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.

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.

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.

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.

Teratogenesis and the epigenetic programming of congenital defects: Why paternal exposures matter.

Until recently, clinicians and researchers did not realize paternal exposures could impact child developmental outcomes. Indeed, although there is growing recognition that sperm carry a large amount of non-genomic information and that paternal stressors influence the health of the next generation, toxicologists are only now beginning to explore the role paternal exposures have in dysgenesis and the incidence of congenital malformations. In this commentary, I will briefly summarize the few studies describing congenital malformations resulting from preconception paternal stressors, argue for the theoretical expansion of teratogenic perspectives into the male preconception period, and discuss some of the challenges in this newly emerging branch of toxicology. I argue that we must consider gametes the same as any other malleable precursor cell type and recognize that environmentally-induced epigenetic changes acquired during the formation of the sperm and oocyte hold equal teratogenic potential as exposures during early development. Here, I propose the term epiteratogen to reference agents acting outside of pregnancy that, through epigenetic mechanisms, induce congenital malformations. Understanding the interactions between the environment, the essential epigenetic processes intrinsic to spermatogenesis, and their cumulative influences on embryo patterning is essential to addressing a significant blind spot in the field of developmental toxicology.

Paternal morphine exposure in rats reduces social play in adolescent male progeny without affecting drug-taking behavior in juvenile males or female offspring.

The ongoing opioid addiction crisis necessitates the identification of novel risk factors to improve prevention and treatment of opioid use disorder. Parental opioid exposure has recently emerged as a potential regulator of offspring vulnerability to opioid misuse, in addition to heritable genetic liability. An understudied aspect of this "missing heritability" is the developmental presentation of these cross-generational phenotypes. This is an especially relevant question in the context of inherited addiction-related phenotypes, given the prominent role of developmental processes in the etiology of psychiatric disorders. Paternal morphine self-administration was previously shown to alter the sensitivity to the reinforcing and antinociceptive properties of opioids in the next generation. Here, phenotyping was expanded to include the adolescent period, with a focus on endophenotypes related to opioid use disorders and pain. Paternal morphine exposure did not alter heroin or cocaine self-administration in male and female juvenile progeny. Further, baseline sensory reflexes related to pain were unaltered in morphine-sired adolescent rats of either sex. However, morphine-sired adolescent males exhibited a reduction in social play behavior. Our findings suggest that, in morphine-sired male offspring, paternal opioid exposure does not affect opioid intake during adolescence, suggesting that this phenotype does not emerge until later in life. Altered social behaviors in male morphine-sired adolescents indicate that the changes in drug-taking behavior in adults sired by morphine-exposed sires may be due to more complex factors not yet fully assessed.

Paternal low-dose benzo(a)pyrene exposure in rats impairs sexual development and fertility of the paternal lineage in F2 generation: A transgenerational study.

The field of Paternal Origins of Health and Disease (POHaD) is highly relevant but remains under-explored. The F2 generation from males indirectly exposed (F1 - via germ cells) to benzo(a)pyrene (BaP), named PF2, was investigated in this study under parameters of sexual development and reproductive performance of male and female rats. Male Wistar rats (F0) were exposed to BaP (0.1 µg/kg/day) for 31 consecutive days (gavage) during prepuberty. The F0 rats were mated with untreated females to produce male offspring (F1), which were exposed to BaP via germ cells. The F1 males were later mated with untreated females to obtain the PF2 generation, which was the focus of our investigation. Our findings showed that PF2 males exhibited a decrease in anogenital distance, fertility potential, testosterone levels, and type A sperm. Meanwhile, PF2 females had an earlier vaginal opening, lower lordosis scores, and decreased fertility. Furthermore, changes in the histomorphology of the testis/epididymis and ovary/uterus were observed. The repercussions of the PF2 generation indicate that these animals showed losses in both sexual development and fertility potential, and we can conclude that this damage remained due to paternal transgenerational inheritance caused by a low dose of BaP.

Benzo[a]pyrene-induced multigenerational changes in gene expression, behavior, and DNA methylation are primarily influenced by paternal exposure.

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is implicated in many developmental and behavioral adverse outcomes in offspring of exposed parents. The objective of this study was to investigate sex-dependent multigenerational effects of preconceptional effects of BaP exposure. Adult wild-type (5D) zebrafish were fed 708 µg BaP/g diet (measured) at a rate of 1% body weight twice/day (14 µg BaP/g fish/day) for 21 days. Fish were spawned using a crossover design, and parental (F0) behavior and reproductive indexes were measured. In offspring, behavioral effects were measured at 96 h post fertilization (hpf) in F1 & F2 larvae, and again when F1s were adults. Compared to controls, there was no significant effect on F0 adult behavior immediately following exposure, but locomotor activity was significantly increased in F1 adults of both sexes. Larval behavior (96 hpf, photomotor response assay) was significantly altered in both the F1 and F2 generations. To assess molecular changes associated with BaP exposure, we conducted transcriptome and DNA methylation profiling in F0 gametes (sperm and eggs) and F1 embryos (10 hpf) from all four crosses. Embryos resulting from the BaP male and control female cross had the most differentially expressed genes (DEGs) and differentially methylated regions (DMRs). Some DMRs were associated with genes encoding chromatin modifying enzymes suggesting regulation of chromatin conformation by DNA methylation. Overall, these results suggest that parental dietary BaP exposure significantly contributes to the multigenerational adverse outcomes.

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.

Preconceptional exposure of adult male rats to bisphenol S impairs insulin sensitivity and glucose tolerance in their male offspring.

Since the use of bisphenol A (BPA) has been restricted because of its endocrine disruptor properties, bisphenol S (BPS) has been widely used as a substitute of BPA. However, BPS exerts similar effects on metabolic health as BPA. The effects of maternal exposure to BPA and BPS on the metabolic health of offspring have been largely documented during the past decade. However, the impact of preconceptional paternal exposure to BPS on progenies remains unexplored. In this study we investigated the impact of paternal exposure to BPS before conception, on the metabolic phenotype of offspring. Male Wistar rats were administered BPS through drinking water at the dose of 4 µg/kg/day (BPS-4 sires) or 40 µg/kg/day (BPS-40 sires) for 2 months before mating with females. The progenies (F1) were studied at fetal stage and in adulthood. We showed that preconceptional paternal exposure to BPS for 2 months did not alter the metabolic status of sires. The female offspring of sires exposed to lower or higher doses of BPS showed no alteration of their metabolic phenotype compared to females from control sires. In contrast, male offspring of BPS-4 sires exhibited increased body weight and body fat/lean ratio, decreased insulin sensitivity and increased glucose-induced insulin secretion at adult age, compared to the male offspring of control sires. Moreover, male offspring of BPS-4 sires developed glucose intolerance later in life. None of these effects were apparent in male offspring of BPS-40 sires. In conclusion, our study provides the first evidence of the non-monotonic and sex-specific effects of preconceptional paternal exposure to BPS on the metabolic health of offspring, suggesting that BPS is not a safe BPA substitute regarding the inter-generational transmission of metabolic disorders through the paternal lineage.

Paternal phthalate exposure-elicited offspring metabolic disorders are associated with altered sperm small RNAs in mice.

Exposure to ubiquitous plastic-associated endocrine disrupting chemicals (EDCs) is associated with the increased risk of many chronic diseases. For example, phthalate exposure is associated with cardiometabolic mortality in humans, with societal costs ∼ $39 billion/year or more. We recently demonstrated that several widely used plastic-associated EDCs increase cardiometabolic disease in appropriate mouse models. In addition to affecting adult health, parental exposure to EDCs has also been shown to cause metabolic disorders, including obesity and diabetes, in the offspring. While most studies have focused on the impact of maternal EDC exposure on the offspring's health, little is known about the effects of paternal EDC exposure. In the current study, we investigated the adverse impact of paternal exposure to a ubiquitous but understudied phthalate, dicyclohexyl phthalate (DCHP) on the metabolic health of F1 and F2 offspring in mice. Paternal DCHP exposure led to exacerbated insulin resistance and impaired insulin signaling in F1 offspring without affecting diet-induced obesity. We previously showed that sperm small non-coding RNAs including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs) contribute to the intergenerational transmission of paternally acquired metabolic disorders. Using a novel PANDORA-seq, we revealed that DCHP exposure can lead to sperm tsRNA/rsRNA landscape changes that were undetected by traditional RNA-seq, which may contribute to DCHP-elicited adverse effects. Lastly, we found that paternal DCHP can also cause sex-specific transgenerational adverse effects in F2 offspring and elicited glucose intolerance in female F2 descendants. Our results suggest that exposure to endocrine disrupting phthalates may have intergenerational and transgenerational adverse effects on the metabolic health of their offspring. These findings increase our understanding of the etiology of chronic human diseases originating from chemical-elicited intergenerational and transgenerational effects.

The effects of transpositions of functional I retrotransposons depend on the conditions and dose of parental exposure.

PURPOSE: Transposable elements (TEs) cause destabilization of animal genomes. I retrotransposons of Drosophila melanogaster, as well as human LINE1 retrotransposons, are sources of intra- and interindividual diversity and responses to the action of internal and external factors. The aim of this study was to investigate the response to irradiation for the offspring of Drosophila melanogaster with the increased activity of inherited functional I elements. MATERIALS AND METHODS: The material used was dysgenic Drosophila females with active I retrotransposons obtained as a result of crossing irradiated/non-irradiated parents of a certain genotype. Non-dysgenic females (without functional I elements) were used as controls. The effects of different conditions (irradiation of both parents simultaneously or separately) and doses (1-100 Gy) of parental irradiation have been assessed by analyzing SF-sterility, DNA damage and lifespan. The presence of full-size I retrotransposons was determined by PCR analysis. RESULTS: The maternal exposure and exposure of both parents are efficient in contrast with paternal exposure. Irradiation of mothers reduces the reproductive potential and viability of their female offspring which undergo high activity of functional I retrotransposons. Though I retrotranspositions negatively affect the female gonads, irradiation of the paternal line can increase the lifespan of SF-sterile females. Radiation stress in the range of 1-100 Gy increases DNA fragmentation in both somatic and germ cells of the ovaries with high I-retrotransposition. CONCLUSIONS: These results allow for the specificity of the radiation-induced behavior of I retrotransposons and their role in survival under conditions of strong radiation stress.

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.