Multi-omics approach characterizes the role of Bisphenol F in disrupting hepatic lipid metabolism.

Bisphenol F (BPF), a substitute for bisphenol A (BPA), is ubiquitous existed in various environmental media. Exposure to BPF may promote non-alcoholic fatty liver disease (NAFLD), while the potential mechanism is still unknown. In current study, we used in vitro and in vivo model to evaluate its hepatotoxicity and molecular mechanism. Using multi-omics approach, we found that BPF exposure led to changes in hepatic transcriptome, metabolome and chromatin accessible regions that were enriched for binding sites of transcription factors in bZIP family. These alterations were enriched with pathways integral to the endoplasmic reticulum stress and NAFLD. These findings suggested that BPF exposure might reprogram the chromatin accessibility and enhancer landscape in the liver, with downstream effects on genes associated with endoplasmic reticulum stress and lipid metabolism, which relied on bZIP family transcription factors. Overall, our study describes comprehensive molecular alterations in hepatocytes after BPF exposure and provides new insights into the understanding of the hepatoxicity of BPF.

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.

Maternal BPAF exposure impaired synaptic development and caused behavior abnormality in offspring.

Bisphenol A (BPA) has been widely restricted, leading to a significant increase in the production of bisphenol AF (BPAF), one of the most common bisphenol analogs use as a substitute for BPA. However, there is limit evidence on the neurotoxicity of BPAF, especially the potential effects of maternal exposed to BPAF on offspring. A maternal BPAF exposure model was used to evaluate its effects on long-term neurobehaviors in offspring. We found that maternal BPAF exposure resulted in immune disorders, characterized by abnormal CD4+T cell subsets, and their offspring exhibited anxiety- and depression-like behaviors, as well as impairments in learning-memory, sociability and social novelty. Further, brain bulk RNA-sequencing (RNA-seq) and hippocampus single-nucleus RNA-sequencing (snRNA-seq) of offspring showed that differentially expressed genes (DEGs) were enriched in pathways related to synaptic and neurodevelopment. Synaptic ultra-structure of offspring was damaged after maternal BPAF exposure. In conclusion, maternal BPAF exposure induced behavior abnormality in adult offspring, together with synaptic and neurodevelopment defects, which might be related to maternal immune dysfunction. Our results provide a comprehensive insight into the neurotoxicity mechanism of maternal BPAF exposure during gestation. Given the increasing and ubiquitous exposure to BPAF, especially during sensitive periods of growth and development, the safety of BPAF requires urgent attention.

Early-life bisphenol AP exposure impacted neurobehaviors in adulthood through microglial activation in mice.

Bisphenol AP (BPAP), a structural analog of bisphenol A (BPA), has been widely detected in environment and biota. BPAP was reported to interfere with hormone and metabolism, while limited data were available about its effects on neurobehavior, especially exposure to it during early-life time. A mouse model of early-life BPAP exposure was established to evaluate the long-term neurobehaviors in offspring. Collectively, early-life BPAP exposure caused anxiety-like behaviors and impaired learning and memory in adult offspring. Through brain bulk RNA-sequencing (RNA-seq), we found differential expressed genes were enriched in pathways related to behaviors and neurodevelopment, which were consistent with the observed phenotype. Besides, single-nucleus RNA-sequencing (snRNA-seq) showed BPAP exposure altered the transcriptome of microglia in hippocampus. Mechanistically, BPAP exposure induced inflammations in hippocampus through upregulating Iba-1 and activating the microglia. In addition, we observed that BPAP exposure could activate peripheral immunity and promote proportion of macrophages and activation of dendritic cells in the offspring. In conclusion, early-life exposure to BPAP impaired neurobehaviors in adult offspring accompanied with excessive activation of hippocampal microglia. Our findings provide new clues to the underlying mechanisms of BPAP's neurotoxic effects and therefore more cautions should be taken about BPAP.

InDelGT: An integrated pipeline for extracting indel genotypes for genetic mapping in a hybrid population using next-generation sequencing data.

Premise: Although several software packages are available for genotyping insertion/deletion (indel) polymorphisms in genomes using next-generation sequencing data, simultaneously calling indel genotypes across many individuals for use in genetic mapping remains challenging. Methods and Results: We present an integrated pipeline, InDelGT, for the extraction of indel genotypes from a segregating population such as backcross or F2 lines, or from an F1 cross between outbred species. The InDelGT algorithm is implemented in three steps: generating an indel catalog, calling indel genotypes, and analyzing indel segregation. We demonstrated the use of the pipeline with an example data set from an F1 hybrid population of Populus and successfully constructed the two parental genetic linkage maps. Conclusions: InDelGT is a practical tool that can quickly genotype a large number of indel markers within a population following Mendelian segregation. The InDelGT pipeline is freely available on GitHub (https://github.com/tongchf/InDelGT).

A Novel Strategy for Constructing an Integrated Linkage Map in an F1 Hybrid Population of Populus deltoides and Populus simonii.

The genetic linkage maps of the traditional F2 population in inbred lines were estimated from the frequency of recombination events in both parents, providing full genetic information for genetic and genomic studies. However, in outbred forest trees, it is almost impossible to generate the F2 population because of their high heterozygosity and long generation times. We proposed a novel strategy to construct an integrated genetic linkage map that contained both parental recombination information, with restriction-site-associated DNA sequencing (RADSeq) data in an F1 hybrid population of Populus deltoides and Populus simonii. We selected a large number of specific RAD tags to construct the linkage map, each of which contained two SNPs, one heterozygous only in the female parent and the other heterozygous only in the male. Consequently, the integrated map contained a total of 1154 RAD tags and 19 linkage groups, with a total length of 5255.49 cM and an average genetic distance of 4.63 cM. Meanwhile, the two parent-specific linkage maps were also constructed with SNPs that were heterozygous in one parent and homozygous in the other. We found that the integrated linkage map was more consensus with the genomic sequences of P. simonii and P. deltoides. Additionally, the likelihood of the marker order in each linkage group of the integrated map was greater than that in both parental maps. The integrated linkage map was more accurate than the parent-specific linkage maps constructed in the same F1 hybrid population, providing a powerful genetic resource for identifying the quantitative trait loci (QTLs) with dominant effects, assembling genomic sequences, and performing comparative genomics in related Populus species. More importantly, this novel strategy can be used in other outbred species to build an integrated linkage map.

A Novel Strategy to Reveal the Landscape of Crossovers in an F1 Hybrid Population of Populus deltoides and Populus simonii.

Although the crossover (CO) patterns of different species have been extensively investigated, little is known about the landscape of CO patterns in Populus because of its high heterozygosity and long-time generation. A novel strategy was proposed to reveal the difference of CO rate and interference between Populus deltoides and Populus simonii using their F1 hybrid population. We chose restriction site-associated DNA (RAD) tags that contained two SNPs, one only receiving the CO information from the female P. deltoides and the other from the male P. simonii. These RAD tags allowed us to investigate the CO patterns between the two outbred species, instead of using the traditional backcross populations in inbred lines. We found that the CO rate in P. deltoides was generally greater than that in P. simonii, and that the CO interference was a common phenomenon across the two genomes. The COs landscape of the different Populus species facilitates not only to understand the evolutionary mechanism for adaptability but also to rebuild the statistical model for precisely constructing genetic linkage maps that are critical in genome assembly in Populus. Additionally, the novel strategy could be applied in other outbred species for investigating the CO patterns.

Genome Assembly of Salicaceae Populus deltoides (Eastern Cottonwood) I-69 Based on Nanopore Sequencing and Hi-C Technologies.

Populus deltoides has important ecological and economic values, widely used in poplar breeding programs due to its superior characteristics such as rapid growth and resistance to disease. Although the genome sequence of P. deltoides WV94 is available, the assembly is fragmented. Here, we reported an improved chromosome-level assembly of the P. deltoides cultivar I-69 by combining Nanopore sequencing and chromosome conformation capture (Hi-C) technologies. The assembly was 429.3 Mb in size and contained 657 contigs with a contig N50 length of 2.62 Mb. Hi-C scaffolding of the contigs generated 19 chromosome-level sequences, which covered 97.4% (418 Mb) of the total assembly size. Moreover, repetitive sequences annotation showed that 39.28% of the P. deltoides genome was composed of interspersed elements, including retroelements (23.66%), DNA transposons (6.83%), and unclassified elements (8.79%). We also identified a total of 44 362 protein-coding genes in the current P. deltoides assembly. Compared with the previous genome assembly of P. deltoides WV94, the current assembly had some significantly improved qualities: the contig N50 increased 3.5-fold and the proportion of gaps decreased from 3.2% to 0.08%. This high-quality, well-annotated genome assembly provides a reliable genomic resource for identifying genome variants among individuals, mining candidate genes that control growth and wood quality traits, and facilitating further application of genomics-assisted breeding in populations related to P. deltoides.