Adverse Effects In Offspring Research Articles

Methylphenidate and Atomoxetine in Pregnancy and Possible Adverse Fetal Outcomes

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders, and it afflicts about 7% of young people. As a consequence, many young women might be pregnant while taking medication for ADHD, but data about safety have not yet been strictly examined. To examine adverse effects in offspring of mothers receiving treatment with atomoxetine and methylphenidate during pregnancy. Electronic databases (PubMed, Embase, and PsycINFO) were searched for articles published through December 31, 2023, with the following search terms: (atomoxetine OR methylphenidate) AND (pregnancy). Observational studies (eg, cohort studies, case-control studies, case-crossover studies, cross-sectional studies, and registry-based studies) that reported offspring outcomes in pregnancy with atomoxetine and/or methylphenidate and in mothers with ADHD but unexposed to ADHD treatment during pregnancy or from the general population were included. Ten studies of 656 records satisfied criteria. Two independent reviewers performed data extraction according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses were conducted based on reported odds ratios (ORs) and corresponding 95% CIs using a linear random effects model. Each study was inversely weighted by the reported variance of the estimators. Risk of publication bias and analysis of heterogeneity through univariate and multivariate metaregressions were also rated. Data were analyzed from January to March 2024. Study outcomes included miscarriages and congenital anomalies. Ten studies involving 16 621 481 pregnant women, 30 830 of them affected by ADHD, were included. Congenital anomalies or miscarriages were not more frequent in offspring of mothers receiving treatment with methylphenidate or atomoxetine during pregnancy compared with unexposed offspring (OR, 1.14; 95% CI, 0.83-1.55; P = .41; I2 = 8% for congenital anomalies; OR, 1.01; 95% CI, 0.70-1.47; P = .96; I2 = 0% for miscarriages) or compared with the general population (OR, 1.19; 95% CI, 0.93-1.53; P = .16; I2 = 74% for congenital anomalies; OR, 1.05, 95% CI, 0.81-1.37; P = .70; I2 = 0% for miscarriage). Evidence from this meta-analysis, which involves a substantial sample of pregnant women with and without ADHD, suggests the maintenance of methylphenidate or atomoxetine during pregnancy is safe, given that congenital anomalies and miscarriages did not appear to significantly increase. Further studies are recommended to support and confirm these findings.

Maternal PFOS exposure in mice induces hepatic lipid accumulation and inflammation in adult female offspring: Involvement of microbiome-gut-liver axis and autophagy

Perfluorooctane sulfonates (PFOS) are the persistent organic pollutants. In the present study, 0, 0.3, or 3-mg/kg PFOS were administered to pregnant mice from GD 11 to GD 18. The histopathology of liver and intestine, serum and hepatic lipid levels, lipid metabolism related genes, and gut microbiota were examined in adult female offspring. The results suggested that maternal PFOS exposure increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and induced F4/80+ macrophage infiltration in adult female offspring, in addition to the elevation of TNF-α and IL-1β mRNA levels in low-dose and high-dose groups, respectively. Furthermore, maternal exposure to PFOS increased serum triglyceride (TG) and hepatic total cholesterol (TC) levels, which was associated with the alteration of the process of fatty acid transport and β-oxidation, TG synthesis and transport, cholesterol synthesis and excretion in the liver. The AMPK/mTOR/autophagy signaling was also inhibited in the liver of adult female offspring. Moreover, changes in gut microbiota were also related to lipid metabolism, especially for the Desulfovibrio, Ligilactobacillus, Enterorhabdus, HT002 and Peptococcaceae_unclassified. Additionally, maternal exposure to PFOS decreased mRNA expressions of the tight junction protein and AB+ goblet cells in the colon, while increasing the overproduction of lipopolysaccharides (LPS) and F4/80+ macrophage infiltration. Collectively, maternal PFOS exposure induced liver lipid accumulation and inflammation, which strongly correlated with the disruption of the gut-liver axis and autophagy in adult female offspring, highlighting the persistent adverse effects in offspring exposed to PFOS.

Paternal high-fat diet altered H3K36me3 pattern of pre-implantation embryos.

The global transition towards diets high in calories has contributed to 2.1 billion people becoming overweight, or obese, which damages male reproduction and harms offspring. Recently, more and more studies have shown that paternal exposure to stress closely affects the health of offspring in an intergenerational and transgenerational way. SET Domain Containing 2 (SETD2), a key epigenetic gene, is highly conserved among species, is a crucial methyltransferase for converting histone 3 lysine 36 dimethylation (H3K36me2) into histone 3 lysine 36 trimethylation (H3K36me3), and plays an important regulator in the response to stress. In this study, we compared patterns of SETD2 expression and the H3K36me3 pattern in pre-implantation embryos derived from normal or obese mice induced by high diet. The results showed that SETD2 mRNA was significantly higher in the high-fat diet (HFD) group than the control diet (CD) group at the 2-cell, 4-cell, 8-cell, and 16-cell stages, and at the morula and blastocyst stages. The relative levels of H3K36me3 in the HFD group at the 2-cell, 4-cell, 8-cell, 16-cell, morula stage, and blastocyst stage were significantly higher than in the CD group. These results indicated that dietary changes in parental generation (F0) male mice fed a HFD were traceable in SETD2/H3K36me3 in embryos, and that a paternal high-fat diet brings about adverse effects for offspring that might be related to SETD2/H3K36me3, which throws new light on the effect of paternal obesity on offspring from an epigenetic perspective.

PREGNANCY OUTCOME AND EARLY DEVELOPMENT OF OFFSPRING IN WOMEN WITH EPILEPSY

Objectives: The aim of the study was to evaluate the outcome of pregnancy and early development of offspring, in women with epilepsy (WWE) who were receiving and not receiving anti-epileptic drugs (AED). Methods: Women with epilepsy who delivered in a teaching hospital (n=60), between November 2017 and October 2018, were identified from the delivery records (n=5202) and their infants (n=39) underwent developmental assessment by Baroda development screening test. Maternal epilepsy syndrome, AEDs during pregnancy, and other details were obtained from medical records and interview. Results: Fourteen mothers received monotherapy, 15 polytherapy and 10 mothers were not taking any AED. There were four major congenital malformations (MCM) among 39 babies. Two were cardiac malformations; one was complex anomaly, caused death in neonate and other was ventricular septal defect (VSD). Both occurred in babies of mothers receiving clobazam in combination with oxcarbazepine and levetiracetam, respectively. There were two urological anomalies in babies unexposed to AEDs. When mothers were receiving monotherapy (14), normal Development Quotient score (DQ score) was observed in 11 babies, but low DQ score was observed in three. In the polytherapy group (15), normal DQ scores were found in five and low DQ in nine (one baby died neonatally). Among the group who were unexposed to AED (10), normal DQ score was found in eight, but low DQ in two (in the antenatal period mother of one of the low DQ babies reported frequent major seizures). Conclusion: Clobazam therapy is a risk factor for developing MCM in babies of WWE. Oxcarbazepine, monotherapy or polytherapy, and Clobazam polytherapy are risk factors for low DQ scores in the offspring of WWE. Polytherapy and frequent seizures during pregnancy are also risk factors for low DQ scores. Widely used drugs which were considered safe demonstrated adverse effects in offspring. Even though sample size is small, it is a matter of concern and curiosity.

Implementation of a healthy diet to lactating rats attenuates the early detrimental programming effects in the offspring born to obese dams. Putative relationship with milk hormone levels

Lactation is a critical period of development and alterations in milk composition due to maternal diet or status may affect infant growth. We aimed to evaluate in rats whether improving maternal nutrition during lactation attenuates early imprinted adverse metabolic effects in the offspring born to obese dams. Three groups were studied: Control (C) dams, fed with standard diet; Western diet (WD) dams, fed with WD 1 month prior to gestation and during gestation and lactation; and Reversion (Rev) dams, fed as WD-dams, but moved to a standard diet during lactation. Macronutrient content, insulin, leptin and adiponectin levels were determined in milk. Phenotypic traits and circulating parameters in dams and their offspring were determined throughout lactation. Results showed that, at weaning, WD-dams displayed lower body weight and greater plasma insulin and non-esterified fatty acids levels than C-dams, and signs of hepatic steatosis. Milk from WD-dams showed lower protein content and insulin, leptin, and adiponectin levels during the entire or the late lactation. Rev-dams retained excess body fat content, but milk composition and most circulating parameters were not different from controls at late lactation and showed higher leptin mRNA levels in mammary gland than WD-dams. The offspring of WD-dams, but not that of Rev-dams, displayed higher body weight, adiposity, and circulating leptin and glucose levels than controls at weaning. In conclusion, dietary improvement during lactation prevents early adverse effects in offspring associated with maternal intake of an obesogenic diet, that may be related with the normalization of milk hormone levels.

Maternal Overnutrition During Gestation in Sheep Alters Autophagy Associated Pathways in Offspring Heart.

Poor maternal nutrition during gestation can negatively affect offspring growth, development, and health pre- and post-natally. Overfeeding during gestation or maternal obesity (MO) results in altered metabolism and imbalanced endocrine hormones in animals and humans which will have long-lasting and detrimental effects on offspring growth and health. In this study, we examined the effects of overnutrition during gestation on autophagy associated pathways in offspring heart muscles at two gestational and one early postnatal time point (n = 5 for treated and untreated male and female heart respectively at each time point). Two-way ANOVA was used to analyze the interaction between treatment and sex at each time point. Our results revealed significant interactions of maternal diet by developmental stages for offspring autophagy signaling. Overfeeding did not affect the autophagy signaling at mid-gestation day 90 (GD90) in both male and female offspring while the inflammatory cytokines were increased in GD90 MO male offsrping; however, overfeeding during gestation significantly increased autophagy signaling, but not inflammation level at a later developmental stage (GD135 and day 1 after birth) in both males and females. We also identified a sexual dimorphic response in which female progeny were more profoundly influenced by maternal diet than male progeny regardless of developmental stages. We also determined the cortisol concentrations in male and female hearts at three developmental stages. We did not observe cortisol changes between males and females or between overfeeding and control groups. Our exploratory studies imply that MO alters autophagy associated pathways in both male and female at later developmental stages with more profound effects in female. This finding need be confirmed with larger sample numbers in the future. Our results suggest that targeting on autophagy pathway could be a strategy for correction of adverse effects in offspring of over-fed ewes.

Metformin therapy in pregnancy [Zastosowanie metforminy w ciąży

Gestational diabetes mellitus (GDM), i.e. a carbohydrate metabolism disorder at pregnancy, is one of the most common metabolic complications that occur during this period. Pancreatic b-cell dysfunction and insulin resistance during pregnancy are considered the main causes of the condition. It is currently estimated that GDM is confirmed in 1-25% of patients. Diagnosis and appropriate management allow to reduce the risk of complications in newborns and the perinatal mortality rate and also improve the prognosis for mother and offspring. Metformin is taken by many patients before pregnancy due to both previously diagnosed type 2 diabetes and in the treatment of prediabetes, obesity and polycystic ovary syndrome (PCOS) as part of therapy for insulin resistance. The use of metformin in pregnancy has been controversial for many years, particularly in terms of the safety of continuation of drug therapy. Available scientific data indicate both benefits and possible drug-related adverse effects in offspring of metformin-treated patients. This problem is related not only to patients with type 2 diabetes, but also to those with PCOS who are at increased risk of miscarriage, preterm delivery and the diagnosis of GDM in subsequent stages of pregnancy. Conclusive and uniform recommendations for the use of metformin at each stage of pregnancy have not been established yet due to the doubts about the mechanisms of action of the drug, particularly at the cellular level. This review paper presents the current state of knowledge on the use of metformin during pregnancy.

Offspring outcomes after prenatal interventions for common mental disorders: a meta-analysis

BackgroundIt is presumed that pharmacological and non-pharmacological treatment of prenatal common mental disorders can mitigate associated adverse effects in offspring, yet strong evidence for the prophylactic benefits of treatment is lacking. We therefore examined the effect of prenatal treatments for common mental disorders on offspring outcomes.MethodsFor this meta-analysis, articles published up to August 31, 2017, were obtained from PubMed, PsycInfo, Embase, and Cochrane databases. Included studies needed to be randomized controlled trials (RCTs) on the effect of treatment of prenatal common mental disorders comparing an intervention to a control condition, including offspring outcome(s). Random effects models were used to calculate Hedges’ g in the program Comprehensive Meta-Analysis© (version 3.0).ResultsSixteen randomized controlled trials among 2778 pregnant women compared offspring outcomes between prenatal interventions and control groups. There were zero pharmacological, 13 psychological, and three other interventions (homeopathy, relaxation interventions, and short psycho-education). Birth weight (mean difference 42.88 g, g = 0.08, 95% CI −0.06 to 0.22, p = 0.27, n = 11), Apgar scores (g = 0.13, 95% CI −0.28 to 0.54, p = 0.53, n = 4), and gestational age (g = 0.03, 95% CI −0.06 to 0.54, p = 0.49, n = 10) were not significantly affected. Other offspring outcomes could not be meta-analyzed due to the inconsistent reporting of offspring outcomes and an insufficient number of studies.ConclusionsNon-pharmacological interventions had no significant effect on birth outcomes, although this outcome should be considered with caution due to the risk of biases. No randomized controlled trial examined the effects of prenatal pharmacological treatments as compared to treatment as usual for common mental disorders on offspring outcomes. Present clinical guidelines may require more research evidence on offspring outcomes, including child development, in order to warrant the current recommendation to routinely screen and subsequently treat prenatal common mental disorders.Trial registrationPROSPERO CRD42016047190

Conjugated Linoleic Acid Supplementation Improves Maternal High Fat Diet-Induced Programming of Metabolic Dysfunction in Adult Male Rat Offspring

The developmental origins of health and disease hypothesis proposes that an adverse early life environment, including in utero exposure to a maternal obesogenic environment, can lead to an increased long-term risk of obesity and related metabolic complications in offspring. We assessed whether maternal supplementation with conjugated linoleic acid (CLA) could prevent some of these adverse effects in offspring exposed to a maternal high fat diet. Sprague-Dawley dams consumed either a: control (CD), control with CLA (CLA), high fat (HF) or high fat with CLA (HFCLA) diet 10 days prior to mating and throughout pregnancy/lactation. Male offspring were weaned onto a standard chow diet. Body composition was quantified by DXA and oral glucose tolerance tests conducted on adult offspring. Gene/protein expression and histological analysis were conducted in adipose tissue. Offspring from HF dams had increased body weight, body fat deposition, impaired insulin sensitivity and adipocyte hypertrophy; all of which were rescued in HFCLA offspring. Molecular and histological analyses of the adipose tissue suggest that disturbances in adipogenesis may mediate the metabolic dysfunction observed in HF offspring. Therefore, CLA supplementation to a maternal obesogenic diet may be a promising strategy to prevent adverse programming outcomes.

In Utero Exposure to Antihypertensive Medication During Pregnancy and Neonatal and Child Health Outcomes

ABSTRACTBackgroundAlthough pharmacotherapy is to be avoided wherever possible during pregnancy, aggressive pharmacotherapy is required for the treatment of pregnancy associated hypertension, which remains a leading cause of morbidity and mortality in the UK. While the teratogenic effects of angiotensin-converting enzyme inhibitors are well documented, the possible long term effects, on the child, following in utero exposure to other antihypertensive agents remains unknown. 
 ApproachThe aim of this study was to systematically review all published literature relevant to possible adverse outcomes on the child associated with in utero exposure to antihypertensive medications. OVID (Medline, Embase), Scopus, EBSCO Collections (PsycINFO, CINAHL), The Cochrane Library and Web of Science databases were searched from January 1950 to January 2016 and a total of 688 papers were identified. Following review 43 primary studies and 4 Meta-analyses were eligible for inclusion. The Critical Appraisal Skills Programme (CASP) checklists were used to assess study quality. ResultsThree studies were of excellent quality the remainder were either mediocre or poor. Increased risk of low birth weight, low size for gestational age, preterm birth and congenital defects following in utero exposure to all antihypertensive agents were identified. The clinical importance of these reported risks is unclear, as many study findings were based on small case numbers. Four studies of mediocre quality reported on the relationship between in utero exposure and neurological adverse effects in offspring. Two studies reported an increased risk of attention deficit hyperactivity disorder following exposure to labetalol, and an increased risk of sleep disorders following exposure to methyldopa and clonidine. The remaining two studies identified no such associations. ConclusionsThis systematic review demonstrates a lack of published high quality studies. Available published studies indicate an increased risk of adverse child health outcomes, although it is unclear whether these outcomes are clinically significant. This review is the first step in a larger project, which is exploring child health outcomes in Scotland following in utero exposure to antihypertensive and psychotropic medications. Dispensed drug data will be used to identify mothers who have been prescribed antihypertensive or psychotropic medication during pregnancy. National databases (PIS, SMR02, SMR01, etc.) will be used to cross-link mother and child data to identify in utero exposure to the drugs of interest, and the resulting child outcomes. All aspects of child health outcomes will be assessed to identify possible adverse effects from in utero exposure to medications.

Association Between Pandemic Influenza A(H1N1) Vaccination in Pregnancy and Early Childhood Morbidity in Offspring

Several studies investigating potential adverse effects of the pandemic A(H1N1) vaccine have supported that influenza A(H1N1) vaccination does not increase the risk for major pregnancy and birth adverse outcomes, but little is known about possible adverse effects in offspring of A(H1N1)-vaccinated mothers beyond the perinatal period and into early childhood. To evaluate whether pandemic influenza A(H1N1) vaccination in pregnancy increases the risk for early childhood morbidity in offspring. Register-based cohort study comprising all live-born singleton children in Denmark from pregnancies overlapping the A(H1N1) influenza vaccination campaign in Denmark, from November 2, 2009, to March 31, 2010. From a cohort of 61 359 pregnancies, offspring exposed and unexposed to the influenza A(H1N1) vaccine during pregnancy were matched 1:4 on propensity scores. Vaccination in pregnancy with a monovalent inactivated AS03-adjuvanted split virion influenza A(H1N1)pdm09 vaccine (Pandemrix; GlaxoSmithKline Biologicals). Rate ratios of hospitalization in early childhood until 5 years of age. Hospitalization was defined as (1) first inpatient hospital admission, (2) all inpatient hospital admissions, and (3) first hospital contact for selected diseases, which included individual infectious diseases and individual neurologic, autoimmune, and behavioral conditions. The mean (SD) age at end of follow-up was 4.6 (0.40) years for the 61 359 children included in the study. In the cohort, the mothers of 55 048 children were unvaccinated, 349 mothers were vaccinated in the first trimester, and 5962 mothers were vaccinated in the second or third trimesters. Children exposed in the first trimester were not more likely to be hospitalized in early childhood than unexposed children (hospitalization rates per 1000 person-years, 300.6 for exposed vs 257.5 for unexposed; rate ratio, 1.17; 95% CI, 0.94-1.45). Similarly, children exposed in the second or third trimester were not more likely to be hospitalized in early childhood than unexposed children (hospitalization rates per 1000 person-years, 203.6 for exposed vs 219.3 for unexposed; rate ratio, 0.93; 95% CI, 0.87-0.99). This 7% decreased risk was primarily a result of reduced risks for infectious disease-related hospitalizations. To our knowledge, this is the most comprehensive study to date of potential adverse effects manifesting after the perinatal period. We detected no increased risk for early childhood morbidity. These results support the safety profile of the influenza A(H1N1) vaccine used in pregnancy.

Pharmacokinetic study of adverse effects in offspring caused by prenatal Bisphenol F exposure

Pharmacokinetic study of adverse effects in offspring caused by prenatal Bisphenol F exposure

Maternal methylmercury from a wild-caught walleye diet induces developmental abnormalities in zebrafish

Maternal methylmercury (MeHg) exposure from a contaminated diet causes adverse effects in offspring, but the underlying mechanism(s) remains unclear. In the present study, we investigated the effects of maternal dietary MeHg-exposure on the offspring, using the zebrafish (Danio rerio) as a model system. Female zebrafish were exposed to MeHg (0.88–3.10ppm) by consuming a diet made from wild-caught walleye originally intended for human consumption. While dietary MeHg exposure did not significantly influence fecundity, offspring showed increases in morphologic alterations and mortality, neurobehavioral dysfunction, and dysregulation of global gene expression. Gene expression analysis suggested that MeHg might affect neuronal and muscular development via dysregulation of genes related to transcriptional regulation (such as supt5h) and cell cycle (such as ccnb1). Results from this study provide evidence that food intended for human consumption, with relatively modest levels of MeHg, may induce adverse effects in offspring.

No Adverse Effects in Offspring Exposed to Maternal Cancer During Pregnancy

The potential effects of maternal cancer and cancer therapies during pregnancy on future development outcomes of the fetus remains a concern. To examine this issue, researchers in Europe conducted a prospective case-control study comparing general health, postnatal cognition, and cardiac function in early childhood between 129 offspring of mothers diagnosed with cancer during pregnancy and a matched control group. …

Maternal effects underlie ageing costs of growth in the zebra finch (Taeniopygia guttata).

Maternal effects provide a mechanism to adapt offspring phenotype and optimize the mother’s fitness to current environmental conditions. Transferring steroids to the yolk is one way mothers can translate environmental information into potential adaptive signals for offspring. However, maternally-derived hormones might also have adverse effects for offspring. For example, recent data in zebra finch chicks suggested that ageing related-processes (i.e. oxidative stress and telomere loss) were increased after egg-injection of corticosterone (CORT). Still, we have few experimental data describing the effect of maternal effects on the growth-ageing trade-off in offspring. Here, we chronically treated pre-laying zebra finch females (Taeniopygia guttata) with 17-β-estradiol (E2) or CORT, and followed offspring growth and cellular ageing rates (oxidative stress and telomere loss). CORT treatment decreased growth rate in male chicks and increased rate of telomere loss in mothers and female offspring. E2 increased body mass gain in male offspring, while reducing oxidative stress in both sexes but without affecting telomere loss. Since shorter telomeres were previously found to be a proxy of individual lifespan in zebra finches, maternal effects may, through pleiotropic effects, be important determinants of offspring life-expectancy by modulating ageing rate during embryo and post-natal growth.

Iodine Supplements During and After Pregnancy

Dr Stagnaro-Green and colleagues1 argued that a randomized controlled trial (RCT) of iodine in pregnancy would be unethical because many international bodies recommend additional iodine intake, largely for the prevention of cognition-related adverse effects in offspring.

Prenatal fluoxetine exposure induces life-long serotonin 5-HT 3 receptor-dependent cortical abnormalities and anxiety-like behaviour

Selective serotonin reuptake inhibitors (SSRIs) are the first choice of drugs to treat depression and anxiety during pregnancy. However, there is evidence that in utero exposure to SSRIs leads to adverse effects in offspring. Here we show that in mice, the adverse effects of the widely used antidepressant and SSRI fluoxetine are critically dependent on the 5-HT 3 receptor, the only ligand-gated ion channel in the family of serotonin receptors. In utero exposure to fluoxetine induces anxiety-like behavior in wildtype, but not in mice lacking the 5-HT 3 receptor. In addition to this behavioral phenotype, these mice show life-long abnormalities of cortical cytoarchitecture, which can be reversed in vitro by pharmacological block of 5-HT 3 receptors. Moreover, the effect of fluoxetine on the development of cortical neurons is absent in 5-HT 3 receptor knockout mice. These findings pinpoint the pivotal role of serotonergic signaling during development and provide a novel basis to investigate the adverse effects of the use of fluoxetine during pregnancy. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Cellular and Mitochondrial Effects of Alcohol Consumption

Alcohol dependence is correlated with a wide spectrum of medical, psychological, behavioral, and social problems. Acute alcohol abuse causes damage to and functional impairment of several organs affecting protein, carbohydrate, and fat metabolism. Mitochondria participate with the conversion of acetaldehyde into acetate and the generation of increased amounts of NADH. Prenatal exposure to ethanol during fetal development induces a wide spectrum of adverse effects in offspring, such as neurologic abnormalities and pre- and post-natal growth retardation. Antioxidant effects have been described due to that alcoholic beverages contain different compounds, such as polyphenols as well as resveratrol. This review analyzes diverse topics on the alcohol consumption effects in several human organs and demonstrates the direct participation of mitochondria as potential target of compounds that can be used to prevent therapies for alcohol abusers.

CNS effects of developmental Pb exposure are enhanced by combined maternal and offspring stress

Lead (Pb) exposure and elevated stress are co-occurring risk factors. Both impact brain mesolimbic dopamine/glutamate systems involved in cognitive functions. We previously found that maternal stress can potentiate Pb-related adverse effects in offspring at blood Pb levels averaging approximately 40 μg/dl. The current study of combined Pb exposure and stress sought to extend those results to lower levels of Pb exposure, and to examine relationships among consequences in offspring for fixed interval (FI) schedule-controlled behavior, neurochemistry and corticosterone levels. Dams were exposed to maternal Pb beginning 2 months prior to breeding (0, 50 or 150 ppm in drinking water), maternal restraint stress on gestational days 16 and 17 (MS), or the combination. In addition, a subset of offspring from each resultant treatment group was also exposed intermittently to variable stressors as adults (MS + OS). Marked “Pb-stress”-related increases in response rates on a fixed interval schedule, a behavioral performance with demonstrated sensitivity to Pb, occurred preferentially in female offspring even at mean blood Pb levels of 11 μg/dl when 50 ppm Pb was combined with maternal and offspring stress. Greater sensitivity of females to frontal cortex catecholamine changes may contribute to the elevated FI response rates as mesocorticolimbic systems are critical to the mediation of this behavior. Basal and final corticosterone levels of offspring used to evaluate FI performance differed significantly from those of non-behaviorally tested (NFI) littermates, demonstrating that purported mechanisms of Pb, stress or Pb/stress effects determined in non-behaviorally trained animals cannot necessarily be generalized to animals with behavioral histories. Finally, the persistent and permanent consequences of Pb, stress and Pb + stress in offspring of both genders suggest that Pb screening programs should include pregnant women at risk for elevated Pb exposure, and that stress should be considered as an additional risk factor. Pb + stress effects observed in the absence of either risk factor alone (i.e., potentiated effects) raise questions about the capacity of current hazard identification approaches to adequately identify human health risks posed by neurotoxicants.

Effect of ATM heterozygosity on heritable DNA damage in mice following paternal F 0 germline irradiation

The ataxia telangiectasia mutated (ATM) gene product maintains genome integrity and initiates cellular DNA repair pathways following exposures to genotoxic agents. ATM also plays a significant role in meiotic recombination during spermatogenesis. Fertilization with sperm carrying damaged DNA could lead to adverse effects in offspring including developmental defects or increased cancer susceptibility. Currently, there is little information regarding the effect of ATM heterozygosity on germline DNA repair and heritable effects of paternal germline-ionizing irradiation. We used neutral pH comet assays to evaluate spermatozoa 45 days after acute whole-body irradiation of male mice (0.1 Gy, attenuated 137Cs γ rays) to determine the effect of ATM heterozygosity on delayed DNA damage effects of Type A/B spermatogonial irradiation. Using the neutral pH sperm comet assay, significant irradiation-related differences were found in comet tail length, percent tail DNA and tail extent moment, but there were no observed differences in effect between wild-type and ATM +/− mice. However, evaluation of spermatozoa from third generation descendants of irradiated male mice for heritable chromatin effects revealed significant differences in DNA electrophoretic mobility in the F 3 descendants that were based upon the irradiated F 0 sire's genotype. In this study, radiation-induced chromatin alterations to Type A/B spermatogonia, detected in mature sperm 45 days post-irradiation, led to chromatin effects in mature sperm three generations later. The early cellular response to and repair of DNA damage is critical and appears to be affected by ATM zygosity. Our results indicate that there is potential for heritable genetic or epigenetic changes following Type A/B spermatogonial irradiation and that ATM heterozygosity increases this effect.