Transgenerational Effects Research Articles

Posttranscriptional regulation of the T-box gene midline via the 3'UTR in Drosophila is complex and cell- and tissue-dependent.

The T-box (Tbx) proteins have a 180-230 amino acid DNA-binding domain, first reported in the Brachyury (T) protein. They are highly conserved among metazoans. They regulate a multitude of cellular functions in development and disease. Here, we report posttranscriptional and translational regulation of midline (mid), a Tbx member in Drosophila. We found that the 3'UTR of mid has mRNA degradation elements and AT-rich sequences. In Schneider S2 cells, mid-mRNA could be detected only when the transgene was without the 3'UTR. Similarly, the 3'UTR linked to the Renilla luciferase reporter significantly reduced the activity of the Luciferase, whereas deleting only the degradation elements from the 3'UTR resulted in reduced activity, but not as much. Overexpression of mid in MP2, an embryonic neuroblast, showed no significant difference in the levels of mid-mRNA between the 2 transgenes, with and without the 3'UTR, indicating the absence of posttranscriptional regulation of mid in MP2. Moreover, while elevated mid-RNA was detected in MP2 in nearly all hemisegments, only a fifth of those hemisegments had elevated levels of the protein. Overexpression of the 2 transgenes resulted in MP2-lineage defects at about the same frequency. These results indicate a translational/posttranslational regulation of mid in MP2. The regulation of ectopically expressed mid in the wing imaginal disc was complex. In the wing disc, where mid is not expressed, the ectopic expression of the transgene lacking the 3'UTR had a higher level of mid-RNA and the protein had a stronger phenotypic effect. These results indicate that the 3'UTR can subject mid-mRNA to degradation in a cell- and tissue-specific manner. We further report a balancer-mediated transgenerational modifier effect on the expression and gain of function effects of the 2 transgenes.

Nutrigenetic and Epigenetic Mechanisms of Maternal Nutrition-Induced Glucolipid Metabolism Changes in the Offspring.

Maternal nutrition during pregnancy regulates the offspring's metabolic homeostasis, including insulin sensitivity and the metabolism of glucose and lipids. The fetus undergoes a crucial period of plasticity in the uterus; metabolic changes in the fetus during pregnancy caused by maternal nutrition not only influence fetal growth and development but also have a long-term or even life-long impact for the offspring. Epigenetic modifications, such as DNA methylation, histone modification, and non-coding RNAs, play important roles in intergenerational and transgenerational effects. In this context, this narrative review comprehensively summarizes and analyzes the molecular mechanisms underlying how maternal nutrition, including a high-fat diet, polyunsaturated fatty acid diet, methyl donor nutrient supplementation, feed restriction, and protein restriction during pregnancy, impacts the genes involved in glucolipid metabolism in the liver, adipose tissue, hypothalamus, muscle, and oocytes of the offspring in terms of the epigenetic modifications. This will provide a foundation for the further exploration of nutrigenetic and epigenetic mechanisms for integrative mother-child nutrition and promotion of the offspring's health through the regulation of maternal nutrition during pregnancy. Note: This paper is part of the Nutrition Reviews Special Collection on Precision Nutrition.

Lethal, sublethal and transgenerational effects of broflanilide on Tuta absoluta

Lethal, sublethal and transgenerational effects of broflanilide on Tuta absoluta

Small but strong: herbivory by sap-feeding insect reduces plant progeny growth but enhances direct and indirect anti-herbivore defenses.

The transmission of resistance traits to herbivores across subsequent generations is an important strategy employed by plants to enhance their fitness in environments with high herbivore pressure. However, our understanding of the impact of maternal herbivory on direct and indirect induced chemical defenses of progeny, as well as the associated costs, is currently limited to herbivory by leaf-chewing insects. In this study, we investigated the transgenerational effects of a sap-feeding insect, the green peach aphid Myzus persicae, on direct and indirect chemical defenses of bell pepper plants (Capsicum annuum), and whether the effects entail costs to plant growth. Aphid herbivory on parental plants led to a reduced number of seeds per fruit, which exhibited lower germination rates and produced smaller seedlings compared to those from non-infested parental plants. In contrast, the progeny of aphid-infested plants were less preferred as hosts by aphids and less suitable than the progeny of non-infested plants. This enhanced resistance in the progeny of aphid-infested plants coincided with elevated levels of both constitutive and herbivore-induced total phenolic compounds, compared to the progeny of non-infested plants. Furthermore, the progeny of aphid-infested plants emitted herbivore-induced plant volatiles (HIPVs) that were more attractive to the aphid parasitoid Aphidius platensis than those emitted by the progeny of non-infested plants. Our results indicate that herbivory by sap-feeding insect induces transgenerational resistance on progeny bell pepper plants, albeit at the expense of vegetative growth.

The generation gap in endocrine disruption: Can the integrated fish endocrine disruptor test (iFEDT) bridge the gap by assessing intergenerational effects of thyroid hormone system disruption?

Thyroid hormones (THs) act early in ontogenesis, even prior to the differentiation of thyrocytes. Maternal transfer of THs is therefore known to play an essential role in early development. Current OECD test guidelines for the assessment of TH system disruption (THSD) do not address inter- or transgenerational effects. The integrated fish endocrine disruptor test (iFEDT), a test combining parental and developmental exposure of filial fish, may fill this gap. We tested the ability of the iFEDT to detect intergenerational effects in zebrafish (Danio rerio): Parental fish were exposed to propylthiouracil (PTU), an inhibitor of TH synthesis, or not exposed. The offspring was submitted to a crossed experimental design to obtain four exposure scenarios: (1) no exposure at all, (2) parental exposure only, (3) embryonic exposure only, and (4) combined parental and embryonic exposure. Swim bladder inflation, visual motor response (VMR) and gene expression of the progeny were analysed. Parental, but not embryonic PTU exposure reduced the size of the swim bladder of 5 d old embryos, indicating the existence of intergenerational effects. The VMR test produced opposite responses in 4.5 d old embryos exposed to PTU vs. embryos derived from exposed parents. Embryonic exposure, but not parental exposure increased gene expression of thyroperoxidase, the target of PTU, most likely due to a compensatory mechanism. The gene expression of pde-6h (phosphodiesterase) was reduced by embryonic, but not parental exposure, suggesting downregulation of phototransduction pathways. Hence, adverse effects on swim bladder inflation appear more sensitive to parental than embryonic exposure and the iFEDT represents an improvement in the testing strategy for THSD.

Parental experiences orchestrate locust egg hatching synchrony by regulating nuclear export of precursor miRNA.

Parental experiences can affect the phenotypic plasticity of offspring. In locusts, the population density that adults experience regulates the number and hatching synchrony of their eggs, contributing to locust outbreaks. However, the pathway of signal transmission from parents to offspring remains unclear. Here, we find that transcription factor Forkhead box protein N1 (FOXN1) responds to high population density and activates the polypyrimidine tract-binding protein1 (Ptbp1) in locusts. FOXN1-PTBP1 serves as an upstream regulator of miR-276, a miRNA to control egg-hatching synchrony. PTBP1 boosts the nucleo-cytoplasmic transport of pre-miR-276 in a "CU motif"-dependent manner, by collaborating with the primary exportin protein exportin 5 (XPO5). Enhanced nuclear export of pre-miR-276 elevates miR-276 expression in terminal oocytes, where FOXN1 activates Ptbp1 and leads to egg-hatching synchrony in response to high population density. Additionally, PTBP1-prompted nuclear export of pre-miR-276 is conserved in insects, implying a ubiquitous mechanism to mediate transgenerational effects.

Clonal Transgenerational Effects of Parental Grazing Environment on Offspring Shade Avoidance

Grassland plants that endure livestock grazing exhibit a dwarf phenotype, which can be transmitted to clonal offspring. Yet to date, it remains poorly understood whether such transgenerational dwarf effects alter the plants’ response to shade. Here, we conducted a common garden experiment under sunlight and shade conditions with clonal Leymus chinensis offspring, the parents of which had endured livestock overgrazing (OG) and non-grazing (NG) in the field, respectively. Plant morphological, physiological, and transcriptomic analyses were carried out. The results indicated that NG offspring showed greater shade avoidance than OG offspring. That is, NG offspring exhibited greater plasticity of vegetative height and leaf width, which may be contributed to their greater photosynthetic capacity and gibberellin (GA3) content compared with OG offspring when treated with shade. In addition, RNA-Seq profiling showed that differentially expressed genes in NG offspring were mainly enriched in RNA modification and metabolic processes, which facilitated rapid response to shade. Phytochrome interacting factors (PIFs) promoted downstream shade marker genes in NG offspring by significantly downregulating the expression of PHYC, SPY, and DELLA. Our findings suggest that light conditions should be taken into account to better understand transgenerational dwarf effects induced by livestock grazing on grassland ecosystems. These results provide new insights into the inducible factors of phenotypic variations in grassland plants that experience grazing.

Mechanistic insights into the parental co-exposure of T-2 toxin and epoxiconazole on the F1 generation of zebrafish (Danio rerio)

Mycotoxins and pesticides frequently coexist in agricultural commodities on a global scale. The potential transgenerational consequences induced by these substances pose a significant threat to human health. However, there is a lack of data concerning the effects of co-contamination by these chemicals in the F1 generation following parental exposure. This investigation delved into the mixture effects of T-2 toxin (T-2) and epoxiconazole (EPO) on the offspring of zebrafish (Danio rerio). The findings revealed that exposure across generations to a combination of T-2 and EPO resulted in toxicity in the larvae of the F1 generation. This was demonstrated by a significant increase in the levels or activities of malondialdehyde (MDA), thyroxine (T4), Caspase3, and cas9, along with a decrease in the levels of cyp19a, ERα, and ERβ. These outcomes suggested that cross-generational exposure to T-2 and EPO in D. rerio disrupted oxidative balance, induced cell apoptosis, and affected the endocrine system. Moreover, these effects were magnified when the F1 generation was continuously exposed to these compounds. Notably, these adverse effects could persist in subsequent generations without additional exposure. This study underscored the potential dangers associated with the simultaneous presence of T-2 and EPO on the development of fish offspring and the resulting environmental hazards to aquatic ecosystems. These findings emphasized the significant health risks posed by cross-generational exposure and highlighted the need for additional legislative measures to address these concerns.

“A Different Creature, Not So Human”: Globalgothic Shapeshifting and Weaponzed Rape in Nnedi Okorafor’s Who Fears Death

Abstract This essay explores Nnedi Okorafor’s engagement with the traumatic consequences of a civil war in Africa through the shapeshifting motif in her novel Who Fears Death (2010). It argues that the interaction between Africanjujuism and globalgothic allows her to transcend the specificities of the conflict and address the transgenerational effects of ethnic violence as a global problem. Okorafor employs Africanjujuism to describe the protagonist’s shapeshifting as a means of healing, empowerment, and knowledge. In contrast, she uses Gothic tropes to depict extreme violence. Representing a girl born of wartime rape as the trickster god Eshu, who adds hope to a dark moment in history, constitutes a strong critique of a society in which women victims of war rape are often ignored and their children stigmatized.

Regeneration niche of Cortaderia selloana in an invaded region: Flower predation, environmental stress, and transgenerational effects

Background and aimsBiological invasions are causing massive environmental, social, and economic impacts worldwide. Understanding the ecological factors that affect the regeneration of invasive plants is critical to develop action plans based on empirical biological evidence. In this study, we investigate ecological limits in the regeneration of Cortaderia selloana, an invasive species with a strong impact in temperate regions. MethodsWe sampled 22 sites invaded by C. selloana along an environmental gradient in northern Spain to evaluate the influence of flower predation, environmental stress, and transgenerational effects on the performance of C. selloana offspring. Key resultsWe found that over half of the sampled flowers per individual contained larvae of Spanolepis selloanae, a recently discovered predator of C. selloana. This finding suggests that the presence of this natural enemy extends over a larger area than previously thought, which might drastically reduce seed production. A common-garden experiment conducted with over 5,200 seeds revealed that seed germination is significantly enhanced with increasing temperatures (with an optimum temperature of 22/12 °C day/night temperatures), and that seedling survival and growth are highest under waterlogged soil conditions. Our experiments also suggest that the minimum temperature for germination of C. selloana is 10 °C, and that seedlings can survive up to one month without water. These findings can improve management programs by delineating which areas are at high risk of invasion and which ones are unsuitable for the regeneration of C. selloana. We also found that seed mass and maternal plant size are positively correlated with seed germination and early seedling growth. Progeny from dry maternal environments performed better under continuous drought conditions and the opposite was found under wet conditions. ConclusionsOverall, our results suggest that flower predators, environmental stress, and transgenerational effects have complex and profound effects on early demographic stages of C. selloana, influencing seed production, seed germination, seedling growth, and seedling survival.

Molecular mechanisms of environmental pollutant-induced cartilage damage: from developmental disorders to osteoarthritis.

The objective of the present study was to review the molecular mechanisms of the adverse effects of environmental pollutants on chondrocytes and extracellular matrix (ECM). Existing data demonstrate that both heavy metals, including cadmium (Cd), lead (Pb), and arsenic (As), as well as organic pollutants, including polychlorinated dioxins and furans (PCDD/Fs) and polychlorinated biphenyls (PCB), bisphenol A, phthalates, polycyclic aromatic hydrocarbons (PAH), pesticides, and certain other organic pollutants that target cartilage ontogeny and functioning. Overall, environmental pollutants reduce chondrocyte viability through the induction apoptosis, senescence, and inflammatory response, resulting in cell death and impaired ECM production. The effects of organic pollutants on chondrocyte development and viability were shown to be mediated by binding to the aryl hydrocarbon receptor (AhR) signaling and modulation of non-coding RNA expression. Adverse effects of pollutant exposures were observed in articular and growth plate chondrocytes. These mechanisms also damage chondrocyte precursors and subsequently hinder cartilage development. In addition, pollutant exposure was shown to impair chondrogenesis by inhibiting the expression of Sox9 and other regulators. Along with altered Runx2 signaling, these effects also contribute to impaired chondrocyte hypertrophy and chondrocyte-to-osteoblast trans-differentiation, resulting in altered endochondral ossification. Several organic pollutants including PCDD/Fs, PCBs and PAHs, were shown to induce transgenerational adverse effects on cartilage development and the resulting skeletal deformities. Despite of epidemiological evidence linking human environmental pollutant exposure to osteoarthritis or other cartilage pathologies, the data on the molecular mechanisms of adverse effects of environmental pollutant exposure on cartilage tissue were obtained from studies in laboratory rodents, fish, or cell cultures and should be carefully extrapolated to humans, although they clearly demonstrate that cartilage should be considered a putative target for environmental pollutant toxicity.

Carry-Over Effects of Broodstock Conditioning on the Salinity Tolerance of Embryos of the New Zealand Geoduck (Panopea zelandica)

The New Zealand geoduck (Panopea zelandica) has seen considerable interest from the NZ aquaculture industry. A major bottleneck in culturing P. zelandica is early life stages mortality (e.g., embryo). Therefore, in this study, we investigated the embryonic performance and their transition to the first feeding larval stage (D-veliger) under different salinities (26, 30, 32, and 35 ppt) of four different offspring groups generated from broodstock being fed different ratios (25 : 75, 50 : 50, 60 : 40, and 75 : 25) of the haptophyte Tisochrysis lutea (formerly Isochrysis galbana) (ISO) and the diatom Chaetoceros muelleri (CM) during gametogenesis. Broodstock within all diet ratio treatments successfully conditioned, producing viable embryos. Average egg size ranged between 75 and 80 µm and was not affected by the diet ratios of the broodstock. Survival 48 hr postfertilization, D-veliger larvae yield, and incidence of abnormalities depended on both the embryo rearing salinity and broodstock feeding ratios. The combined salinity of 32−35 ppt and a feeding ratio of 50 : 50 and 60 : 40 (ISO:CM) had the highest survival of embryos (56.0%–77.5%), highest production of D-veliger larvae (>65%), and lowest incidence of abnormalities within D-Veliger (<47%). The size of the larvae decreased with decreasing salinities, with the largest found at 35 ppt (101.22 ± 0.49 µm in shell length). Embryos and larvae did not survive at salinity 26 ppt. These results suggest that diet during gametogenesis can play a role on the offspring ability to cope with environmental stressors at least during the critical first few days after fertilization. These findings provide important information on transgenerational effects due to broodstock diet, especially during the early life stages.

Microplastic exposure is associated with epigenomic effects in the model organism Pimephales promelas (fathead minnow).

Microplastics have evolutionary and ecological impacts across species, affecting organisms' development, reproduction, and behavior along with contributing to genotoxicity and stress. As plastic pollution is increasing and ubiquitous, gaining a better understanding of organismal responses to microplastics is necessary. Epigenetic processes such as DNA methylation are heritable forms of molecular regulation influenced by environmental conditions. Therefore, determining such epigenetic responses to microplastics will reveal potential chronic consequences of this environmental pollutant. We performed an experiment across two generations of fathead minnows (Pimephales promelas) to elucidate transgenerational epigenetic effects of microplastic exposure. We exposed the first generation of fish to four different treatments of microplastics: two concentrations of each of pre-consumer polyethylene (PE) and PE collected from Lake Ontario. We then raised the first filial generation with no microplastic exposure. We used enzymatic methylation sequencing on adult liver tissue and homogenized larvae to evaluate DNA methylation differences among treatments, sexes, and generations. Our findings show the origin of the plastic had a larger effect in female minnows whereas the effect of concentration was stronger in the males. We also observed transgenerational effects, highlighting a mechanism in which parents can pass on the effects of microplastic exposure to their offspring. Many of the genes found within differentially methylated regions in our analyses are known to interact with estrogenic chemicals associated with plastic and are related to metabolism. This study highlights the persistent and potentially serious impacts of microplastic pollution on gene regulation in freshwater systems.

Transmission of reduced levels of miR-34/449 from sperm to preimplantation embryos is a key step in the transgenerational epigenetic inheritance of the effects of paternal chronic social instability stress

ABSTRACT The transgenerational effects of exposing male mice to chronic social instability (CSI) stress are associated with decreased sperm levels of multiple members of the miR-34/449 family that persist after their mating through preimplantation embryo (PIE) development. Here we demonstrate the importance of these miRNA changes by showing that restoring miR-34c levels in PIEs derived from CSI stressed males prevents elevated anxiety and defective sociability normally found specifically in their adult female offspring. It also restores, at least partially, levels of sperm miR-34/449 normally reduced in their male offspring who transmit these sex-specific traits to their offspring. Strikingly, these experiments also revealed that inducing miR-34c levels in PIEs enhances the expression of its own gene and that of miR-449 in these cells. The same induction of embryo miR-34/449 gene expression likely occurs after sperm-derived miR-34c is introduced into oocytes upon fertilization. Thus, suppression of this miRNA amplification system when sperm miR-34c levels are reduced in CSI stressed mice can explain how a comparable fold-suppression of miR-34/449 levels can be found in PIEs derived from them, despite sperm containing ~50-fold lower levels of these miRNAs than those already present in PIEs. We previously found that men exposed to early life trauma also display reduced sperm levels of miR-34/449. And here we show that miR-34c can also increase the expression of its own gene, and that of miR-449 in human embryonic stem cells, suggesting that human PIEs derived from men with low sperm miR-34/449 levels may also contain this potentially harmful defect.

Photoaged Nanopolystyrene Affects Neurotransmission to Induce Transgenerational Neurotoxicity in Caenorhabditis elegans.

Nanopolystyrene (NPS), a frequently employed nanoplastic, is an emerging environmental contaminant known to cause neurotoxicity in various organisms. However, the potential for transgenerational neurotoxic effects, especially from photoaged NPS (P-NPS), remains underexplored. This study investigated the aging of virgin NPS (V-NPS) under a xenon lamp to simulate natural sunlight exposure, which altered the physicochemical characteristics of the NPS. The parental generation (P0) of Caenorhabditis elegans was exposed to environmental concentrations (0.1-100 μg/L) of V-NPS and P-NPS, with subsequent offspring (F1-F4 generations) cultured under NPS-free conditions. Exposure to 100 μg/L P-NPS resulted in more pronounced deterioration in locomotion behavior in the P0 generation compared to V-NPS; this deterioration persisted into the F1-F2 generations but returned to normal in the F3-F4 generations. Additionally, maternal exposure to P-NPS damaged dopaminergic, glutamatergic, and serotonergic neurons in subsequent generations. Correspondingly, there was a significant decrease in the levels of dopamine, glutamate, and serotonin, associated with reduced expression of neurotransmission-related genes dat-1, eat-4, and tph-1 in the P0 and F1-F2 generations. Further analysis showed that the effects of P-NPS on locomotion behavior were absent in subsequent generations of eat-4(ad572), tph-1(mg280), and dat-1(ok157) mutants, highlighting the pivotal roles of these genes in mediating P-NPS-induced transgenerational neurotoxicity. These findings emphasize the crucial role of neurotransmission in the transgenerational effects of P-NPS on locomotion behavior, providing new insights into the environmental risks associated with exposure to photoaged nanoplastics.

Effect of transgenerational diabetes via maternal lineage in female rats

AimTo investigate the transgenerational effect of maternal hyperglycemia on oxidative stress markers, lipid profile, glycemia, pancreatic beta (β)-cells, and reproductive outcomes in the F2 adult generation. Additionally, to expand the knowledge on transgenerational diabetes the F3 generation at birth will be evaluated. MethodsOn day 5 of postnatal life female Sprague-Dawley rat newborns (F0 generation) were distributed into two groups: Diabetic (Streptozotocin-STZ, 70 mg/kg body weight, subcutaneous route) and Control rats. Adult female rats from the F0 generation and subsequently the F1 generation were mated to obtain the F2 generation, which was distributed into F2 generation (granddaughters) from control (F2_C) and diabetic (F2_D) rats. Oral Glucose Tolerance Test (OGTT), the area under the curve (AUC), blood biochemical analyses, and pancreatic morphology were analyzed before pregnancy. Reproductive outcomes were performed at the end of pregnancy. At birth, the glycemia and body weight of F3_C and F3_D rats were determined. p < 0.05 was considered significant. ResultsF2_D had higher body weight, triglyceride levels, and percentage of insulin-immunostained cells, contributing to glucose intolerance, and insulin resistance before pregnancy. At day 21 of pregnancy, the F2_D showed increased embryonic losses before and after implantation (84.33 and 83.74 %, respectively). At birth, F3_D presented hyperglycemia, and 16.3 % of newborns were large for pregnancy age (LGA). ConclusionDiabetes induction since the neonatal period in the first generation (F0) led to transgenerational (F2 and F3 generations) changes via the maternal lineage of female rats, confirming the relevance of control strictly the glycemia all the time.

Long-term exposure of zebrafish (Danio rerio) to Cr(VI): Reproductive toxicity and neurotoxicity

Hexavalent chromium (Cr (VI) or Cr6+) has gradually become an ecological threat to animal reproductive and nervous systems. In the current study, zebrafish (wild-type AB) were used as model to evaluate the effects of Cr (VI) exposure toxicity on the reproduction, neurotoxicity and offspring adverse development in adult zebrafish and larval offspring. In this study, Cr (VI) exposure interfered with gonadal development and serum hormone in zebrafish. Furthermore, Cr6+-induced brain injury, AChE activity and abnormal behavior in zebrafish. Finally, Cr (VI) exposure induces spontaneous movements, heart rate and malformation rate abnormalities in larval offspring (F1). Together, these results provide the evidence for Cr (VI)-induced reproductive toxicity and transgenerational effects in zebrafish.

Sex-specific transgenerational effects of diet on offspring life history and physiology.

Dietary variation in males and females can shape the expression of offspring life histories and physiology. However, the relative contributions of maternal and paternal dietary variation to phenotypic expression of latter generations is currently unknown. We provided male and female Drosophila melanogaster grandparents with diets differing in sucrose concentration prior to reproduction, and similarly subjected their grandoffspring to the same treatments. We then investigated the phenotypic consequences of this dietary variation among the grandsons and granddaughters. We observed transgenerational effects of dietary sucrose, mediated through the grandmaternal lineage, which mimic the direct effects of sucrose on lifespan, with opposing patterns across sexes; low sucrose increased female, but decreased male, lifespan. Dietary mismatching of grandoffspring-grandparent diets increased lifespan and reproductive success, and moderated triglyceride levels of grandoffspring, providing insights into the physiological underpinnings of the complex transgenerational effects on life histories.

Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism

Exposure to PM2.5, a harmful type of air pollution, has been associated with compromised male reproductive health; however, it remains unclear whether such exposure can elicit transgenerational effects on male fertility. Here, we aim to examine the effect of paternal exposure to real-world PM2.5 on the reproductive health of male offspring. We have observed that paternal exposure to real-world PM2.5 can lead to transgenerational primary hypogonadism in a sex-selective manner, and we have also confirmed this phenotype by using an external model. Mechanically, we have identified small RNAs (sRNAs) that play a critical role in mediating these transgenerational effects. Specifically, miR6240 and piR016061, which are present in F0 PM sperm, regulate intergenerational transmission by targeting Lhcgr and Nsd1, respectively. We have also uncovered that piR033435 and piR006695 indirectly regulate F1 PM sperm methylation by binding to the 3′-untranslated region of Tet1 mRNA. The reduced expression of Tet1 resulted in hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, impaired Leydig cell function and ultimately led to transgenerational primary hypogonadism. Our findings provide insights into the mechanisms underlying the transgenerational effects of paternal PM2.5 exposure on reproductive health, highlighting the crucial role played by sRNAs in mediating these effects. The findings underscore the significance of paternal pre-conception interventions in alleviating the adverse effects of environmental pollutants on reproductive health.

The transgenerational effects of maternal low-protein diet during lactation on offspring

Environmental factors such as diet and lifestyle can influence the health of both mothers and offspring. However, its transgenerational transmission and underlying mechanisms remain largely unknown. Here, using a maternal lactation-period low-protein diet (LPD) mouse model, we show that maternal LPD during lactation causes decreased survival and stunted growth, significantly reduces ovulation and litter size, and alters the gut microbiome in the female LPD-F1 offspring. The transcriptome of LPD-F1 metaphase II (MII) oocytes shows that differentially expressed genes are enriched in female pregnancy and multiple metabolic processes. Moreover, maternal LPD causes early stunted growth and impairs metabolic health, which is transmitted over two generations. The methylome alteration of LPD-F1 oocytes can be partly transmitted to the F2 oocytes. Together, our results reveal that LPD during lactation transgenerationally affects offspring health, probably via oocyte epigenetic changes.