Cyclosporine A: Review of genotoxicity and potential for adverse human reproductive and developmental effects: Report of a working group on the genotoxicity of cyclosporine A,August 18, 1993

Cyclosporine is an important therapeutic agent for transplant recipients and for a growing number of autoimmune diseases. Experimental animal and human data has indicated that cyclosporine is unlikely to be genotoxic. In contrast, azathioprine, an agent often given with cyclosporine, is considered to be genotoxic making the assessment of the independent effects of cyclosporine difficult. Cyclosporine does appear to be related to the development of tumors, primarily lymphomas, in animals and humans, but the basis of its potential carcinogenicity is not completely understood. In terms of reproductive and developmental toxicity, cyclosporine produces some adverse effects in both experimental animals and humans. In animals, the effects are seen at high doses sufficient to cause maternal toxicity. In humans, outcomes such as growth retardation have been noted, but the confounding effects of renal toxicity and resultant pregnancy complications cloud the interpretation. An increase in congenital anomalies and genetic disease have not been found reported in human studies that are limited in sample size.     

Genetic sensitivity analysis: Adjusting for genetic confounding in epidemiological associations

Associations between exposures and outcomes reported in epidemiological studies are typically unadjusted for genetic confounding. We propose a two-stage approach for estimating the degree to which such observed associations can be explained by genetic confounding. First, we assess attenuation of exposure effects in regressions controlling for increasingly powerful polygenic scores. Second, we use structural equation models to estimate genetic confounding using heritability estimates derived from both SNP-based and twin-based studies. We examine associations between maternal education and three developmental outcomes – child educational achievement, Body Mass Index, and Attention Deficit Hyperactivity Disorder. Polygenic scores explain between 14.3% and 23.0% of the original associations, while analyses under SNP- and twin-based heritability scenarios indicate that observed associations could be almost entirely explained by genetic confounding. Thus, caution is needed when interpreting associations from non-genetically informed epidemiology studies. Our approach, akin to a genetically informed sensitivity analysis can be applied widely.     

Association between Maternal Exposure to di(2-ethylhexyl) Phthalate and Reproductive Hormone Levels in Fetal Blood: The Hokkaido Study on Environment and Children's Health

Prenatal di(2-ethylhexyl) phthalate (DEHP) exposure can produce reproductive toxicity in animal models. Only limited data exist from human studies on maternal DEHP exposure and its effects on infants. We aimed to examine the associations between DEHP exposure in utero and reproductive hormone levels in cord blood. Between 2002 and 2005, 514 pregnant women agreed to participate in the Hokkaido Study Sapporo Cohort. Maternal blood samples were taken from 23–35 weeks of gestation and the concentration of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), was measured. Concentrations of infant reproductive hormones including estradiol (E2), total testosterone (T), and progesterone (P4), inhibin B, insulin-like factor 3 (INSL3), steroid hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone were measured from cord blood. Two hundred and two samples with both MEHP and hormones'' data were included in statistical analysis. The participants completed a self-administered questionnaire regarding information on maternal characteristics. Gestational age, birth weight and infant sex were obtained from birth records. In an adjusted linear regression analysis fit to all study participants, maternal MEHP levels were found to be associated with reduced levels of T/E2, P4, and inhibin B. For the stratified analyses for sex, inverse associations between maternal MEHP levels T/E2, P4, inhibin B, and INSL3 were statistically significant for males only. In addition, the MEHP quartile model showed a significant p-value trend for P4, inhibin B, and INSL3 decrease in males. Since inhibin B and INSL3 are major secretory products of Sertoli and Leydig cell, respectively, the results of this study suggest that DEHP exposure in utero may have adverse effects on both Sertoli and Leydig cell development in males, which agrees with the results obtained from animal studies. Comprehensive studies investigating phthalates'' exposure in humans, as well as their long-term effects on reproductive development are needed.     

Associations between Maternal Biomarkers of Phthalate Exposure and Inflammation Using Repeated Measurements across Pregnancy

Phthalate exposure is prevalent in populations worldwide, including pregnant women. Maternal urinary metabolite concentrations have been associated with adverse reproductive outcomes, but underlying mechanisms remain unclear. Here we investigate inflammation as a possible pathway by examining phthalates in association with inflammation biomarkers, including C-reactive protein (CRP) and a panel of cytokines (IL-1β, IL-6, IL-10, and TNF-α) in a repeated measures analysis of pregnant women (N = 480). Urinary phthalate metabolites and plasma inflammation biomarkers were measured from samples collected at up to four visits per subject during gestation (median 10, 18, 26, and 35 weeks). Associations were examined using mixed models to account for within-individual correlation of measures. Few statistically significant associations or clear trends were observed, although in full models mono-carboxypropyl phthalate (MCPP) was significantly (percent change with interquartile range increase in exposure [%Δ] = 8.89, 95% confidence interval [CI] = 3.28, 14.8), and mono-benzyl phthalate (MBzP) was suggestively (%Δ = 6.79, 95%CI = -1.21, 15.4) associated with IL-6. Overall these findings show little evidence of an association between phthalate exposure and peripheral inflammation in pregnant women. To investigate inflammation as a mechanism of phthalate effects in humans, biomarkers from target tissues or fluids, though difficult to measure in large-scale studies, may be necessary to detect effects.     

Effets d’une exposition à la Vinclozoline et à la Génistéine de la gestation à l’âge adulte sur la fonction de reproduction du ratWistar mâle: protocole et résultats préliminaires

Current evidence indicates that endocrine disrupters (EDs) can induce adverse effects on the male reproductive tract in various mammalian species. Recent reports indicate deterioration in male reproductive health in several human populations, but the evidence for a causal link with endocrine disruption is still weak. In addition, the experimental conditions of most of the reportedin vivo studies are not representative of environmental exposures (for example, high doses, short-term exposure, a single ED) and the mechanisms by which EDs disrupt the reproductive system are poorly understood. The objective of the present study is to develop an animal model to assess the reproductive effects and study the putative cellular and molecular mechanisms involved after exposure to genistein (phytoestrogen) and vinclozolin (fungicide with a known antiandrogenic potential) alone or in combination. The study will be performed in male Wistar rats, with administration of low and high doses of the compounds from conception to adulthood and a subset of the males in each treatment group will be mated with unexposed females. We plan to assess the level of sperm production, histology of the reproductive organs, motility and morphometry of spermatozoa and hormone levels, as well as DNA fragmentation of spermatozoa and determination of the number of germ cells, Sertoli cells and the diameters of seminiferous tubules. Estrogen, androgen, progesterone and FSH receptors will be detected and quantified and the level of testicular apoptosis and several apoptosis pathways will be studied to determine the putative cellular and molecular mechanisms involved. The preliminary results confirmed the developmental effects previously reported for high doses of vinclozolin. More interestingly, they indicated a number of deleterious effects for male rats exposed to low dosages alone or mixtures of low and high dosages compared to controls and rats exposed to high dosages alone. For example, a number of developmental anomalies of the genitalia were observed and a significant decrease of sperm motility and motion and fertilizing ability were observed. These preliminary results provide evidence that chronic exposure to environmental levels of EDs or mixtures of EDs have a detrimental impact on the male reproductive tract. The next step involves assessment of the anatomical disorders and the study of some of the cellular and molecular mechanisms possibly involved.     

Bridging epidemiology and model organisms to increase understanding of endocrine disrupting chemicals and human health effects

Concerning temporal trends in human reproductive health has prompted concern about the role of environmentally mediated risk factors. The population is exposed to chemicals present in air, water, food and in a variety of consumer and personal care products, subsequently multiple chemicals are found human populations around the globe. Recent reviews find that endocrine disrupting chemicals (EDCs) can adversely affect reproductive and developmental health. However, there are still many knowledge gaps. This paper reviews some of the key scientific concepts relevant to integrating information from human epidemiologic and model organisms to understand the relationship between EDC exposure and adverse human health effects. Additionally, areas of new insights which influence the interpretation of the science are briefly reviewed, including: enhanced understanding of toxicity pathways; importance of timing of exposure; contribution of multiple chemical exposures; and low dose effects. Two cases are presented, thyroid disrupting chemicals and anti-androgens chemicals, which illustrate how our knowledge of the relationship between EDCs and adverse human health effects is strengthened and data gaps reduced when we integrate findings from animal and human studies.     

Adverse reproductive outcomes from exposure to environmental mutagens.

The effect of environmental pollution on reproductive outcomes has been studied in the research project 'Teplice Program' analyzing the impact of air pollution on human health. Genotoxicity of urban air particles <10 microm (PM10) in in vitro system was determined by the analysis of DNA adducts. The highest DNA binding activity was observed in aromatic fraction, identifying DNA adducts of carcinogenic polycyclic aromatic hydrocarbons (PAHs) presumably diolepoxide-derived from: 9-hydroxybenzo[a]pyrene (9-OH-B[a]P), benzo[a]pyrene-r-7,-dihydrodiol-t-9,10-epoxide[+] (anti-BPDE), benzo[b]fluoranthene (B[b]F), chrysene (CHRY), benz[a]antracene (B[a]A), indeno[1,2,3-cd]pyrene (I[cd]P). Reproductive studies were conducted in both females and males. A study of the effects of PM10 exposure on pregnancy outcomes found the relationship between the intrauterine growth retardation (IUGR) and PM10 levels over 40 microg/m(3) in the first gestational month (Odds Ratio for 40-50 microg/m(3)50 microg/m(3)=1.9). Selected biomarkers were analyzed in venous blood, cord blood (chromosomal aberrations, comet assay) and placenta (DNA adducts, genetic polymorphisms of GSTM1 and NAT2 genotypes) of women enrolled in a nested case-control study. DNA adduct levels were higher in polluted vs. control districts, in smoking vs. nonsmoking mothers, and in GSTM1 null genotype, which was more pronounced in polluted district. No effect of air pollution was observed by cytogenetic analysis of chromosomal aberrations or by comet assay. The reproductive development of young men was followed by measures of semen quality, adjusted for ambient SO(2) exposure. The analysis identified significant associations with air pollution for <13% morphologically normal sperm, <29% sperm with normal head shape, <24% motile sperm. Analysis of aneuploidy in human sperm by FISH showed, aneuploidy YY8 was associated with season of heaviest air pollution. These findings are suggestive for an influence of air pollution on YY8 disomy. All these results indicate that air pollution may increase DNA damage in human population, which may be even higher for susceptible groups. Biomarkers of exposure (DNA adducts) and susceptibility (GSTM1 and NAT2) may indicate the risk of presumable low environmental exposure. Pregnancy outcome and semen studies imply that relatively low air pollution (higher than 40 microg PM10/m(3)) can significantly increase the adverse reproductive outcomes affecting both genders.     

Impact of mental disorders on clinical outcomes of physical diseases: an umbrella review assessing population attributable fraction and generalized impact fraction

Empirical evidence indicates a significant bidirectional association between mental disorders and physical diseases, but the prospective impact of men­tal disorders on clinical outcomes of physical diseases has not been comprehensively outlined. In this PRISMA- and COSMOS-E-compliant umbrella review, we searched PubMed, PsycINFO, Embase, and Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, up to March 15, 2022, to identify systematic reviews with meta-analysis that examined the prospective association between any mental disorder and clinical outcomes of physical diseases. Primary outcomes were disease-specific mortality and all-cause mortality. Secondary outcomes were disease-specific incidence, functioning and/or disability, symptom severity, quality of life, recurrence or progression, major cardiac events, and treatment-related outcomes. Additional inclusion criteria were further applied to primary studies. Random effect models were employed, along with I² statistic, 95% prediction intervals, small-study effects test, excess significance bias test, and risk of bias (ROBIS) assessment. Associations were classified into five credibility classes of evidence (I to IV and non-significant) according to established criteria, complemented by sensitivity and subgroup analyses to examine the robustness of the main analysis. Statistical analysis was performed using a new package for conducting umbrella reviews ( https://metaumbrella.org ). Population attributable fraction (PAF) and generalized impact fraction (GIF) were then calculated for class I-III associations. Forty-seven systematic reviews with meta-analysis, encompassing 251 non-overlapping primary studies and reporting 74 associations, were included (68% were at low risk of bias at the ROBIS assessment). Altogether, 43 primary outcomes (disease-specific mortality: n=17; all-cause mortality: n=26) and 31 secondary outcomes were investigated. Although 72% of associations were statistically significant (p<0.05), only two showed convincing (class I) evidence: that between depressive disorders and all-cause mortality in patients with heart failure (hazard ratio, HR=1.44, 95% CI: 1.26-1.65), and that between schizophrenia and cardiovascular mortality in patients with cardiovascular diseases (risk ratio, RR=1.54, 95% CI: 1.36-1.75). Six associations showed highly suggestive (class II) evidence: those between depressive disorders and all-cause mortality in patients with diabetes mellitus (HR=2.84, 95% CI: 2.00-4.03) and with kidney failure (HR=1.41, 95% CI: 1.31-1.51); that between depressive disorders and major cardiac events in patients with myocardial infarction (odds ratio, OR=1.52, 95% CI: 1.36-1.70); that between depressive disorders and dementia in patients with diabetes mellitus (HR=2.11, 95% CI: 1.77-2.52); that between alcohol use disorder and decompensated liver cirrhosis in patients with hepatitis C (RR=3.15, 95% CI: 2.87-3.46); and that between schizophrenia and cancer mortality in patients with cancer (standardized mean ratio, SMR=1.74, 95% CI: 1.41-2.15). Sensitivity/subgroup analyses confirmed these results. The largest PAFs were 30.56% (95% CI: 27.67-33.49) for alcohol use disorder and decompensated liver cirrhosis in patients with hepatitis C, 26.81% (95% CI: 16.61-37.67) for depressive disorders and all-cause mortality in patients with diabetes mellitus, 13.68% (95% CI: 9.87-17.58) for depressive disorders and major cardiac events in patients with myocardial infarction, 11.99% (95% CI: 8.29-15.84) for schizophrenia and cardiovascular mortality in patients with cardiovascular diseases, and 11.59% (95% CI: 9.09-14.14) for depressive disorders and all-cause mortality in patients with kidney failure. The GIFs confirmed the preventive capacity of these associations. This umbrella review demonstrates that mental disorders increase the risk of a poor clinical outcome in several physical diseases. Prevention targeting mental disorders – particularly alcohol use disorders, depressive disorders, and schizophrenia – can reduce the incidence of adverse clinical outcomes in people with physical diseases. These findings can inform clinical practice and trans-speciality preventive approaches cutting across psychiatric and somatic medicine.     

Current Clinical Evidence on the Effect of General Anesthesia on Neurodevelopment in Children: An Updated Systematic Review with Meta-Regression

Background

Several epidemiological studies have been conducted to address the later effect of anesthesia on neurodevelopment in children. However, the results are still inconclusive.

Methods

We here conducted a systematic review and meta-analysis to summarize the currently available clinical and epidemiologic evidence on the association of anesthesia/surgery with neurodevelopmental outcomes in children by searching PubMed, EMBASE, and Web of Science database (from January-1 2000 to February-1, 2013). The evaluation of neurodevelopment includes language and learning disabilities, cognition, behavioral development, and academic performance. Both retrospective and prospective studies were included. Data were abstracted from seven eligible studies. We estimated the synthesized hazard ratios (HR) and 95% confidence interval (CI) according to inter-study heterogeneity.

Results

The pooled HR for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.25 (95% CI, 1.13–1.38, P<0.001; random-effects model) in children undergoing the first anesthesia before the age of 4-year. Then we analyzed the factors for this association using meta-regression method. It showed that it was the number of times of exposure (HR = 1.75, 95% CI 1.31–2.33; P<0.001) rather than the time at exposure before 4-year (HR = 1.08, 95% CI 0.87–1.34 for the effect of per 1-year early exposure; P = 0.47) is a risk factor for neurodevelopmental impairment.

Conclusion

The current clinical evidence suggests modestly elevated risk of adverse neurodevelopmental outcomes in children who were exposed to anesthesia/surgery during early childhood, especially for those with multiple times of exposure. Due to limitation of retrospective studies, prospective investigations are needed to determine whether anesthesia/surgery is causative.     

Cross-sectional association of Toxoplasma gondii exposure with BMI and diet in US adults

Toxoplasmosis gondii exposure has been linked to increased impulsivity and risky behaviors, which has implications for eating behavior. Impulsivity and risk tolerance is known to be related with worse diets and a higher chance of obesity. There is little known, however, about the independent link between Toxoplasma gondii (T. gondii) exposure and diet-related outcomes. Using linear and quantile regression, we estimated the relationship between T. gondii exposure and BMI, total energy intake (kcal), and diet quality as measured by the Health Eating Index-2015 (HEI) among 9,853 adults from the 2009–2014 National Health and Nutrition Examination Survey. Previous studies have shown different behavioral responses to T. gondii infection among males and females, and socioeconomic factors are also likely to be important as both T. gondii and poor diet are more prevalent among U.S. populations in poverty. We therefore measured the associations between T. gondii and diet-related outcomes separately for men and women and for respondents in poverty. Among females <200% of the federal poverty level Toxoplasmosis gondii exposure was associated with a higher BMI by 2.0 units (95% CI [0.22, 3.83]) at median BMI and a lower HEI by 5.05 units (95% CI [-7.87, -2.24]) at the 25^th percentile of HEI. Stronger associations were found at higher levels of BMI and worse diet quality among females. No associations were found among males. Through a detailed investigation of mechanisms, we were able to rule out T. gondii exposure from cat ownership, differing amounts of meat, and drinking water source as potential confounding factors; environmental exposure to T. gondii as well as changes in human behavior due to parasitic infection remain primary mechanisms.     

Health effects of static magnetic fields--a review of the epidemiological evidence

Potential health effects of static magnetic fields have received far less attention than, for example, power frequency or radiofrequency fields. Static fields are found in certain occupational settings, e.g. in the aluminium and chloralkali industries, in arc-welding processes, and certain railways systems. Magnetic resonance imaging (MRI) for medical diagnosis is another source. This paper summarizes the epidemiological evidence of static magnetic field exposure and long-term health effects. There are only a few epidemiological studies available, and the majority of these have focused on cancer risks. There are some reports on reproductive outcomes, and sporadic studies of other outcomes. Overall, few occupational studies have focused specifically on effects of static magnetic field exposure, and exposure assessment have consequently been poor or non-existent. Results from studies that have estimated static magnetic field exposure have not indicated any increased cancer risks, but they are generally based on small numbers of cases and crude exposure assessment. Control of confounding has been limited, and it is likely that the “healthy worker” effect have influenced the results. A few studies have reported results on reproductive outcomes among aluminium workers and MRI operators, but limitations in study designs prevent conclusions. A problem in epidemiological studies of static magnetic fields is that workers in exposed occupations are also exposed to a wide variety of other potentially harmful agents, including some known carcinogens. In conclusion, the available evidence from epidemiological studies is not sufficient to draw any conclusions about potential health effects of static magnetic field exposure.     

Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis.

Despite a growing number of studies that have investigated the reproductive effects of maternal cocaine use, a homogeneous pattern of fetal effects has not been established and there is little consensus on the adverse effects of the drug. We used meta-analysis to evaluate the reproductive risks of cocaine. We reviewed the 45 scientific papers published in the English language dealing with effects of cocaine used during pregnancy on pregnancy outcome in humans, and identified 20 papers eligible for meta-analysis (cocaine use in pregnancy, pregnancy/fetal outcome studies, human studies, original work, cohort or case control studies, control group present, English language). Our analysis revealed that very few adverse reproductive effects could be shown to be significantly associated with cocaine use by polydrug users when compared to control groups of polydrug users not using cocaine [genitourinary malformations; odds ratio of 6.08 (95% CI 1.18-31.3); gestation age: Cohen's d 0.37 (CI 0.2-0.55)]. When the control groups consisted of no drug users, the polydrug users abusing cocaine had a higher risk for spontaneous abortions [odds ration 10.50 (CI 11.74-64.1)]. Similarly, comparison of users of cocaine alone or no drug users revealed a higher risk for in utero death, in addition to genitourinary tract malformations. Analysis of continuous variables (head circumference, gestational age, birth weight and length) revealed that the effect size was dependent upon the nature of the comparison. Comparison of cocaine users to no drug users consistently yielded a medium effect size (Cohen's d) between 0.50 and 0.58, while comparison of polydrug/cocaine users to polydrug/no cocaine users provided effect sizes small to non existent (0.06-0.37). These discrepancies suggest that a variety of adverse reproductive effects commonly quoted to be associated with maternal use of cocaine may be caused by confounding factors clustering in cocaine users.     

Endocrine disrupting properties of perfluorooctanoic acid

Perfluoroalkyl acids (PFAAs) have attracted attention in recent years for their environmental ubiquity, as well as their toxicity. Several PFAAs are found in human tissues globally, as humans are exposed on a daily basis through intake of contaminated food, water, and air, irrespective of proximity to industry. Perfluorooctanoic acid (PFOA) is a PFAA shown to be developmentally toxic in mice, with broad and varied health consequences that may include long-lasting effects in reproductive tissues and metabolic reprogramming. To date, the only demonstrated mode of action by which the health effects of PFOA are mediated is via the activation of the peroxisome proliferator-activated receptor alpha (PPARα). The endogenous roles for this receptor, as well as the adverse outcomes of activation by exogenous agents during development, are currently under investigation. Recent studies suggest that PFOA may alter steroid hormone production or act indirectly, via ovarian effects, as a novel means of endocrine disruption. Here we review the existing literature on the known health effects of PFOA in animal models, focusing on sensitive developmental periods. To complement this, we also present epidemiologic health data, with the caveat that these studies largely address only associations between adult exposures and outcomes, rarely focusing on endocrine-specific endpoints, susceptible subpopulations, or windows of sensitivity. Further research in these areas is needed.     

Mechanisms and consequences of paternally-transmitted chromosomal abnormalities

Paternally-transmitted chromosomal damage has been associated with pregnancy loss, developmental and morphological defects, infant mortality, infertility, and genetic diseases in the offspring, including cancer. There is epidemiological evidence linking paternal exposure to occupational or environmental agents with an increased risk of abnormal reproductive outcomes. There is also a large body of literature on germ cell mutagenesis in rodents showing that treatment of male germ cells with mutagens has dramatic consequences on reproduction, producing effects such as those observed in human epidemiological studies. However, we know very little about the etiology, transmission, and early embryonic consequences of paternally-derived chromosomal abnormalities. The available evidence suggests that: 1) there are distinct patterns of germ cell-stage differences in the sensitivity of induction of transmissible genetic damage, with male postmeiotic cells being the most sensitive; 2) cytogenetic abnormalities at first metaphase after fertilization are critical intermediates between paternal exposure and abnormal reproductive outcomes; and 3) there are maternal susceptibility factors that may have profound effects on the amount of sperm DNA damage that is converted into chromosomal aberrations in the zygote and that directly affect the risk for abnormal reproductive outcomes.     

Formaldehyde exposure and leukemia: a new meta-analysis and potential mechanisms

Formaldehyde is an economically important chemical, to which more than 2 million U.S. workers are occupationally exposed. Substantially more people are exposed to formaldehyde environmentally, as it is generated by automobile engines, is a component of tobacco smoke and is released from household products, including furniture, particleboard, plywood, and carpeting. The International Agency for Research on Cancer (IARC) recently classified formaldehyde as a human carcinogen that causes nasopharyngeal cancer and also concluded that there is "strong but not sufficient evidence for a causal association between leukemia and occupational exposure to formaldehyde". Here, we review the epidemiological studies published to date on formaldehyde-exposed workers and professionals in relation to lymphohematopoietic malignances. In a new meta-analysis of these studies, focusing on occupations known to have high formaldehyde exposure, we show that summary relative risks (RRs) were elevated in 15 studies of leukemia (RR=1.54; confidence interval (CI), 1.18-2.00) with the highest relative risks seen in the six studies of myeloid leukemia (RR=1.90; 95% CI, 1.31-2.76). The biological plausibility of this observed association is discussed and potential mechanisms proposed. We hypothesize that formaldehyde may act on bone marrow directly or, alternatively, may cause leukemia by damaging the hematopoietic stem or early progenitor cells that are located in the circulating blood or nasal passages, which then travel to the bone marrow and become leukemic stem cells. To test these hypotheses, we recommend that future studies apply biomarkers validated for other chemical leukemogens to the study of formaldehyde.     

Developmental stress increases reproductive success in male zebra finches

There is increasing evidence that exposure to stress during development can have sustained effects on animal phenotype and performance across life-history stages. For example, developmental stress has been shown to decrease the quality of sexually selected traits (e.g. bird song), and therefore is thought to decrease reproductive success. However, animals exposed to developmental stress may compensate for poor quality sexually selected traits by pursuing alternative reproductive tactics. Here, we examine the effects of developmental stress on adult male reproductive investment and success in the zebra finch (Taeniopygia guttata). We tested the hypothesis that males exposed to developmental stress sire fewer offspring through extra-pair copulations (EPCs), but invest more in parental care. To test this hypothesis, we fed nestlings corticosterone (CORT; the dominant avian stress hormone) during the nestling period and measured their adult reproductive success using common garden breeding experiments. We found that nestlings reared by CORT-fed fathers received more parental care compared with nestlings reared by control fathers. Consequently, males fed CORT during development reared nestlings in better condition compared with control males. Contrary to the prediction that developmental stress decreases male reproductive success, we found that CORT-fed males also sired more offspring and were less likely to rear non-genetic offspring compared with control males, and thus had greater overall reproductive success. These data are the first to demonstrate that developmental stress can have a positive effect on fitness via changes in reproductive success and provide support for an adaptive role of developmental stress in shaping animal phenotype.     

Phthalates and other additives in plastics: human exposure and associated health outcomes

Concern exists over whether additives in plastics to which most people are exposed, such as phthalates, bisphenol A or polybrominated diphenyl ethers, may cause harm to human health by altering endocrine function or through other biological mechanisms. Human data are limited compared with the large body of experimental evidence documenting reproductive or developmental toxicity in relation to these compounds. Here, we discuss the current state of human evidence, as well as future research trends and needs.Because exposure assessment is often a major weakness in epidemiological studies, and in utero exposures to reproductive or developmental toxicants are important, we also provide original data on maternal exposure to phthalates during and after pregnancy (n = 242). Phthalate metabolite concentrations in urine showed weak correlations between pre- and post-natal samples, though the strength of the relationship increased when duration between the two samples decreased. Phthalate metabolite levels also tended to be higher in post-natal samples.In conclusion, there is a great need for more human studies of adverse health effects associated with plastic additives. Recent advances in the measurement of exposure biomarkers hold much promise in improving the epidemiological data, but their utility must be understood to facilitate appropriate study design.     

Using genetic variation to disentangle the complex relationship between food intake and health outcomes

Diet is considered as one of the most important modifiable factors influencing human health, but efforts to identify foods or dietary patterns associated with health outcomes often suffer from biases, confounding, and reverse causation. Applying Mendelian randomization in this context may provide evidence to strengthen causality in nutrition research. To this end, we first identified 283 genetic markers associated with dietary intake in 445,779 UK Biobank participants. We then converted these associations into direct genetic effects on food exposures by adjusting them for effects mediated via other traits. The SNPs which did not show evidence of mediation were then used for MR, assessing the association between genetically predicted food choices and other risk factors, health outcomes. We show that using all associated SNPs without omitting those which show evidence of mediation, leads to biases in downstream analyses (genetic correlations, causal inference), similar to those present in observational studies. However, MR analyses using SNPs which have only a direct effect on the exposure on food exposures provided unequivocal evidence of causal associations between specific eating patterns and obesity, blood lipid status, and several other risk factors and health outcomes.     

Teratogen update: inorganic arsenic

BACKGROUND: Inorganic arsenic has been used by many laboratories to study the pathogenesis of exencephaly in rodents. These studies, which used predominantly injection exposures, coupled with the paucity of epidemiology data, resulted in the erroneous inference that inorganic arsenic should be considered a human teratogen. METHODS: This study assembles and assesses literature analyses of older human and animal investigations together with the results of new experimental studies. These recent studies were performed according to modern regulatory guidelines, and relevant exposure routes (inhalation and ingestion) were used to evaluate the potential risk of developmental effects in humans. RESULTS: The existing epidemiological data are inadequate to support risk assessment because of the failure to confirm or measure arsenic exposure during early gestation and the deficiencies in accounting for potential confounding factors. The animal data revealed that inorganic arsenic caused malformations in offspring only when it was injected into the veins or peritoneal cavity of pregnant animals during early gestation. Exposure via inhalation or oral ingestion, even at concentrations that were nearly fatal to pregnant females, caused no arsenic-related malformations. CONCLUSIONS: Inorganic arsenic poses virtually no danger to developing offspring when maternal exposure occurs by relevant routes (oral and inhalation) at concentrations that are likely to be experienced in the environment or in the workplace.