAR alpha-null mice were orally dosed for 7 days with PFOA (1 or 3 mg/kg) or the PPAR alpha agonist Wy14,643(50 mg/kg). Gene expression was evaluated using commercial microarrays. In wild-type mice, PFOA and Wy14,643 induced changes consistent with activation of PPAR alpha. PFOA-treated wild-type mice deviated from Wy14,643-exposed mice with respect to genes involved in xenobiotic metabolism. In PFOA-treated null mice, changes were observed in transcripts related to fatty acid metabolism, inflammation, xenobiotic metabolism, and cell cycle regulation. Hence, a component of the PFOA response was found to be independent of PPAR alpha. Although the signaling pathways responsible for these effects are not readily apparent, overlapping gene regulation by additional PPAR isoforms could account for changes related to fatty acid metabolism and inflammation, whereas regulation of xenobiotic metabolizing genes is suggestive of constitutive androstane receptor activation.

Clinical genetics, a board-certified specialty, is now fully integrated into medical practice. Rapid advances in this field have been translated and transferred almost instantly, via the media, into the public domain. Not unexpectedly, the informed public (often prematurely) have developed immediate expectations of benefitting from these new developments. Hence, physicians are expected to be sufficiently well informed and up-to-date to provide or to refer for appropriate genetic counseling, evaluation, or laboratory testing. Certainly, genetic considerations are necessary in every family.Genetics has a role in virtually every disorder, in causation, predisposition and susceptibility, immune response, modulation, or reaction to medical treatment. It is estimated that each of us carries at least 20 harmful genes. About 1 in 13 conceptions results in a conceptus with a chromosome abnormality,50 whereas about 50% of first-trimester spontaneous abortions are associated with such defects.7 Clinically significant chromosomal defects occur in 0.65% of all births, an additional 0.2% being born with balanced structural chromosome rearrangements that have implications for reproduction later in life. Between 5.6% and 11.5% of stillbirths and neonatal deaths are associated with chromosome defects.2 Three percent to four percent of all births are associated with a major congenital malformation, mental retardation, or genetic disorder, a rate that doubles by 7 to 8 years of age, given later-appearing or later-diagnosed genetic disorders.44Genetic counseling is a communication process concerning the occurrence and the risks of recurrence of genetic disorders within a family. Such counseling aims to provide the patient with a clear and comprehensive understanding of all the important implications and possible options of the disorder in question, to facilitate rational decision making.44 The basis and guidelines for genetic counseling have been extensively reviewed and are not covered here.43, 44 Indications for genetic counseling are summarized below: 1Advanced maternal age2Abnormal maternal serum triple screen3Abnormal ultrasound evaluation during pregnancy4A previous fetus or child with a genetic disorder or congenital defect5Parent with a genetic disorder6Family history of a specific genetic disorder7A maternal disorder with or without specific drug treatment associated with an increased risk of congenital defects8A maternal disorder in which pregnancy could threaten maternal or fetal life or health9Known or possible carriers of specific harmful genes (including ethnic-related disorders)10Exposure to teratogenic drugs, infections, x-rays, toxins, or occupational hazards during or before pregnancy11Known or suspected consanguinity12Consideration of presymptomatic/predictive laboratory testingPreconception care and counseling, with appropriate anticipatory guidance, is important in the identification of risk factors, disease states, and potential teratogens, and prompts the offering of carrier and prenatal diagnostic testing. The availability of first-trimester prenatal diagnosis and the advent of presymptomatic diagnosis by DNA analysis has created increasing opportunities to avoid disorders characterized by early death, severe disease, or irreparable mental retardation. Periconceptional maternal folic acid supplementation has now been shown conclusively to provide a high protective effect against neural tube defects.38, 41Certain maternal disease states, including diabetes, lupus, and myotonic muscular dystrophy, impose their own specific potential maternal, fetal, neonatal, and other complications. So far as pregnancy and fetal defects are concerned, the preconception visit provides important opportunities for intervention, avoidance, or prevention. The patients' ethnicity and medical and genetic family history are key elements in this evaluation. Patients with prolonged infertility of unknown cause or recurrent spontaneous abortion, who may have a 3% to 10% risk of a parental chromosome abnormality,55, 60 require chromosome analysis, as do their spouses. Virtually all ethnic groups carry some “genetic burden.”40 For example, whites have a risk of about 1 in 25 for carrying the gene for cystic fibrosis (CF). Ashkenazi Jews have a risk of about 1 in 30 for carrying the gene for Tay-Sachs disease and a risk of about 1 in 12 for carrying the gene for Gaucher's disease.DNA testing for carrier states are now readily available at major diagnostic centers. These relatively inexpensive and accurate tests enable more precise genetic counseling, information that becomes important for those who might select prenatal diagnosis as an option, or for couples who prefer to avoid the possibilities of abortion and prefer artificial insemination from a donor known not to carry that specific gene. In the future, preimplantation diagnosis may require discussion during the preconception visit, because technically this now is a reality. With the traditional modes of inheritance come several nontraditional modes and mechanisms of inheritance that often pose complex issues in genetic counseling.

The postnatal effects of in utero exposure to perfluorooctane sulfonate (PFOS, C8F17SO3-) were evaluated in the rat and mouse. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestation day (GD) 2 to GD 21; pregnant CD-1 mice were treated with 1, 5, 10, 15, and 20 mg/kg PFOS from GD 1 to GD 18. Controls received 0.5% Tween-20 vehicle (1 ml/kg for rats and 10 ml/kg for mice). At parturition, newborns were observed for clinical signs and survival. All animals were born alive and initially appeared to be active. In the highest dosage groups (10 mg/kg for rat and 20 mg/kg for mouse), the neonates became pale, inactive, and moribund within 30-60 min, and all died soon afterward. In the 5 mg/kg (rat) and 15 mg/kg (mouse) dosage groups, the neonates also became moribund but survived for a longer period of time (8-12 h). Over 95% of these animals died within 24 h. Approximately 50% of offspring died at 3 mg/kg for rat and 10 mg/kg for mouse. Cross-fostering the PFOS-exposed rat neonates (5 mg/kg) to control nursing dams failed to improve survival. Serum concentrations of PFOS in newborn rats mirrored the maternal administered dosage and were similar to those in the maternal circulation at GD 21; PFOS levels in the surviving neonates declined in the ensuing days. Small but significant and persistent growth lags were detected in surviving rat and mouse pups exposed to PFOS prenatally, and slight delays in eye opening were noted. Significant increases in liver weight were observed in the PFOS-exposed mouse pups. Serum thyroxine levels were suppressed in the PFOS-treated rat pups, although triiodothyronine and thyroid-stimulating hormone [TSH] levels were not altered. Choline acetyltransferase activity (an enzyme that is sensitive to thyroid status) in the prefrontal cortex of rat pups exposed to PFOS prenatally was slightly reduced, but activity in the hippocampus was not affected. Development of learning, determined by T-maze delayed alternation in weanling rats, was not affected by PFOS exposure. These results indicate that in utero exposure to PFOS severely compromised postnatal survival of neonatal rats and mice, and caused delays in growth and development that were accompanied by hypothyroxinemia in the surviving rat pups.

The impacts of adverse environments during the prenatal and/or early postnatal periods may be manifested as functional deficits that occur later in life. Epidemiological studies have shown an association of sub-optimal pregnancy outcomes in one generation with similar events in the following one, a phenomenon termed the "intergenerational effect". Data indicate that the incidence of adverse pregnancy outcomes and/or low birth weight infants is more closely correlated with the mother's perinatal environment than with that during her pregnancy. However, epidemiological studies are inherently limited given the variability of lifestyles, ethnicity, nutritional status, and exposures to environmental factors. An appropriate animal model would permit control of parameters that may be impossible to evaluate in human populations. The current studies investigated the mouse as a possible animal model. Pregnant CD-1 mice were placed on an ad libitum or food-restricted diet (50% normal) throughout gestation to generate control (CON) and intrauterine growth retarded (IUGR) litters. At birth (postnatal day (PD) 1) pups (F1) were cross-fostered to control dams in litters of either 8 (CON) or 16 (postnatal food restriction (FR)). The experimental groups thus generated represented adequate nutrition (CON-CON) and undernutrition during the prenatal (IUGR-CON), or postnatal periods (CON-FR), or both (IUGR-FR). Pups of dams on a restricted diet during gestation had significant IUGR (P<0.001) as compared to controls (birth weights of 1.32 g versus 1.63 g). At weaning, the average weight of the pups was dependent on postnatal litter size and the difference in birth weights between IUGR and CON animals was not a significant factor. CON-CON pup weight was 24.1g and IUGR-CON was 22.2 g as compared to the CON-FR (17.0 g) and IUGR-FR (17.3 g) groups. The difference in weaning pup weights between the FR and CON groups was significant (P<0.01). The F1 FR females did not reach CON female weights at any time point through 11 months after weaning. At PD60, a single breeding period for all groups of females with CON males began and continued for 75 days with 17 opportunities for breeding. Animals that became pregnant during this time were removed and allowed to litter. No significant differences were noted in average F2 litter size or average pup weight at birth: (CON-CON 12.2/1.62 g; IUGR-CON 11.9/1.6 2 g; CON-FR 10.9/1.70 g; IUGR-FR 11.3/1.61 g). We conclude that body weight at birth in the CD-1 mouse is not correlated with growth through the period of weaning (PD28). We did not find any evidence for an intergenerational reproductive effect after developmental undernutrition.

BACKGROUND:The purine analog 2-chloro-2'-deoxyadenosine (2-CdA) caused ocular and limb defects in the mouse and rabbit. The current study examined the teratogenic potential of this drug in the rat and compared the adverse developmental outcomes with the other species.METHODS:Timed-pregnant Sprague-Dawley rats were given a single intraperitoneal injection of various doses of 2-CdA ranging from 5-60 mg/kg, at gestational day (GD) 9.5 and GD 14. 2-CdA concentrations in maternal serum and embryos were measured by HPLC and termed fetuses were prepared for teratological examination.RESULTS:Full-litter resorption was seen in dams receiving 50 mg/kg of 2-CdA at GD 9.5, whereas post-implantation loss was significantly increased and fetal weights significantly reduced at 40 mg/kg. Gross examination of the surviving fetuses revealed microphthalmia, a shortened body trunk and lumbar hernia, manifested by a soft mass protrusion at the lumbar region on one or both sides of the spine. Incidence of these defects increased in a dose-dependent fashion. Histological examination indicated that the hernia was associated with hypoplasia of the body wall, poorly developed skeletal muscle bundles surrounding the vertebral column in the lumbar region, and an absence of the lateral muscle groups that allowed protrusion of the abdominal viscera. The lumbar hernia was generally accompanied by spina bifida, deformed ribs and a wide spectrum of soft tissue-abnormalities that included kidney, genitourinary and heart defects. At GD 14, exposure to 2-CdA at 60 mg/kg produced oligodactyly in one of six litters.CONCLUSIONS:2-CdA produced similar ocular defects in the rat and mouse, although the incidence was much lower in the former species. In contrast, the drug-induced lumbar hernia was only seen in the rat. These apparent disparities were not readily explained by species differences in pharmacokinetic parameters. the similarities between the teratological features of 2-CdA-induced lumbar hernia in the rat and the clinical description of lumbocostovertebral syndrome, however, may provide a key to unlock the etiology of this rare birth defect in humans.

Biologically based dose-response (BBDR) models comprise one way to incorporate mechanistic information into a dose-response assessment to be used for risk assessments. The chemotherapeutic drug 5-fluorouracil (5-FU) has been used as a prototypic compound for the construction of a BBDR model for developmental toxicity. Previous work has provided data and a general mechanistic framework for the developmental toxicity of 5-FU when it was administered to pregnant rats subcutaneously on gestation day 14. In this paper, a mathematical model relating maternally administered treatment with 5-FU to embryonal thymidylate synthetase inhibition and thymidylate synthetase inhibition to various measures of deoxyribonucleotide triphosphate (dNTP) pool perturbation is developed, and parameters are estimated using the data collected. The strategy used was to develop semi-empirical submodels for each of the intervening steps, and to estimate model parameters from previously described data. The models developed predict that there is no practical threshold for dNTP pool perturbation; that is, even minimal doses of 5-FU should result in some perturbation of dNTP pools. In particular, the relationship between dNTP pool perturbation and fetal weight deficit suggests that if there is a biological threshold for the effect of 5-FU on fetal weight, the responsible repair or compensation mechanism must be downstream of dNTP pool perturbation, and saturable at 5-FU doses lower than 10 mg/kg (the lowest dose examined for developmental effects in these studies).

BACKGROUNDTreatment of pregnant mice with 2-chloro-2'-deoxyadenosine (2CdA) on day 8 of gestation induces microphthalmia through a mechanism coupled to the p53 tumor suppressor gene. The present study defines 2CdA dosimetry with respect to exposure (pharmacokinetics), p53 protein induction, and disease (microphthalmia).METHODSPregnant CD-1 mice dosed with 0.5-10.0 mg/kg 2CdA on day 8 provided fetuses for teratological evaluation; 2CdA was measured by HPLC in the antimesometrium through 180 min postexposure, and p53 was assessed with immunostaining of the embryo through 270 min. 5'-/3'-RACE was used to sequence the candidate gene for 2CdA bioactivation from target cells.RESULTSMicrophthalmia appeared first in the dose-response curve. The highest 2CdA dose having no observable adverse effect (NOAEL) was 1.5 mg/kg; the benchmark dose that produced an extra 5% risk of microphthalmia (BMD(5)) was 2.5 mg/kg, and the lower confidence limit (BMDL) was 2.0 mg/kg. Pharmacokinetic parameters for doses encompassing the threshold (1.5-2.5 mg/kg) were modeled at 1.0-1.8 microM (C(max)) and 30-80 microM-min (AUC). The p53 response was not detected below the BMDL; however, a low-grade response appeared 4.5 hr after a teratogenic dose (5.0 mg/kg), and high-grade induction followed an embryolethal dose (10.0 mg/kg). RACE identified a novel splice variant of mitochondrial deoxyguanosine kinase, dGK-3, as the likely candidate for 2CdA bioactivation in the embryo.CONCLUSIONSMicrophthalmia represented the critical effect malformation of 2CdA. The findings suggest a mitochondrial mechanism for 2CdA bioactivation, leading to an embryonic p53 response only after 2CdA elimination and implying pharmacodynamic coupling to the exposure-disease continuum. Published 2001 Wiley-Liss, Inc.

Glucocorticoids play a key role in controlling numerous cellular processes during embryogenesis and fetal development. Excess glucocorticoids during development have been linked to dysmorphogenesis and/or intrauterine growth impairment in rodents. The actions of glucocorticoids are mediated by interaction with their receptors. Negative feedback regulation of glucocorticoid receptor (GR) is important for limiting cellular sensitivity to the hormones. Hence, acute exposure of the adult rat to the synthetic glucocorticoid dexamethasone (DEX) reduced both GR mRNA and protein in a variety of tissues that include hippocampus and liver, in a dose- and time-dependent fashion. Reduction in GR mRNA and protein were observable when DEX was given repeatedly at doses as low as 0. 05 mg/kg. In the control whole rat embryo, GR mRNA was low but measurable at as early as gestational day (GD) 10, but underwent rapid ontogenetic increase in the ensuring days. In contrast to the adult, neither GR mRNA nor protein in the whole rat embryo was affected by acute or repeated DEX administration to pregnant rats on GD10-13, even at doses as high as 0.8 mg/kg. Similar results were obtained in embryonic palate and liver, tissues known to be glucocorticoid targets. These data suggest that GR autoregulation does not occur during organogenesis in the rat. Accordingly, hormonal elevations from stress or chemical insults can be transduced unrestrictedly, ultimately leading to aberrant cell function and development. The unique mode of GR regulation seen in the embryonic cells may provide a potential common mechanism for developmental perturbation and toxicity for a variety of insults.

Biologically based dose-response (BBDR) modeling represents a novel approach for quantitative assessment of health risk by incorporating pharmacokinetic and pharmacodynamic characteristics of a chemical and by relating the immediate cellular responses to a cascade of aberrant biological actions that leads to detectable adverse outcomes. The quantitative relationship of each of the intervening events can be described in mathematical forms that are amenable for adjustment and extrapolation over a range of doses and across species. A team of investigators at the Reproductive Toxicology Division of the U.S. Environmental Protection Agency has explored the feasibility of BBDR modeling by examining the developmental toxicity of a known teratogen, 5-fluorouracil. A panel of researchers from academic and industrial laboratories, biomathematical modelers, and risk assessment scientists was convened in a workshop to evaluate the approaches undertaken by the EPA team and to discuss the future prospects of BBDR modeling. This report summarizes the lessons learned from one approach to BBDR modeling and comments from the panelists: while it is possible to incorporate mechanistic information into quantitative dose-response models for the assessment of health risks, the process is enormously data-intensive and costly; in addition, the confidence of the model is directly proportional to our current understanding of basic biology and can be enhanced only through the ongoing novel discoveries. More importantly, the extent of "uncertainty" (inherent with the default assumptions associated with the NOAEL or benchmark approach) reducible by BBDR modeling requires further scrutiny and comparison.