Pediatric leukemia and maternal occupational exposure to anticancer drugs: the Japan Environment and Children's Study.

ABSTRACT: Occupational exposure to medical agents and ionizing radiation has been suggested as a possible risk factor for childhood cancer. However, the relationship between such exposure and pediatric malignant neoplasms has not yet been comprehensively studied. This cohort study aimed to investigate the association between parental occupational exposure to hazardous medical agents or ionizing radiation and the risk of childhood cancer in offspring. Data from a large birth cohort in Japan, which included 104 062 fetuses, were analyzed. The primary outcome was the development of leukemia or brain tumors diagnosed by community physicians during the first 3 years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for 3 months before conception. The incidence of leukemia, but not of brain tumors, was higher in mothers exposed to anticancer drugs. Multivariable regression analysis showed that maternal exposure to anticancer drugs was associated with an increased risk of leukemia in offspring older than 1 year (adjusted relative risk, 7.99 [95% confidence interval, 1.98-32.3]). Detailed information obtained from medical certificates of patients with identified leukemia revealed no infant leukemia but acute lymphoblastic leukemias in the exposed group. Our findings suggest that maternal occupational exposure to anticancer drugs may be a potential risk factor for acute lymphoblastic leukemia in offspring older than 1 year. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignant neoplasms.

Maternal and Paternal Household Pesticide Exposure During Pregnancy and Risk of Childhood Acute Lymphoblastic Leukemia.

OBJECTIVE: The aim of this study was to investigate whether risk estimates for childhood acute lymphoblastic leukemia change when restricting model comparison groups to "nonpesticide exposure" (NPE10) households. METHODS: Cases ( n = 1810) 15 years or younger were identified through Children's Cancer Group institutions between 1989 and 1993 and age-/sex-matched to controls ( n = 1951). Household pesticide use during pregnancy/month prior was collected via telephone. NPE10 comparison group reporting no parental exposure to 10 pesticide classes was identified. RESULTS: Adjusted odds ratios increased from 15% to 49% when limiting the comparison to NPE10. Maternal termite insecticide exposure was associated with greatest risk (adjusted odds ratio, 4.21; 95% confidence interval, 2.00-8.88). There was minimal evidence of interaction by child sex or occupational pesticide exposure, and no monotonic dose-response pattern with frequency of use (times per year). CONCLUSIONS: Elevated risks are consistent with published pooled-/meta-analyses and DNA damage. The consistency and magnitude of these associations warrant product labeling, exposure reduction interventions, or both.

Paternal genetic intergenerational and transgenerational effects of cadmium exposure on hormone synthesis disorders in progeny ovarian granulosa cells.

To investigate the paternal genetic effects of cadmium (Cd) exposure on hormone synthesis disorders in the ovarian granulosa cells (GCs) of offspring. Here, male Sprague‒Dawley (SD) rats were gavaged with CdCl2 (0, 0.5, 2, 8 mg/kg) from postnatal day (PND) 28-56, followed by mating with newly purchased healthy adult females to produce F1, and F1 adult males (PND 56) were mated with newly purchased healthy adult females to produce F2. The serum levels of estradiol (E2) and progesterone (Pg) decreased in F1 but essentially returned to normal in F2. The levels of StAR, CYP11A1, CYP17A1, CYP19A1, and SF-1 showed different alterations in F1 and F2 ovarian GCs. The expression patterns of miRNAs and imprinted genes related to hormone synthesis in GCs of F1 and F2 differed, but methylation of hormone synthesis-related genes was not significantly altered (except for individual loci in F1). In addition, there were significant changes in the expression of imprinted genes and miRNAs in F0 and F1 sperm. We conclude that paternal Cd exposure causes intergenerational genetic effects (hormone synthesis disorders) and transgenerational effects (reparative changes in hormone synthesis function) in ovarian GCs. These genetic effects were related to the downregulation of StAR in F1 and the upregulation of CYP17A1, CYP19A1, StAR and SF-1 in F2. Important changes in miRNAs and imprinted genes were also observed, but not all alterations originated from paternal inheritance.

Paternal Nicotine/Ethanol/Caffeine Mixed Exposure Induces Offspring Rat Dysplasia and Its Potential "GC-IGF1" Programming Mechanism.

Clinical and animal studies suggest that paternal exposure to adverse environments (bad living habits and chronic stress, etc.) has profound impacts on offspring development; however, the mechanism of paternal disease has not been clarified. In this study, a meta-analysis was first performed to suggest that paternal exposure to nicotine, ethanol, or caffeine is a high-risk factor for adverse pregnancy outcomes. Next, we created a rat model of paternal nicotine/ethanol/caffeine mixed exposure (PME), whereby male Wistar rats were exposed to nicotine (0.1 mg/kg/d), ethanol (0.5 g/kg/d), and caffeine (7.5 mg/kg/d) for 8 weeks continuously, then mated with normal female rats to obtain a fetus (n = 12 for control group, n = 10 for PME group). Then, we analyzed the changes in paternal hypothalamic-pituitary-adrenal (HPA) axis activity, testicular function, pregnancy outcomes, fetal serum metabolic indicators, and multiple organ functions to explore the mechanism from the perspective of chronic stress. Our results demonstrated that PME led to enhanced paternal HPA axis activity, decreased sperm quality, and adverse pregnancy outcomes (stillbirth and absorption, decreased fetal weight and body length, and intrauterine growth retardation), abnormal fetal serum metabolic indicators (corticosterone, glucolipid metabolism, and sex hormones), and fetal multi-organ dysfunction (including hippocampus, adrenal, liver, ossification, and gonads). Furthermore, correlation analysis showed that the increased paternal corticosterone level was closely related to decreased sperm quality, adverse pregnancy outcomes, and abnormal offspring multi-organ function development. Among them, the decreased activity of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis may be the main mechanism of offspring development and multi-organ dysfunction caused by PME. This study explored the impact of common paternal lifestyle in daily life on offspring development, and proposed the GC-IGF1 programming mechanisms of paternal chronic stress-induced offspring dysplasia, which provides a novel insight for exploring the important role of paternal chronic stress in offspring development and guiding a healthy lifestyle for men.

The safety of paternal and maternal use of 5-aminosalicylic acid during conception and pregnancy: a nationwide cohort study.

BACKGROUND: Data on the safety of paternal use of 5-aminosalicylic acid (5-ASA) prior to conception are lacking, and the safety of maternal use of 5-ASA during pregnancy has not been examined in nationwide data. AIMS: To examine offspring outcomes after paternal pre-conception use of 5-ASA, and after maternal use during pregnancy METHODS: This nationwide cohort study was based on Danish health registries. The study population included live born singletons of patients with ulcerative colitis (UC) or Crohn's disease (CD). Paternal exposure included 2168 children fathered by men treated with 5-ASA, and 7732 unexposed. Maternal exposure included 3618 children exposed in utero to 5-ASA, and 7128 unexposed. The outcomes were pre-term birth, small for gestational age (SGA), low Apgar score and major congenital abnormalities (CAs) according to EUROCAT guidelines. RESULTS: The vast majority of fathers and mothers used mesalazine. In children fathered by men with UC using 5-ASA, we found no increased risk of pre-term birth, SGA or low Apgar score. The hazard ratio (HR) of CAs was 1.30 (95% CI 0.92-1.85). In children of fathers with CD, the odds ratio (OR) of SGA was 1.52 (95% CI 0.65-3.55). After maternal 5-ASA exposure, the OR of SGA in children of women with UC was 1.46 (95% CI: 0.93-2.30); for CAs in children of women with CD, HR was 1.44 (95% CI 0.84-2.47). CONCLUSIONS: Paternal and maternal use of 5-ASA was safe across offspring outcomes; none of the findings reached statistical significance. The safety of 5-ASA formulations that are used infrequently cannot be settled here.

Paternal nicotine taking elicits heritable sex-specific phenotypes that are mediated by hippocampal Satb2.

Nicotine intake, whether through tobacco smoking or e-cigarettes, remains a global health concern. An emerging preclinical literature indicates that parental nicotine exposure produces behavioral, physiological, and molecular changes in subsequent generations. However, the heritable effects of voluntary parental nicotine taking are unknown. Here, we show increased acquisition of nicotine taking in male and female offspring of sires that self-administered nicotine. In contrast, self-administration of sucrose and cocaine were unaltered in male and female offspring suggesting that the intergenerational effects of paternal nicotine taking may be reinforcer specific. Further characterization revealed memory deficits and increased anxiety-like behaviors in drug-naive male, but not female, offspring of nicotine-experienced sires. Using an unbiased, genome-wide approach, we discovered that these phenotypes were associated with decreased expression of Satb2, a transcription factor known to play important roles in synaptic plasticity and memory formation, in the hippocampus of nicotine-sired male offspring. This effect was sex-specific as no changes in Satb2 expression were found in nicotine-sired female offspring. Finally, increasing Satb2 levels in the hippocampus prevented the escalation of nicotine intake and rescued the memory deficits associated with paternal nicotine taking in male offspring. Collectively, these findings indicate that paternal nicotine taking produces heritable sex-specific molecular changes that promote addiction-like phenotypes and memory impairments in male offspring.

Environmental Exposures and Congenital Heart Disease.

Congenital heart disease (CHD) is the most common congenital abnormality worldwide, affecting 8 to 12 infants per 1000 births globally and causing >40% of prenatal deaths. However, its causes remain mainly unknown, with only up to 15% of CHD cases having a determined genetic cause. Exploring the complex relationship between genetics and environmental exposures is key in understanding the multifactorial nature of the development of CHD. Multiple population-level association studies have been conducted on maternal environmental exposures and their association with CHD, including evaluating the effect of maternal disease, medication exposure, environmental pollution, and tobacco and alcohol use on the incidence of CHD. However, these studies have been done in a siloed manner, with few examining the interplay between multiple environmental exposures. Here, we broadly and qualitatively review the current literature on maternal and paternal prenatal exposures and their association with CHD. We propose using the framework of the emerging field of the exposome, the environmental complement to the genome, to review all internal and external prenatal environmental exposures and identify potentiating or alleviating synergy between exposures. Finally, we propose mechanistic pathways through which susceptibility to development of CHD may be induced via the totality of prenatal environmental exposures, including the interplay between placental and cardiac development and the internal vasculature and placental morphology in early stages of pregnancy.

Increased Frequency of Copy Number Variations Revealed by Array Comparative Genomic Hybridization in the Offspring of Male Mice Exposed to Low Dose-Rate Ionizing Radiation.

There is very little information on the transgenerational or genetic effects of low dose-rate ionizing radiation. We report the detection of the transgenerational effects of chronic low dose-rate irradiation in mice, at the molecular level in the whole genome, using array comparative genomic hybridization technology. We observed that the number of the mice with de novo copy number variations (specifically, deletions) was significantly increased in the offspring of C57BL/6J male mice exposed to 20 mGy/day gamma-rays for 400 days (total dose: 8000 mGy), as compared to non-irradiated controls. We did not detect any difference in the size of the de novo deletions between the irradiated and the non-irradiated groups. An analysis of the life span of the offspring suggested a possibility that de novo copy-number variations may be associated with shorter life spans.

The effects of cadmium on the development of Drosophila and its transgenerational inheritance effects.

A new focus in toxicology research is the impact of parental exposure to environmental toxic substances on the characteristics of offspring. In the present study, newly produced eggs of Drosophila melanogaster were treated with different concentrations of cadmium (0, 1, 2, 4, 8 mg/kg) to study the effects of development. The results showed that cadmium changed the larval body length and weight, prolonged the pupation and eclosion time, and changed the relative expression levels of development-related genes (baz, ß-Tub60D, tj). Furthermore, the parental Drosophila (F0) were treated with cadmium (4.5 mg/kg) from egg stage, and when grows to adults, they mated in standard medium to produce the de-stressed offspring (F1-F4) to assess the transgenerational effects of developmental delay. The results showed that the delayed effects of the pupation and eclosion time could be maintained for two generations, and the inhibiting effects of juvenile hormone (JH) and ecdysone (20-hydroxyecdysone, 20E) could be maintained for two or three generations. More importantly, cadmium increased the expression of DNA methylation-related genes (dDnmt2, dMBD2/3) in the ovaries (F0-F2) and testicles (F0 and F1). In addition, cadmium accumulated in parental Drosophila (F0) was not transmitted to offspring through reproductive pathway. These results demonstrate that the developmental toxicity caused by cadmium could be transmitted to the de-stressed offspring, and the observed transgenerational inheritance effects may be associated with epigenetic regulation, underscoring the need to consider fitness of future generations in evaluating the toxicity and environmental risks of cadmium.

Paternal Cannabis Exposure Prior to Mating, but Not Δ9-Tetrahydrocannabinol, Elicits Deficits in Dopaminergic Synaptic Activity in the Offspring.

The legalization and increasing availability of cannabis products raises concerns about the impact on offspring of users, and little has appeared on the potential contribution of paternal use. We administered cannabis extract to male rats prior to mating, with two different 28-day exposures, one where there was a 56-day interval between the end of exposure and mating ("Early Cannabis"), and one just prior to mating ("Late Cannabis"); the extract delivered 4 mg/kg/day of the main psychoactive component, Δ9-tetrahydrocannabinol. We then assessed the impact on dopamine (DA) systems in the offspring from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), measuring the levels of DA and its primary metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) in various brain regions. Paternal cannabis with either regimen elicited a profound and persistent deficit in DA utilization (DOPAC/DA ratio) in the offspring, indicative of subnormal presynaptic activity. However, the two regimens differed in the underlying mechanism, with Early Cannabis reducing DOPAC whereas Late Cannabis increased DA and elicited a smaller reduction in DOPAC. Effects were restricted to male offspring. The effects of cannabis were not reproduced by equivalent exposure to its Δ9-tetrahydrocannabinol, nor did we see the effects with perinatal exposure to tobacco smoke or some of its fetotoxic contributors (benzo[a]pyrene without or with nicotine). Our studies provide some of the first evidence for adverse effects of paternal cannabis administration on neurodevelopment in the offspring, and reinforce the important consequences of paternal drug use in the preconception period.

Exposures during the prepuberty period and future offspring's health: evidence from human cohort studies†.

Emerging evidence suggests that exposures in prepuberty, particularly in fathers-to-be, may impact the phenotype of future offspring. Analyses of the RHINESSA cohort find that offspring of father's exposed to tobacco smoking or overweight that started in prepuberty demonstrate poorer respiratory health in terms of more asthma and lower lung function. A role of prepuberty onset smoking for offspring fat mass is suggested in the RHINESSA and ALSPAC cohorts, and historic studies suggest that ancestral nutrition during prepuberty plays a role for grand-offspring's health and morbidity. Support for causal relationships between ancestral exposures and (grand-)offspring's health in humans has been enhanced by advancements in statistical analyses that optimize the gain while accounting for the many complexities and deficiencies in human multigeneration data. The biological mechanisms underlying such observations have been explored in experimental models. A role of sperm small RNA in the transmission of paternal exposures to offspring phenotypes has been established, and chemical exposures and overweight have been shown to influence epigenetic programming in germ cells. For example, exposure of adolescent male mice to smoking led to differences in offspring weight and alterations in small RNAs in the spermatozoa of the exposed fathers. It is plausible that male prepuberty may be a time window of particular susceptibility, given the extensive epigenetic reprogramming taking place in the spermatocyte precursors at this age. In conclusion, epidemiological studies in humans, mechanistic research, and biological plausibility, all support the notion that exposures in the prepuberty of males may influence the phenotype of future offspring.

Heritable consequences of paternal nicotine exposure: from phenomena to mechanisms†.

Our understanding of the interactions between genetic and environmental factors in shaping behavioral phenotypes has expanded to include environment-induced epigenetic modifications and the intriguing possibility of their association with heritable behavioral phenotypes. The molecular basis of heritability of phenotypes arising from environment-induced epigenetic modifications is not well defined yet. However, phenomenological evidence in favor of it is accumulating rapidly. The resurgence of interest has led to focus on epigenetic modification of germ cells as a plausible mechanism of heritability. Perhaps partly because of practical reasons such as ease of access to male germ cells compared to female germ cells, attention has turned toward heritable effects of environmental influences on male founders. Public health implications of heritable effects of paternal exposures to addictive substances or to psycho-social factors may be enormous. Considering nicotine alone, over a billion people worldwide use nicotine-containing products, and the majority are men. Historically, the adverse effects of nicotine use by pregnant women received much attention by scientists and public policy experts alike. The implications of nicotine use by men for the physical and mental well-being of their children were not at the forefront of research until recently. Here, we review progress in the emerging field of heritable effects of paternal nicotine exposure and its implications for behavioral health of individuals in multiple generations.

Parental occupation and childhood germ cell tumors: a case-control study in Denmark, 1968-2016.

PURPOSE: To examine associations between parental occupation and childhood germ cell tumors (GCTs) in offspring while distinguishing by common histologic subtype (i.e., yolk sac tumor and teratoma). METHODS: This population-based case-control study included childhood GCT cases in Denmark diagnosed 1968-2015 (< 16 years old at diagnosis) and sex and birth year-matched controls. Demographic information and parental employment histories were obtained from Danish registries. Parental occupation was assessed by industry; job-exposure matrices were used to examine specific occupational exposures (i.e., potentially carcinogenic organic solvents and social contact). Conditional multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: Overall, 178 childhood GCT cases (50 yolk sac tumors; 65 teratomas) and 4,355 controls were included for analysis. Maternal employment in education during pregnancy was associated with offspring GCTs (OR 2.45, 95% CI 1.23-4.90), especially yolk sac tumors (OR 5.27, 95% CI 1.94-14.28). High levels of both maternal and paternal occupational social contact were also associated with offspring yolk sac tumors across all exposure periods (ORs 2.30-4.63). No signals were observed for paternal occupational solvent exposure, while imprecise associations were estimated for maternal exposure (e.g., dichloromethane exposure during pregnancy, OR 1.51, 95% CI 0.77-2.95). CONCLUSION: Our findings suggest that parental occupation is associated with offspring GCTs, with most consistent evidence supporting an association between maternal employment in education or other high social contact jobs and offspring yolk sac tumors.

Paternal Exposure to Immunosuppressive and/or Biologic Agents and Birth Outcomes in Patients With Immune-Mediated Inflammatory Diseases.

BACKGROUND & AIMS: We conducted a retrospective cohort study to inform the safety of exposure to immunosuppressive and/or biologic agents around conception in expectant fathers with immune-mediated inflammatory diseases (IMIDs) on birth outcomes. METHODS: Using a deidentified administrative claims database (OptumLabs Data Warehouse), we identified 7453 expectant fathers with IMIDs (inflammatory bowel diseases, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis) linked to newborns with periconception medication exposure between 38 and 60 weeks before the newborn birth date (34-58 weeks prior for preterm newborns) and neonatal follow-up for 3 months after the birth date. Through logistic regression adjusting for paternal age and race (and, in a subset, for maternal age, race, presence of IMIDs, and nonsingleton births), we compared the risk of major congenital malformations (primary outcome) and preterm birth and low birth weight in fathers exposed to thiopurines (n = 461), methotrexate (n = 171), tumor necrosis factor (TNF) α antagonists (n = 1082), or non-TNF-targeting biologic agents (n = 132) vs fathers not exposed to any of these medications (n = 5607). RESULTS: As compared to unexposed fathers (3.4% prevalence of major congenital malformations), exposure to thiopurines (relative risk [RR], 1.12; 95% confidence interval [CI], 0.66-1.76), methotrexate (RR, 0.67; 95% CI, 0.21-1.55), TNF-α antagonists (RR, 1.14; 95% CI, 0.81-1.57), and non-TNF-targeting biologic agents (RR, 1.75; 95% CI, 0.80-3.24) was not associated with increased risk of major congenital malformations. No association was observed between paternal medication exposure and risk of preterm birth or low birth weight. Results were stable on subanalyses of linked father-mother-newborn triads. CONCLUSIONS: In a large cohort study of 7453 expectant fathers with IMIDs, exposure to immunosuppressive or biologic agents around conception was not associated with increased risk of adverse birth outcomes.

Multigenerational nicotine exposure affects offspring nicotine metabolism, nicotine-induced hypothermia, and basal corticosterone in a sex-dependent manner.

Parental nicotine exposure can impact phenotypes in unexposed offspring. Our laboratory recently published data showing that nicotine reward and hippocampal gene expression involved in stress pathways were perturbed in F1 offspring of male C57BL/6J mice chronically exposed to nicotine. For the current study, we aimed to further test nicotine and stress-sensitivity phenotypes that may predict vulnerability to nicotine addiction in new cohorts of F1 offspring derived from nicotine-exposed males. We tested locomotor and body temperature sensitivity to acute nicotine administration, serum concentration of nicotine and nicotine metabolites after acute nicotine dosing, and serum corticosterone levels in male and female F1 offspring of nicotine- or saline-exposed males. Paternal nicotine exposure reduced sensitivity to nicotine-induced hypothermia in males, altered nicotine metabolite concentrations in males and females, and reduced serum basal corticosterone levels in females. These findings may point to reduced susceptibility to nicotine addiction-related phenotypes as a result of parental nicotine exposure.

Paternal prescription medication before conception: A retrospective cohort study of all births in Denmark 1997-2017.

AIM: To study what medication fathers are being prescribed in the months preceding conception. METHODS: A retrospective cohort study of Danish national registries, comprising all births in Denmark 1997-2017 (1.3 million births). Time trends and absolute levels of paternal prescription medication in the 6 months prior to conception were assessed. While all medications were examined (N = 1335), we focused on the main medication groups, medications that have increased in use over time, and medications for which previous evidence exists of an effect on sperm quality. RESULTS: The average number of prescriptions increased over the study period (from 0.75 prescriptions to 0.82 per birth). Polypharmacy (three or more prescriptions) increased from less than 8% to 10% of fathers. The use of pain medication, proton-pump inhibitors, selective serotonin reuptake inhibitors and some inhalants have all increased markedly over the last 20 years. CONCLUSIONS: Potential harm to the offspring done by paternal medication may present an increasing problem. As paternal medication exposure is increasing, examination of generational effects, such as major birth defects, is necessary.

Impact of paternal transmission of gamma radiation on reproduction, oogenesis, and spermatogenesis of the housefly, Musca domestica L. (Diptera: Muscidae).

PURPOSE: This study aimed to investigate the impact of gamma radiation of Musca domestica males (resulted from irradiated pupae) crossed with unirradiated females on fecundity, egg hatchability, adult emergence, sex ratio, sterility, in addition to reproductive development at the level of oogenesis and spermatogenesis compared to unirradiated group. MATERIAL AND METHODS: The housefly, M. domestica pupae were exposed to three sublethal doses of 5, 10, and 15 Gy. RESULTS: Fecundity was severely reduced particularly in F2 (11.33 ± 1.528; 7.33 ± 1.115 eggs/♀) and F3 (9.0 ± 1.00; 4.67 ± 1.115 eggs/♀) for doses of 10 and 15 Gy, respectively, compared with (52.0 ± 1.4 eggs/♀) for the control. Data revealed latent dose- and generation-dependent reduction in egg hatchability. Hatchability percentages reduced from 93.59 for the control to 10.07 (F1), 8.09 (F2), and 8.34 (F3) when the highest radiation dose 15 Gy was applied. Irradiation induced paternal deleterious substerility effects. Irradiation with 15 Gy induced substerility that reached about 97.0% in F2 and F3 generations. A significant (P < 0.05) reduction of the mean numbers of adult emergence was remarkably detected in the F1, F2, and F3 generations. Applied gamma doses did not affect the male to female ratio in the Parental or F1 generations. However, the F2 and F3 generations did show changes to the sex ratio with males occurring more frequently than females. This trend became more pronounced as dose increased. Ultrastructural examinations exhibited unusual damage and malformation either for males or female reproductive organs. CONCLUSION: The obtained results clearly show that gamma radiation of M. domestica irradiated as pupae induced considerably visible impact on tested biological aspects and reproductive potential.

Paternal nicotine enhances fear memory, reduces nicotine administration, and alters hippocampal genetic and neural function in offspring.

Nicotine use remains highly prevalent with tobacco and e-cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self-administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine-sired mice, as assessed in a self-administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocampal cholinergic currents, and altered methylation and expression of hippocampal genes related to neural development and plasticity. Gene expression analysis suggests multigenerational effects on broader gene networks potentially involved in neuroplasticity and mental disorders. The changes in fear conditioning similarly suggest phenotypes analogous to anxiety disorders similar to post-traumatic stress.

Childhood exposure to parental smoking and life-course overweight and central obesity.

OBJECTIVE: To evaluate the association between childhood parental smoking exposure and the risk of overweight/obesity from childhood to adulthood. METHODS: This study leverages the data from two longitudinal population based cohort studies, the Cardiovascular Risk in Young Finns Study between years 1980-2011/2012 (YFS; N = 2,303; baseline age 3-18 years) and the Special Turku Coronary Risk Factor Intervention Project between years 1989-2009/2010 (STRIP; N = 632; baseline age 7 months). Weight, height and waist circumference were measured from childhood to adulthood. Overweight/obesity was defined as body mass index ≥25 kg/m2 in adults and using the Cole criteria in children. Central obesity was defined as waist circumference > 100/90 cm in men/women and as a waist-to-height ratio > 0.50 in children. Statistical analyses were adjusted for age, sex, socioeconomic status, smoking, birth weight, parental ages, diet and physical activity. RESULTS: Childhood parental smoking exposure was associated with increased risk for life-course overweight/obesity (YFS: RR1.13, 95%CI 1.02-1.24; STRIP: RR1.57, 95%CI 1.10-2.26) and central obesity (YFS: RR1.18, 95%CI 1.01-1.38; STRIP: RR1.45, 95%CI 0.98-2.15). CONCLUSIONS: Childhood exposure to parental smoking is associated with increased risk of overweight/obesity over the life-course. KEY MESSAGES Exposure to parental smoking in childhood was associated with increased risk of overweight/obesity, central obesity and adiposity measured by skinfold thickness from childhood to adulthood.

Pregnancy outcomes of women whom spouse fathered children after tyrosine kinase inhibitor therapy for chronic myeloid leukemia: A systematic review.

INTRODUCTION: The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML). Although the efficacy of TKIs is beyond dispute, conception-related safety issues are still waiting to be explored, particularly in males. This systematic review aimed to summarize all available evidence on pregnancy outcomes of female spouses of male CML patients who fathered children after TKI treatment for CML. METHODS: We performed a systematic search in seven electronic databases for studies that reported on male CML patients who did or did not discontinue TKI treatment before conceiving, and the pregnancy outcomes of their female spouse are available. The search centered on the TKI era (from 2001 onward) without any other language or study design restrictions. RESULTS: Out of a total of 38 potentially eligible papers, 27 non-overlapping study cohorts were analyzed. All were descriptive studies (case or case series studies). Altogether, 428 pregnancies from 374 fathers conceived without treatment discontinuation, 400 of which (93.5%) ended up in a live birth. A total of ten offspring with a malformation (2.5%) were reported: six with imatinib (of 313 live births, 1.9%), two with nilotinib (of 26 live births, 7.7%), one with dasatinib (of 43 live births, 2.3%), and none with bosutinib (of 12 live births). Data on CML status were scarcely reported. Only nine pregnancies (from nine males) and no malformation were reported in males who discontinued TKI treatment before conception. CONCLUSION: Malformations affected, on average 2.5% of live births from fathers who did not discontinue TKI treatment before conception, which is comparable with the rate of malformations in the general population. Large-scale studies with representative samples are awaited to confirm our results.