Paternal Use of Metformin During the Sperm Development Period Preceding Conception and Risk for Major Congenital Malformations in Newborns.

BACKGROUND: Metformin is the most used oral antidiabetic medication. Despite its established safety profile, it has known antiandrogenic and epigenetic modifying effects. This raised concerns about possible adverse developmental effects caused by genomic alterations related to paternal use of metformin during the spermatogenesis period preceding conception. OBJECTIVE: To assess the potential adverse intergenerational effect of metformin by examining the association between paternal metformin use during spermatogenesis and major congenital malformations (MCMs) in newborns. DESIGN: Nationally representative cohort study. SETTING: A large Israeli health fund. PARTICIPANTS: 383 851 live births linked to fathers and mothers that occurred in 1999 to 2020. MEASUREMENTS: MCMs and parental cardiometabolic conditions were ascertained using clinical diagnoses, medication dispensing information, and laboratory test results. The effect of metformin use on MCMs was estimated using general estimating equations, accounting for concurrent use of other antidiabetic medications and parental cardiometabolic morbidity. RESULTS: Compared with unexposed fathers, the prevalence of cardiometabolic morbidity was substantially higher among fathers who used metformin during spermatogenesis, and their spouses. Whereas the crude odds ratio (OR) for paternal metformin exposure in all formulations and MCMs was 1.28 (95% CI, 1.01 to 1.64), the adjusted OR was 1.00 (CI, 0.76 to 1.31). Within specific treatment regimens, the adjusted OR was 0.86 (CI, 0.60 to 1.23) for metformin in monotherapy and 1.36 (CI, 1.00 to 1.85) for metformin in polytherapy, a treatment that was more common in patients with more poorly controlled diabetes. LIMITATION: Laboratory test results for hemoglobin A1c to assess underlying diabetes severity were available only for a subset of the cohort. CONCLUSION: Paternal use of metformin in monotherapy does not increase the risk for MCMs. Association for metformin in polytherapy could potentially be explained by worse underlying parental cardiometabolic risk profile. PRIMARY FUNDING SOURCE: None.

Valproate Use During Spermatogenesis and Risk to Offspring.

Importance: Concerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis. Objective: To evaluate the association between paternal use of valproate during spermatogenesis and offspring risk of congenital malformations and neurodevelopmental disorders. Design, Setting, and Participants: This nationwide cohort study included 1 235 353 singletons born in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth Register; 1336 children had fathers who had filled prescriptions for valproate during spermatogenesis. Congenital malformations were identified in the first year of life and neurodevelopmental disorders were identified from 1 year of age until December 31, 2018. Statistical analysis was performed March 2024. Exposures: Paternal valproate exposure was defined as fathers who filled 1 or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 3 months prior to conception). Main Outcomes and Measures: Children with major congenital malformations in the first year of life and with neurodevelopmental disorders before death or end of follow-up were identified in Danish health registers. Log-binomial regression was used to estimate adjusted relative risks (ARRs) of congenital malformations, and Cox proportional hazards regression was used to estimate adjusted hazards ratios (AHRs) of neurodevelopmental disorders, adjusted for relevant confounders. Results: Among 1 235 353 live births (634 415 boys [51.4%] and 600 938 girls [48.6%]), 1336 children (0.1%) had fathers who filled prescriptions for valproate during spermatogenesis. The median follow-up was 10.1 years (IQR, 5.1-14.8 years) for valproate-exposed children and 10.3 years (IQR, 5.2-15.6 years) for valproate-unexposed children. A total of 43 903 children (3.6%) received a diagnosis of major congenital malformations in the first year of life, and 51 633 children (4.2%) received a diagnosis of neurodevelopmental disorders during follow-up. When comparing the risk among valproate-exposed children with that among unexposed children, the ARR of major congenital malformations was 0.89 (95% CI, 0.67-1.18), the AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37), and the AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30). In analyses addressing the robustness of the findings (ie, dose-response analyses, sibling analyses, analyses restricted to children of fathers with epilepsy, analyses that used children with paternal lamotrigine exposure as active comparator, and analyses that used children with paternal exposure to valproate only before spermatogenesis as a negative control exposure), there still was no increased risk of any of the included end points. Conclusions and Relevance: In all analyses based on this large Danish cohort study, results suggest that exposure to valproate during spermatogenesis was not associated with offspring risk of congenital malformations or neurodevelopmental disorders, including autism spectrum disorder.

Intergenerational toxicity of 17α-ethinylestradiol (EE2): Effects of parental exposure on early larval development and transcriptomic profiles in the Sydney rock oyster, Saccostrea glomerata.

This study exposed adult Sydney rock oysters, of either sex or both, to the synthetic estrogen 17α-ethinylestradiol (EE2) at 50 ng/L for 21 days, followed by an examination of developmental endpoints and transcriptomic responses in unexposed larvae. Reduced survival was observed at 1 day post-fertilisation (dpf) in larvae from bi-parental exposure (FTMT). Motile larvae at 2 dpf were fewer from maternal (FTMC), paternal (FCMT), and FTMT exposures. Additionally, shell length at 7 dpf decreased in larvae from FTMC and FTMT parents. RNA sequencing (RNA-seq) revealed 1064 differentially expressed genes (DEGs) in 1-dpf larvae from FTMT parents, while fewer DEGs were detected in larvae from FTMC and FCMT parents, with 258 and 7, respectively. GO and KEGG analyses showed significant enrichment of DEGs in diverse terms and pathways, with limited overlap among treatment groups. IPA results indicated potential inhibition of pathways regulating energy production, larval development, transcription, and detoxification of reactive oxygen species in FTMT larvae. qRT-PCR validation confirmed significant downregulation of selected DEGs involved in these pathways and relevant biological processes, as identified in the RNA-seq dataset. Overall, our results suggest that the intergenerational toxicity of EE2 is primarily maternally transmitted, with bi-parental exposure amplifying these effects.

MicroRNA and Gut Microbiota Alter Intergenerational Effects of Paternal Exposure to Polyethylene Nanoplastics.

Nanoplastics (NPs), as emerging contaminants, have been shown to cause testicular disorders in mammals. However, whether paternal inheritance effects on offspring health are involved in NP-induced reproductive toxicity remains unclear. In this study, we developed a mouse model where male mice were administered 200 nm polyethylene nanoparticles (PE-NPs) at a concentration of 2 mg/L through daily gavage for 35 days to evaluate the intergenerational effects of PE-NPs in an exclusive male-lineage transmission paradigm. We observed that paternal exposure to PE-NPs significantly affected growth phenotypes and sex hormone levels and induced histological damage in the testicular tissue of both F0 and F1 generations. In addition, consistent changes in sperm count, motility, abnormalities, and gene expression related to endoplasmic reticulum stress, sex hormone synthesis, and spermatogenesis were observed across paternal generations. The upregulation of microRNA (miR)-1983 and the downregulation of miR-122-5p, miR-5100, and miR-6240 were observed in both F0 and F1 mice, which may have been influenced by reproductive signaling pathways, as indicated by the RNA sequencing of testis tissues and quantitative real-time polymerase chain reaction findings. Furthermore, alterations in the gut microbiota and subsequent Spearman correlation analysis revealed that an increased abundance of Desulfovibrio (C21_c20) and Ruminococcus (gnavus) and a decreased abundance of Allobaculum were positively associated with spermatogenic dysfunction. These findings were validated in a fecal microbiota transplantation trial. Our results demonstrate that changes in miRNAs and the gut microbiota caused by paternal exposure to PE-NPs mediated intergenerational effects, providing deeper insights into mechanisms underlying the impact of paternal inheritance.

Parental Exposure to Morphine Before Conception Decreases Morphine and Cocaine-Induced Locomotor Sensitization in Male Offspring.

Repeated exposure to abused drugs leads to reorganizing synaptic connections in the brain, playing a pivotal role in the relapse process. Additionally, recent research has highlighted the impact of parental drug exposure before gestation on subsequent generations. This study aimed to explore the influence of parental morphine exposure 10 days prior to pregnancy on drug-induced locomotor sensitization. Adult male and female Wistar rats were categorized into morphine-exposed and control groups. Ten days after their last treatment, they were mated, and their male offspring underwent morphine, methamphetamine, cocaine, and nicotine-induced locomotor sensitization tests. The results indicated increased locomotor activity in both groups after drug exposure, although the changes were attenuated in morphine and cocaine sensitization among the offspring of morphine-exposed parents (MEPs). Western blotting analysis revealed altered levels of D2 dopamine receptors (D2DRs) in the prefrontal cortex and nucleus accumbens of the offspring from MEPs. Remarkably, despite not having direct in utero drug exposure, these offspring exhibited molecular alterations affecting morphine and cocaine-induced sensitization. The diminished sensitization to morphine and cocaine suggested the development of a tolerance phenotype in these offspring. The changes in D2DR levels in the brain might play a role in these adaptations.

Parental exposure to Cypermethrin causes intergenerational toxicity in zebrafish offspring.

Cypermethrin (CYP), a synthetic pyrethroid pesticide, has been detected in agriculture and aquaculture. However, there is limited knowledge about the transgenerational impacts. This study aimed to investigate the developmental toxicity of CYP on F1 larvae offspring of adult zebrafish exposed to various CYP concentrations (5, 10, and 20 µg/L) for 28 days. The results indicated that CYP accumulated in parental zebrafish, and CYP was below the limit of quantification in offspring. Paternal exposure impacted the hatching rate and heart rate of the F1 generation. Furthermore, CYP significantly impacted the development of swim bladders in progeny and dysregulated the genes relevant to swim bladder development. The neutrophil migrated to the swim bladder. The mRNA levels of the inflammatory factors were also significantly elevated. According to network toxicology, PI3-AKT may be the signaling pathway for CYP-influenced bladder development. Subsequent molecular docking and Western blot analysis showed CYP affected the PI3-AKT signaling pathway. Notably, MK-2206, a specific Akt inhibitor, rescued the CYP-induced damage of swim bladder development in offspring. The present study highlights the potential risks of CYP on the development of offspring and lasting impact in aquatic environments.

Maternal 129S1/SvImJ background attenuates the placental phenotypes induced by chronic paternal alcohol exposure.

Paternal alcohol use is emerging as a plausible driver of alcohol-related growth and patterning defects. Studies from our lab using an inbred C57Bl/6 J mouse model suggest that these paternally-inherited phenotypes result from paternally programmed deficits in the formation and function of the placenta. The 129S1/SvImJ genetic background is typically more susceptible to fetoplacental growth defects due to strain-specific differences in placental morphology. We hypothesized that these placental differences would sensitize 129S1/SvImJ-C57Bl/6 J hybrid offspring to paternally-inherited fetoplacental growth phenotypes induced by paternal alcohol exposure. Using a limited access model, we exposed C57Bl/6 J males to alcohol and bred them to naïve 129S1/SvImJ dams. We then assayed F1 hybrid offspring for alterations in fetoplacental growth and used micro-CT imaging to contrast placental histological patterning between the preconception treatments. F1 hybrid placentae exhibit larger placental weights than pure C57Bl/6 J offspring but display a proportionally smaller junctional zone with increased glycogen content. The male F1 hybrid offspring of alcohol-exposed sires exhibit modest placental hyperplasia but, unlike pure C57Bl/6 J offspring, do not display observable changes in placental histology, glycogen content, or measurable impacts on fetal growth. Although F1 hybrid female offspring do not exhibit any measurable alterations in fetoplacental growth, RT-qPCR analysis of placental gene expression reveals increased expression of genes participating in the antioxidant response. The reduced placental junctional zone but increased glycogen stores of 129S1/SvImJ-C57Bl/6 J F1 hybrid placentae ostensibly attenuate the previously observed placental patterning defects and fetal growth restriction induced by paternal alcohol use in the C57Bl/6 J strain.

Mimicking bacterial infection in male mice changes sperm small RNA profiles and multigenerationally alters offspring behavior and physiology.

Paternal pre-conceptual exposures, including stress, diet, substance abuse, parasite infection, and viral immune activation via Poly I:C, have been reported to influence the brains and behavior of offspring through sperm epigenetic changes. However, the effects of paternal (F0) pre-conceptual exposure to bacterial-induced immune activation on the behavior and physiology of F1 and F2 generations remain unexplored. We examined this using C57BL/6J mice. Eight-week-old males (F0) received a single intraperitoneal injection of the bacterial mimetic lipopolysaccharide (LPS: 5 mg/kg) or 0.9 % saline (vehicle control) before mating with naïve females at four weeks post-injection. Comprehensive behavioral assessments were conducted to investigate anxiety, social behaviors, depressive-like behaviors and cognition in both the F1 and F2 generations within the age range of 8 to 14 weeks. Results demonstrated that only female offspring of LPS-exposed fathers exhibited reduced anxiety levels in the light/dark box, large open field, and novelty-suppressed feeding test. These F1 female offspring also exhibited heightened sociability in the 3-chambered social interaction test and a reduced preference for saccharin in the saccharin preference test. Additionally, the F1 male offspring of LPS-challenged males demonstrated an increased total distance traveled in the light/dark box and a longer distance covered in the light zone. They also exhibited diminished preference for social novelty in the 3-chambered social interaction test and an elevated novel arm preference index in the Y-maze. In the F2 generation, male descendants of LPS-treated fathers showed reduced latency to feed in the novelty-suppressed feeding test. Additionally, the F2 generation of LPS-challenged fathers, but not the F1 generation, displayed enhanced immune response in both sexes after an acute LPS immune challenge (5 mg/kg). Analysis of sperm small noncoding RNA profiles from LPS-treated F0 mice revealed significant changes at 4 weeks after administration of LPS. These changes included three microRNAs, eight PIWI-interacting RNAs, and two transfer RNAs, exhibiting significant upregulation (mmu-miR-146a-5p, mmu-piR-27082 and mmu-piR-29102) or downregulation (mmu-miR-5110, mmu-miR-467e-3p, mmu-piR-22583, mmu-piR-23548, mmu-piR-36341, mmu-piR-50293, mmu-piR-16583, mmu-piR-36507, Mus_musculus_tRNA-Ile-AAT-2-1 and Mus_musculus_tRNA-Tyr-GTA-1-1). Additionally, we detected 52 upregulated small noncoding RNAs (including 9 miRNAs, 41 piRNAs, and 2 tRNAs) and 7 downregulated small noncoding RNAs (3 miRNAs, 3 piRNAs, and 1 tRNA) in the sperm of F1 offspring from LPS-treated males. These findings provide compelling evidence for the involvement of epigenetic mechanisms in the modulation of brain function and immunity, and associated behavioral and immunological traits, across generations, in response to bacterial infection.

Pregnancy and fetal outcomes following paternal exposure to glatiramer acetate.

OBJECTIVES: This study aimed to examine pregnancy and fetal outcomes following paternal exposure to glatiramer acetate (GA). METHODS: Pregnancy reports of paternal GA-exposure at time of conception from 2001 to 2022 were extracted from Teva Global Pharmacovigilance database. Pregnancy reports obtained prior to (prospective) or after (retrospective) knowledge of the pregnancy outcome were included. The primary endpoint was major congenital malformation (MCM) in the offspring according to the US Metropolitan Atlanta Congenital Defects Program (MACDP) and European Surveillance of Congenital Anomalies and Twins (EUROCAT) classification. Other pregnancy and fetal outcomes, including spontaneous abortion, pregnancy termination, fetal death, preterm birth, and low birth weight, were assessed. RESULTS: A total of 466 paternal GA-exposed pregnancies were retrieved, 232 prospective cases and 234 retrospective cases. Of 349 (74.9%) pregnancies with known outcomes, 316 (90.5%) were live births, 28 (8.0%) were spontaneous abortions, 3 (0.9%) were elective pregnancy terminations, and 2 (0.6%) were stillbirths. In prospective live birth cases, there were 7/111 (6.3%) preterm births and 5/115 (4.3%) neonates with a low birth weight. The prevalence of total MCM among prospective cases was 1.7% (2 cases of 116 live births and fetal death/stillbirth), which is slightly lower than the background rates from MACDP (3%) and EUROCAT (2.1%). CONCLUSIONS: This study did not indicate an increase in the rate of adverse pregnancy and fetal outcomes after paternal exposure to GA. These results provide additional information regarding pregnancy outcomes following paternal exposure to GA for healthcare professionals, male patients and their female partners who are considering pregnancy while their male partner is using GA.

This research aimed to look at how pregnancies and babies were affected when fathers with multiple sclerosis have been prescribed and taken the medication, glatiramer acetate (GA). Researchers looked at reports of pregnancies where the father had taken GA around the time of conception, from 2001 to 2022. They got this information from the Teva Global Pharmacovigilance database. They included reports where the pregnancy was known about either before (prospective) or after (retrospective) the outcome was known. They looked at outcomes like major birth defects, miscarriages, pregnancy terminations, fetal deaths, premature births, and low birth weight. The study found a total of 466 pregnancies where the father had taken GA. Of these pregnancies, the final outcome of pregnancy was found for 349 pregnancies. Most of these pregnancies (90.5%) resulted in live births, 8.0% ended in miscarriage, 0.9% in termination, and 0.6% in stillbirth. Among prospective live births, 6.3% were premature, and 4.3% had low birth weight. The amount of major birth defects was 1.7%, which was slightly lower than usual. The study did not suggest that exposure of the father to GA negatively affects the pregnancy or the baby. These findings can help healthcare providers, male patients taking GA, and their partners who are thinking about pregnancy while the male partner is taking GA.

Paternal exposures to endocrine-disrupting chemicals induce intergenerational epigenetic influences on offspring: A review.

Endocrine-disrupting chemicals (EDCs) are ubiquitous in ecological environments and have become a great issue of public health concern since the 1990 s. There is a deep scientific understanding of the toxicity of EDCs. However, recent studies have found that the abnormal physiological functions of the parents caused by EDCs could be transmitted to their unexposed offspring, leading to intergenerational toxicity. We questioned whether sustained epigenetic changes occur through the male germline. In this review, we (1) systematically searched the available research on the intergenerational impacts of EDCs in aquatic and mammal organisms, including 42 articles, (2) summarized the intergenerational genetic effects, such as decreased offspring survival, abnormal reproductive dysfunction, metabolic disorders, and behavioral abnormalities, (3) summarized the mechanisms of intergenerational toxicity through paternal interactions, and (4) propose suggestions on future research directions to develop a deeper understanding of the ecological risk of EDCs.

Future in the past: paternal reprogramming of offspring phenotype and the epigenetic mechanisms.

That certain preconceptual paternal exposures reprogram the developmental phenotypic plasticity in future generation(s) has conceptualized the "paternal programming of offspring health" hypothesis. This transgenerational effect is transmitted primarily through sperm epigenetic mechanisms-DNA methylation, non-coding RNAs (ncRNAs) and associated RNA modifications, and histone modifications-and potentially through non-sperm-specific mechanisms-seminal plasma and circulating factors-that create 'imprinted' memory of ancestral information. The epigenetic landscape in sperm is highly responsive to environmental cues, due to, in part, the soma-to-germline communication mediated by epididymosomes. While human epidemiological studies and experimental animal studies have provided solid evidences in support of transgenerational epigenetic inheritance, how ancestral information is memorized as epigenetic codes for germline transmission is poorly understood. Particular elusive is what the downstream effector pathways that decode those epigenetic codes into persistent phenotypes. In this review, we discuss the paternal reprogramming of offspring phenotype and the possible underlying epigenetic mechanisms. Cracking these epigenetic mechanisms will lead to a better appreciation of "Paternal Origins of Health and Disease" and guide innovation of intervention algorithms to achieve 'healthier' outcomes in future generations. All this will revolutionize our understanding of human disease etiology.

Paternal DDT exposure induces sex-specific programming of fetal growth, placenta development and offspring's health phenotypes in a mouse model.

Mounting evidence suggests that environmentally induced epigenetic inheritance occurs in mammals and that traits in the progeny can be shaped by parental environmental experiences. Epidemiological studies link parental exposure to environmental toxicants, such as the pesticide DDT, to health phenotypes in the progeny, including low birth and increased risk of chronic diseases later in life. Here, we show that the progeny of male mice exposed to DDT in the pre-conception period are born smaller and exhibit sexual dimorphism in metabolic function, with male, but not female, offspring developing severe glucose intolerance compared to controls. These phenotypes in DDT offspring were linked to reduced fetal growth and placenta size as well as placenta-specific reduction of glycogen levels and the nutrient sensor and epigenetic regulator OGT, with more pronounced phenotypes observed in male placentas. However, placenta-specific genetic reduction of OGT only partially replicates the metabolic phenotype observed in offspring of DDT-exposed males. Our findings reveal a role for paternal pre-conception environmental experiences in shaping placenta development and in fetal growth restriction. While many questions remain, our data raise the tantalizing possibility that placenta programming could be a mediator of environmentally induced intergenerational epigenetic inheritance of phenotypes and needs to be further evaluated.

Where are the data to assess the safety of paternal drug exposure? A systematic review of secondary databases: A contribution from IMI concePTION.

BACKGROUND: Most studies assessing the safety of parental drug exposures during pregnancy and around the time of conception describe the effects of maternal exposure. Recent publications have raised awareness of the need for additional research regarding the safety of paternal drug exposures on pregnancy outcomes. OBJECTIVES: To identify and describe studies that use secondary databases in paternal drug safety studies and to describe the secondary databases that were used. METHODS: A systematic review of studies assessing paternal medication exposure and pregnancy and infant outcomes using secondary databases was performed. In addition, the secondary databases used for these studies was described. Literature search was conducted using Embase, Web of Science, and PubMed, over the period January 1, 2012 to April 30, 2023. For each eligible study, paternal drug exposure, outcome, and data source characteristics were extracted in a data extraction form. RESULTS: After reviewing the literature, 17 studies met inclusion criteria. The medications assessed for paternal safety were anti-rheumatic drugs (n = 10), anti-depressants (n = 3), anticonvulsants (n = 2), and anti-diabetes medications (n = 2). Pregnancy safety outcomes included congenital malformations, birth weight, and developmental disorders. The studies used five different databases across Europe and North America. The included studies used databases from Denmark (n = 12), Norway (n = 2), Sweden (n = 1), Canada (n = 1), and the United States (n = 1). The European studies utilized national patient registers that linked fathers to births and prescription histories. The North American databases used included insurance claims and electronic health records. CONCLUSIONS: Our review shows that few studies have been completed on paternal medication exposures and pregnancy outcomes, despite the availability of secondary databases that contain data necessary to link fathers to infants. More research on the potential adverse impacts of paternal medication exposures is needed.

Paternal p,p'-DDE exposure and pre-pubertal high-fat diet increases the susceptibility to fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring.

The hypothesis of paternal origins of health and disease (POHaD) indicates that paternal exposure to adverse environment could alter the epigenetic modification in germ line, increasing the disease susceptibility in offspring or even in subsequent generations. p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) is an anti-androgenic chemical and male reproductive toxicant. Gestational p,p'-DDE exposure could impair reproductive development and fertility in male offspring. However, the effect of paternal p,p'-DDE exposure on fertility in male offspring remains uncovered. From postnatal day (PND) 35 to 119, male rats (F0) were given 10 mg/body weight (b.w.) p,p'-DDE or corn oil by gavage. Male rats were then mated with the control females to generate male offspring. On PND35, the male offspring were divided into 4 groups according whether to be given the high-fat diet (HF): corn oil treatment with control diet (C-C), p,p'-DDE treatment with control diet (DDE-C), corn oil treatment with high-fat diet (C-HF) or p,p'-DDE treatment with high-fat diet (DDE-HF) for 35 days. Our results indicated that paternal p,p'-DDE exposure did not affect the male fertility of male offspring directly, but decreased sperm quality and induced testicular apoptosis after the high-fat diet treatment. Further analysis demonstrated that paternal exposure to p,p'-DDE and pre-pubertal high-fat diet decreased sperm Igf2 DMR2 methylation and gene expression in male offspring. Hence, paternal exposure to p,p'-DDE and pre-pubertal high-fat diet increases the susceptibility to male fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring, posing a significant implication in the disease etiology.

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.

Alterations in sperm DNA methylation may as a mediator of paternal air pollution exposure and offspring birth outcomes: Insight from a birth cohort study.

Paternal exposure to environmental risk factors influences the offspring health. This study aimed to evaluate the association between paternal air pollution exposure mediated by sperm DNA methylation and adverse birth outcomes in offspring. We recruited 1607 fertile men and their partners from 2014 to 2016 and collected semen samples to detect sperm DNA methylation. Multivariate linear regression and weighted quantile sum regression models were used to assess the associations between paternal air pollution exposure and offspring birth outcomes. A critical exposure window was identified. Reduced representation bisulfite sequencing was used to detect sperm DNA methylation. The results demonstrated that high paternal exposure to PM2.5 (ß = -211.31, 95% CI: (-386.37, -36.24)), PM10 (ß = -178.20, 95% CI: (-277.13, -79.27)), and NO2 (ß = -84.22, 95% CI: (-165.86, -2.57)) was negatively associated with offspring's birthweight, especially in boys. Additionally, an early exposure window of 15-69 days before fertilization was recognized to be the key exposure window, which increased the risk of low birth weight and small for gestational age. Furthermore, paternal co-exposure to six air pollutants contributed to lower birthweight (ß = -51.91, 95% CI: (-92.72, -11.10)) and shorter gestational age (ß = -1.72, 95% CI: (-3.26, -0.17)) and PM2.5 was the most weighted pollutant. Paternal air pollution exposure resulted in 10,328 differentially methylated regions and the IGF2R gene was the key gene involved in the epigenetic process. These differentially methylated genes were predominantly associated with protein binding, transcriptional regulation, and DNA templating. These findings indicate that spermatogenesis is a susceptible window during which paternal exposure to air pollution affects sperm DNA methylation and the birth outcomes of offspring.

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.

The Dutch Pregnancy Drug Register: Suitable to Study Paternal Drug Exposures?

Paternal medication use around the time of conception is common, but information about its effects on pregnancy outcome and the health of the child is generally limited. The aim of this study is to examine the feasibility of studying paternal exposure in the Dutch Pregnancy Drug Register by using immunosuppressants as a proof of concept. In 113 of 15,959 pregnancies, long-term paternal immunosuppressant use was reported 3 months before conception. In total, 134 immunosuppressants were used. Pregnancy outcome was known for 54 cases and was in accordance with previous findings. Two spontaneous abortions, two premature births, six small for gestational age babies, and two major congenital malformations were reported. Time to pregnancy (TTP) was known for 9548 pregnancies, including 89 with paternal immunosuppressant use. TTP analysis did not show a difference in pregnancies with paternal immunosuppressant use compared to the control group. Moreover, the number of fertility treatments in the paternal immunosuppressant group was similar to the control group. In our opinion, it is feasible to use the Dutch Pregnancy Drug Register to study the effects of paternal exposure on pregnancy outcome. However, to study the potential effects on fertility, more information is needed, particularly since the beginning of pregnancy attempts.

Whole transcriptome analysis in offspring whose fathers were exposed to a developmental insult: a novel avian model.

Although the effects of paternal exposure to insults on the offspring received limited attention in the past, it is currently gaining interest especially after understanding the mechanisms which may mediate such exposure effects. In the current study, the well-controlled avian model (Fayoumi) was utilized to investigate the effects of paternal exposure to the developmental insult, chlorpyrifos on the offspring's gene expression via mRNA and small RNA sequencing. Numerous mRNA gene expression changes were detected in the offspring after paternal exposure to the developmental insult, especially in genes related to neurogenesis, learning and memory. qPCR analysis of several genes, that were significantly changed in mRNA sequencing, confirmed the results obtained in mRNA sequencing. On the other hand, small RNA sequencing did not identify significant microRNA genes expression changes in the offspring after paternal exposure to the developmental insult. The effects of the paternal exposure were more pronounced in the female offspring compared to the male offspring. The results identified expression alterations in major genes (some of which were pertinent to the functional changes observed in other forms of early developmental exposure) after paternal insult exposure and provided a direction for future studies involving the most affected genes.