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.

Risk of breast cancer in daughters of agricultural workers in Denmark.

OBJECTIVES: Agricultural workers face unique occupational hazards such as pesticide exposure, which has been associated with breast cancer. However, research considering the association between parental agricultural work and breast cancer in female offspring is lacking. Therefore, the aim of the present nested case-control study was to explore this association. METHODS: The Danish Cancer Registry was utilized to identify women diagnosed with primary breast cancer. A total of 5587 cases were included in the study, and for each case, 20 cancer-free female controls were selected, matched on year of birth. It was a requisition that both cases and controls were born in Denmark and that either maternal or paternal employment history was available. RESULTS: Adverse associations were consistently noted for different time windows of maternal employment in "Horticulture" and breast cancer. Inverse associations were observed for paternal employment in most of the examined agricultural industries, although a small increased risk was indicated for perinatal employment in "Horticulture". Furthermore, maternal preconceptional employment in "Horticulture" was observed to increase the risk of ER positive tumors (odds ratio [OR] = 1.79, 95% confidence interval [CI]: 1.13-2.85, whereas parental perinatal employment was linked to an elevated risk of ER negative tumors (maternal employment: OR = 2.48, 95% CI: 1.18-5.21; paternal employment: OR = 1.62, 95% CI: 0.70-3.77). CONCLUSIONS: The present study indicates that maternal horticultural employment in different potential susceptible time windows may elevate the risk of breast cancer subtypes in daughters. These findings need to be reproduced in future prospective cohort studies, including information on e.g., pesticide exposure withing agricultural job categories and lifestyle factors.

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.

Occupational exposure to pesticides in mothers and fathers and risk of cancer in the offspring: A register-based case-control study from Sweden (1960-2015).

Maternal and paternal occupational exposure to pesticides was linked to leukemia in the offspring in some previous studies. Risks for other cancers, particularly from maternal exposure, are largely unknown. We examined the association between maternal and paternal exposure to pesticides and childhood cancer in a Swedish register-based case-control study (1960-2015). Cancer cases <20 years old were identified from the Cancer Register (n = 17313) and matched to controls (1:25) on birth year and sex. Employment history of each biological parent around the child's birth was retrieved from six censuses and a nationwide register, and exposure to any of herbicides, insecticides, and fungicides was evaluated using the Swedish job-exposure matrix (SWEJEM) in 9653/172194 mothers and 12521/274434 fathers of cases/controls. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression models for any cancer, leukemia, lymphoma, central nervous system [CNS], and other solid tumors. We found an OR of 1.42 (95% CI 0.78, 2.57; 12 exposed cases) for lymphoma and 1.30 (95% CI 0.88, 1.93; 27 exposed cases) for other solid tumors associated with maternal occupational exposure to pesticides. No associations were observed between maternal exposure and leukemia or CNS tumors, or paternal exposure and any of the cancers examined, except for a potential association between pesticides exposure and myeloid leukemia (OR 1.15 [95% CI 0.73, 1.79; 22 exposed cases]). Although these findings merit further investigation, they indicate that parental exposure to pesticides may lead to higher risks of childhood cancer even in settings of low exposure.

Transgenerational effects of parental crude oil exposure on the morphology of adult Fundulus grandis.

The current study involved exposing adult F0 Gulf killifish (Fundulus grandis) to Macondo-252 oil for 36 to 44 days and assessing the effects of this oiling on the swimming performance and morphology in two generations of progeny reared in clean water. Following exposure to oil, the F0 fish were used as broodstock to generate four lineages of F1 fish using a full-matrix mating design derived from the gametes of clean and oil-exposed parents. Later, the four lineages of F1 fish were used as broodstock to create an F2 generation of the same four lineages. We found few differences in embryonic outcome (% dead,% hatched, and% unhatched) in any of the four lineages of F1 and F2 fish. However, as adults, F1 and F2 fish derived from oil-exposed males from the F0 generation had significantly lower critical swimming speeds (Ucrit) than both the control and maternally oil-exposed lineages. Additionally, progeny of oil-exposed fish had altered body shape based on the statistical analysis of two-dimensional landmark-based geometric morphometrics. Fish from oil-exposed lineages showed increased body depth, altered spinal curvature, and changes in the upward angle of projection of the head. Both generations had a significant main effect of maternal and paternal oil exposure on shape; however, F0 paternal oil exposure explained more of the variance in shape across both generations relative to F0 maternal exposure. Our findings demonstrate that parental exposure to oil can impact the shape and aerobic swimming capacity of offspring for at least two generations after the original paternal oiling.

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.

Protective role of intergenerational paternal resistance training on fibrosis, inflammatory profile, and redox status in the adipose tissue of rat offspring fed with a high-fat diet.

AIMS: We evaluated the role of intergenerational paternal exercise on fibrosis, inflammatory profile, and redox status in the adipose tissue of male rat offspring fed with high-fat diet (HFD) and explored to what extent programming affects the systemic metabolic profile. MAIN METHODS: Adult wistar rats were randomly divided into two groups: sedentary fathers and trained fathers (8 weeks of resistance training (RT), three times per week). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into four groups (7 animals per group): offspring of sedentary fathers exposed to either a control diet (SFO-C) or a high-fat diet (SFO-HF); offspring of trained fathers exposed to a control diet (TFO-C) or a high-fat diet (TFO-HF). KEY FINDINGS: Paternal RT was effective in attenuating body weight gain, adipocyte size, collagen deposition, as well as downregulating genes (CTGF, VEGF, C/EBPα SREBP1, MCP-1, and NF-kB), pro-inflammatory cytokine levels (Tumor Necrosis Factor alpha and Interleukin-1-beta), matrix metalloproteinase -2 activity, and ROS production in the epididymal adipose tissue of offspring fed with HFD (TFO-HF vs. SFO-HF; P < 0.05). Moreover, paternal RT increased adiponectin and superoxide dismutase (SOD) activity in the tissue. These beneficial effects were accompanied by the increase of antioxidant enzymes (SOD and α-Klotho), while decreasing pro-oxidant agents (F2-isoprostanes, protein carbonyls levels), and metabolic markers (insulin and leptin, HOMA-ß, and HOMA-IR) in the offspring blood circulation. SIGNIFICANCE: Our findings reveal protective effects of intergenerational paternal RT on adipose tissue remodeling and metabolic health of offspring fed with HFD.

Effects of paternal exposure to cigarette smoke on sperm DNA methylation and long-term metabolic syndrome in offspring.

BACKGROUND: Although paternal exposure to cigarette smoke may contribute to obesity and metabolic syndrome in offspring, the underlying mechanisms remain uncertain. METHODS: In the present study, we analyzed the sperm DNA-methylation profiles in tobacco-smoking normozoospermic (SN) men, non-tobacco-smoking normozoospermic (N) men, and non-smoking oligoasthenozoospermic (OA) men. Using a mouse model, we also analyzed global methylation and differentially methylated regions (DMRs) of the DLK1 gene in paternal spermatozoa and the livers of progeny. In addition, we quantified DLK1 expression, executed an intra-peritoneal glucose tolerance test (IPGTT), measured serum metabolites, and analyzed liver lipid accumulation in the F1 offspring. RESULTS: Global sperm DNA-methylation levels were significantly elevated (p < 0.05) in the SN group, and the methylation patterns were different among N, SN, and OA groups. Importantly, the methylation level of the DLK1 locus (cg11193865) was significantly elevated in the SN group compared to both N and OA groups (p < 0.001). In the mouse model, the group exposed to cigarette smoke extract (CSE) exhibited a significantly higher global methylation DNA level in spermatozoa (p < 0.001) and on the DMR sites of Dlk1 in 10-week-old male offspring (p < 0.05), with a significant increase in Dlk1 expression in their livers (p < 0.001). In addition, IPGTT and LDL levels were significantly altered (p < 0.001), with elevated liver fat accumulation (p < 0.05) in F1 offspring. CONCLUSION: Paternal exposure to cigarette smoke led to increased global methylation of sperm DNA and alterations to the DMR of the DLK1 gene in the F1 generation, which may be inherited parentally and may perturb long-term metabolic function.

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.

Association between occupational testicular radiation exposure and lower male sex ratio of offspring among orthopedic surgeons.

BACKGROUND: Exposure to occupational radiation can lower the male sex ratio. However, specific radiation exposure to the testes has not been evaluated. OBJECTIVE: This study aimed to examine the association between testicular radiation exposure and lower male sex ratio in children. METHODS: A comprehensive questionnaire survey was administered to 62 full-time male doctors with children aged < 10 years at 5 hospitals. Based on the possibility of testicular radiation exposure 1 year before the child's birth, participants were assigned to 3 groups as follows: RT (orthopedic surgery), RNT (cardiology/neurosurgery), and N (others). Intergroup differences in the proportion of female children were ascertained, and the female sex ratio (number of female/total number) of each group was compared against the standard value of 0.486. Multivariate logistic regression analysis with a generalized estimating equation was used to model the effects on the probability of female birth while controlling for the correlation among the same fathers. RESULTS: The study population included 62 fathers and 109 children, 49 were female: 19/27, 11/30, and 19/52 in the RT, RNT, and N group, respectively; the RT group had the highest proportion of females (p = 0.009). The p values for comparisons with the standard sex ratio (0.486) were 0.02, 0.19, and 0.08 for the RT, RNT, and N groups, respectively. Based on the N group, the adjusted odds ratios for the child to be female were 4.40 (95% confidence interval 1.60-2.48) and 1.03 (0.40-2.61) for the RT and RNT groups, respectively. CONCLUSIONS: Our results imply an association between testicular radiation exposure and low male sex ratio of offspring. Confirmatory evidence is needed from larger studies which measure the pre-conceptional doses accumulated in various temporal periods, separating out spermatogonial and spermatid effects.

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.

Exposure to pesticides and childhood leukemia risk: A systematic review and meta-analysis.

Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15-3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39-4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00-1.99) and insecticide (OR: 1.60, 95%CI: 1.11-2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12-0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44-3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98-5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (ORparental: 1.75, 95%CI: 1.08-2.85; ORpaternal: 1.20, 95%CI: 1.07-1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure.

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.

Cannabis and synaptic reprogramming of the developing brain.

Recent years have been transformational in regard to the perception of the health risks and benefits of cannabis with increased acceptance of use. This has unintended neurodevelopmental implications given the increased use of cannabis and the potent levels of Δ9-tetrahydrocannabinol today being consumed by pregnant women, young mothers and teens. In this Review, we provide an overview of the neurobiological effects of cannabinoid exposure during prenatal/perinatal and adolescent periods, in which the endogenous cannabinoid system plays a fundamental role in neurodevelopmental processes. We highlight impaired synaptic plasticity as characteristic of developmental exposure and the important contribution of epigenetic reprogramming that maintains the long-term impact into adulthood and across generations. Such epigenetic influence by its very nature being highly responsive to the environment also provides the potential to diminish neural perturbations associated with developmental cannabis exposure.