Inheritance Of Phenotype Research Articles

Phenotypic and genotypic approach of a large family with early onset tricuspid aortic valve sclerosis-stenosis: A multimodality evaluation

Aortic valve sclerosis-stenosis (AVS) is regarded a consequence of cardiovascular risk and genetic factors. Severe AVS is a significant cause of morbidity and mortality in 5% of individuals over 65 years of age. Despite previous attempts, little is known about genetics of AVS. We aimed to study genetic and non-genetic determinants of AVS in a large family with little cardiovascular risk factors. We identified a 5 generations large family of AVS. We proposed a screening to all relatives with clinical, biological and echocardiography assessment. Aortic valve (AV) calcium score was evaluated by CT scan. Biological assessment comprised especially DNA extraction for Next Generation Sequencing. The family comprises >100 relatives. To date 34 members (53.1 ± 14.7 years, 17 males) have been screened, 15 are affected (59.6 ± 10.8 years) and 19 non-affected (46.3 ± 13.6, P < 0.01). The youngest patient is a 36 years old woman with AV sclerosis. Echocardiographic examination revealed a unique inheritable phenotype of sclerosis or calcified progressive stenosis with a fusiform aorta in 7 patients. All AV were tricuspid, with a sclerosis in 12 (35.3%) or stenosis in 3 (8.8%). Aortic insufficiency (n = 6, 17.6%) was greater in affected members (P < 0.01). Ascending aorta was larger (38.8 ± 4.4 vs. 34.8 ± 8.7 mm, P = 0.05) and AV calcium was score greater (88.4 ± 199 vs. 0 UH) in affected members. High rate genotyping of 20 individuals allowed us to identify a common IBD (Identity By Descendance) region for all affected members on chromosome 5(rs4129875 to rs31619). Whole genome analysis was carried out in 4 cousins allowing the identification of 18 rare functional variants shared by at least 3 out of 4 sequenced individuals. Preliminary phenotypic and genetic approach of a large family of AVS reports a homogeneous and unique clinical portrait with early onset tricuspid AVS and fusiform aorta. While specific gene remains to be identified, IBD found a chromosome 5 region associated with AVS (Fig. 1).

Chromatin Modifiers SET-25 and SET-32 Are Required for Establishment but Not Long-Term Maintenance of Transgenerational Epigenetic Inheritance

Some epigenetic modifications are inherited from one generation to the next, providing a potential mechanism for the inheritance of environmentally acquired traits. Transgenerational inheritance of RNAi phenotypes in Caenorhabditis elegans provides an excellent model to study this phenomenon, and although studies have implicated both chromatin modifications and small RNA pathways in heritable silencing, their relative contributions remain unclear. Here, we demonstrate that the putative histone methyltransferases SET-25 and SET-32 are required for establishment of a transgenerational silencing signal but not for long-term maintenance of this signal between subsequent generations, suggesting that transgenerational epigenetic inheritance is a multi-step process with distinct genetic requirements for establishment and maintenance of heritable silencing. Furthermore, small RNA sequencing reveals that the abundance of secondary siRNAs (thought to be the effector molecules of heritable silencing) does not correlate with silencing phenotypes. Together, our results suggest that the current mechanistic models of epigenetic inheritance are incomplete.

Thyroid hormone influences brain gene expression programs and behaviors in later generations by altering germ line epigenetic information.

Genetic factors do not fully account for the relatively high heritability of neurodevelopmental conditions, suggesting that non-genetic heritable factors contribute to their etiology. To evaluate the potential contribution of aberrant thyroid hormone status to the epigenetic inheritance of neurological phenotypes, we examined genetically normal F2 generation descendants of mice that were developmentally overexposed to thyroid hormone due to a Dio3 mutation. Hypothalamic gene expression profiling in postnatal day 15 F2 descendants on the paternal lineage of ancestral male and female T3-overexposed mice revealed, respectively, 1089 and 1549 differentially expressed genes. A large number of them, 675 genes, were common to both sets, suggesting comparable epigenetic effects of thyroid hormone on both the male and female ancestral germ lines. Oligodendrocyte- and neuron-specific genes were strongly overrepresented among genes showing, respectively, increased and decreased expression. Altered gene expression extended to other brain regions and was associated in adulthood with decreased anxiety-like behavior, increased marble burying and reduced physical activity. The sperm of T3-overexposed male ancestors revealed significant hypomethylation of CpG islands associated with the promoters of genes involved in the early development of the central nervous system. Some of them were candidates for neurodevelopmental disorders in humans including Nrg3, Nrxn1, Gabrb3, Gabra5, Apba2, Grik3, Reln, Nsd1, Pcdh8, En1 and Elavl2. Thus, developmental levels of thyroid hormone influence the epigenetic information of the germ line, disproportionately affecting genes with critical roles in early brain development, and leading in future generations to disease-relevant alterations in postnatal brain gene expression and adult behavior.

Phenotypic plasticity of polyploid plant species promotes transgressive behaviour in their hybrids.

Hybridization is a frequent process that leads to relevant evolutionary consequences, but there is a lack of studies regarding the relationships of the variability of the response of parental plant species to environmental gradients and the responses of their hybrids at a phenotypic level. We designed an experiment in which we exposed two reciprocal cordgrass hybrids, Spartina maritima × densiflora and S. densiflora × maritima, and their parental species to four salinity concentrations for 30 days. The main objectives were to compare the performance of the hybrids with that of their parents, to distinguish the phenotypic inheritance operating in the hybrids and to analyse the relationships between the variability in the responses of the parents and the responses of their hybrids to salinity. We characterized the responses and the degree of variability for 37 foliar traits. Both hybrids presented greater salinity tolerance than their parents, showing their highest percentage of transgressive traits at both extremes of the salinity gradient. When the parental plants themselves showed a more plastic response for a given trait, there was a greater chance that their hybrid developed a transgressive behaviour for this trait. This finding supports a new focus to be applied for the artificial development of vigorous hybrid crops.

New Insights into the Melanophilin (MLPH) Gene Affecting Coat Color Dilution in Rabbits.

Coat color dilution corresponds to a specific pigmentation phenotype that leads to a dilution of wild type pigments. It affects both eumelanin and pheomelanin containing melanosomes. The mode of inheritance of the dilution phenotype is autosomal recessive. Candidate gene approaches focused on the melanophilin (MLPH) gene highlighted two variants associated with the dilution phenotype in rabbits: The c.111-5C>A variant that is located in an acceptor splice site or the c.585delG variant, a frameshift mutation. On the transcript level, the skipping of two exons has been reported as the molecular mechanism responsible for the coat color dilution. To clarify, which of the two variants represents the causal variant, (i) we analyzed their allelic segregation by genotyping Castor and Chinchilla populations, and (ii) we evaluated their functional effects on the stability of MLPH transcripts in skin samples of animals with diluted or wild type coat color. Firstly, we showed that the c.585delG variant showed perfect association with the dilution phenotype in contrast to the intronic c.111-5C>A variant. Secondly, we identified three different MLPH isoforms including the wild type isoform, the exon-skipping isoform and a retained intron isoform. Thirdly, we observed a drastic and significant decrease of MLPH transcript levels in rabbits with a coat color dilution (p-values ranging from 10−03 to 10−06). Together, our results bring new insights into the coat color dilution trait.

Novel Epigenetic Techniques Provided by the CRISPR/Cas9 System.

Epigenetics classically refers to the inheritable changes of hereditary information without perturbing DNA sequences. Understanding mechanisms of how epigenetic factors contribute to inheritable phenotype changes and cell identity will pave the way for us to understand diverse biological processes. In recent years, the emergence of CRISPR/Cas9 technology has provided us with new routes to the epigenetic field. In this review, novel epigenetic techniques utilizing the CRISPR/Cas9 system are the main contents to be discussed, including epigenome editing, temporal and spatial control of epigenetic effectors, noncoding RNA manipulation, chromatin in vivo imaging, and epigenetic element screening.

Effects of DISC1 Polymorphisms on Resting-State Spontaneous Neuronal Activity in the Early-Stage of Schizophrenia

Background: Localized abnormalities in the synchrony of spontaneous neuronal activity, measured with regional homogeneity (ReHo), has been consistently reported in patients with schizophrenia (SCZ) and their unaffected siblings. To date, little is known about the genetic influences affecting the spontaneous neuronal activity in SCZ. DISC1, a strong susceptible gene for SCZ, has been implicated in neuronal excitability and synaptic function possibly associated with regional spontaneous neuronal activity. This study aimed to examine the effects of DISC1 variations on the regional spontaneous neuronal activity in SCZ.Methods: Resting-state fMRI data were obtained from 28 SCZ patients and 21 healthy controls (HC) for ReHo analysis. Six single nucleotide polymorphisms (SNPs) of DISC1 gene were genotyped using the PCR and direct sequencing.Results: Significant diagnosis × genotype interactions were noted for three SNPs (rs821616, rs821617, and rs2738880). For rs821617, the interactions were localized to the precuneus, basal ganglia and pre-/post-central regions. Significant interactive effects were identified at the temporal and post-central gyri for rs821616 (Ser704Cys) and the inferior temporal gyrus for rs2738880. Furthermore, post-hoc analysis revealed that the DISC1 variations on these SNPs exerted different influences on ReHo between SCZ patients and HC.Conclusion: To our knowledge this is the first study to unpick the influence of DISC1 variations on spontaneous neuronal activity in SCZ; Given the emerging evidence that ReHo is a stable inheritable phenotype for schizophrenia, our findings suggest the DISC1 variations are possibly an inheritable source for the altered ReHo in this disorder.

Dairy cows - an opportunity in the research field of non-genetic inheritance?

More than 1 billion cattle are raised annually for meat and milk production. Dairy cows are repeatedly impregnated and separated from their calves, usually within the first 24 h after birth. Here, I suggest that dairy cows undergo a procedure comparable to the ‘Maternal separation combined with unpredictable maternal stress’ paradigm (MSUS), which is used to study the non-genetic inheritance (NGI) of phenotypes in rodents. I discuss what research on dairy cows may bring to the research field of NGI. The resulting research findings are likely to have benefits to our understanding of MSUS, NGI and consumer safety.

Modelling the influence of parental effects on gene-network evolution.

Understanding the importance of nongenetic heredity in the evolutionary process is a major topic in modern evolutionary biology. We modified a classical gene-network model by allowing parental transmission of gene expression and studied its evolutionary properties through individual-based simulations. We identified ontogenetic time (i.e. the time gene networks have to stabilize before being submitted to natural selection) as a crucial factor in determining the evolutionary impact of this phenotypic inheritance. Indeed, fast-developing organisms display enhanced adaptation and greater robustness to mutations when evolving in presence of nongenetic inheritance (NGI). In contrast, in our model, long development reduces the influence of the inherited state of the gene network. NGI thus had a negligible effect on the evolution of gene networks when the speed at which transcription levels reach equilibrium is not constrained. Nevertheless, simulations show that intergenerational transmission of the gene-network state negatively affects the evolution of robustness to environmental disturbances for either fast- or slow-developing organisms. Therefore, these results suggest that the evolutionary consequences of NGI might not be sought only in the way species respond to selection, but also on the evolution of emergent properties (such as environmental and genetic canalization) in complex genetic architectures.

A Genomic Imprinting Model of Termite Caste Determination: Not Genetic but Epigenetic Inheritance Influences Offspring Caste Fate.

Eusocial insects exhibit the most striking example of phenotypic plasticity. There has been a long controversy over the factors determining caste development of individuals in social insects. Here we demonstrate that parental phenotypes influence the social status of offspring not through genetic inheritance but through genomic imprinting in termites. Our extensive field survey and genetic analysis of the termite Reticulitermes speratus show that its breeding system is inconsistent with a genetic caste determination model. We therefore developed a genomic imprinting model, in which queen- and king-specific epigenetic marks antagonistically influence sexual development of offspring. The model accounts for all known empirical data on caste differentiation of R. speratus and other related species. By conducting colony-founding experiments and additively incorporating relevant socio-environmental factors into our genomic imprinting model, we show the relative importance of genomic imprinting and environmental factors in caste determination. The idea of epigenetic inheritance of sexual phenotypes solves the puzzle of why parthenogenetically produced daughters carrying only maternal chromosomes exclusively develop into queens and why parental phenotypes (nymph- or worker-derived reproductives) strongly influence caste differentiation of offspring. According to our model, the worker caste is seen as a "neuter" caste whose sexual development is suppressed due to counterbalanced maternal and paternal imprinting and opens new avenues for understanding the evolution of caste systems in social insects.

Piecing together cis-regulatory networks: insights from epigenomics studies in plants.

5-Methylcytosine, a chemical modification of DNA, is a covalent modification found in the genomes of both plants and animals. Epigenetic inheritance of phenotypes mediated by DNA methylation is well established in plants. Most of the known mechanisms of establishing, maintaining and modifying DNA methylation have been worked out in the reference plant Arabidopsis thaliana. Major functions of DNA methylation in plants include regulation of gene expression and silencing of transposable elements (TEs) and repetitive sequences, both of which have parallels in mammalian biology, involve interaction with the transcriptional machinery, and may have profound effects on the regulatory networks in the cell. Methylome and transcriptome dynamics have been investigated in development and environmental responses in Arabidopsis and agriculturally and ecologically important plants, revealing the interdependent relationship among genomic context, methylation patterns, and expression of TE and protein coding genes. Analyses of methylome variation among plant natural populations and species have begun to quantify the extent of genetic control of methylome variation vs. true epimutation, and model the evolutionary forces driving methylome evolution in both short and long time scales. The ability of DNA methylation to positively or negatively modulate binding affinity of transcription factors (TFs) provides a natural link from genome sequence and methylation changes to transcription. Technologies that allow systematic determination of methylation sensitivities of TFs, in native genomic and methylation context without confounding factors such as histone modifications, will provide baseline datasets for building cell-type- and individual-specific regulatory networks that underlie the establishment and inheritance of complex traits. This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Biological Mechanisms > Regulatory Biology.

Atrazine induced epigenetic transgenerational inheritance of disease, lean phenotype and sperm epimutation pathology biomarkers.

Ancestral environmental exposures to a variety of environmental toxicants and other factors have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The current study examined the potential transgenerational actions of the herbicide atrazine. Atrazine is one of the most commonly used herbicides in the agricultural industry, in particular with corn and soy crops. Outbred gestating female rats were transiently exposed to a vehicle control or atrazine. The F1 generation offspring were bred to generate the F2 generation and then the F2 generation bred to generate the F3 generation. The F1, F2 and F3 generation control and atrazine lineage rats were aged and various pathologies investigated. The male sperm were collected to investigate DNA methylation differences between the control and atrazine lineage sperm. The F1 generation offspring (directly exposed as a fetus) did not develop disease, but weighed less compared to controls. The F2 generation (grand-offspring) was found to have increased frequency of testis disease and mammary tumors in males and females, early onset puberty in males, and decreased body weight in females compared to controls. The transgenerational F3 generation rats were found to have increased frequency of testis disease, early onset puberty in females, behavioral alterations (motor hyperactivity) and a lean phenotype in males and females. The frequency of multiple diseases was significantly higher in the transgenerational F3 generation atrazine lineage males and females. The transgenerational transmission of disease requires germline (egg or sperm) epigenetic alterations. The sperm differential DNA methylation regions (DMRs), termed epimutations, induced by atrazine were identified in the F1, F2 and F3 generations. Gene associations with the DMRs were identified. For the transgenerational F3 generation sperm, unique sets of DMRs (epimutations) were found to be associated with the lean phenotype or testis disease. These DMRs provide potential biomarkers for transgenerational disease. The etiology of disease appears to be in part due to environmentally induced epigenetic transgenerational inheritance, and epigenetic biomarkers may facilitate the diagnosis of the ancestral exposure and disease susceptibility. Observations indicate that although atrazine does not promote disease in the directly exposed F1 generation, it does have the capacity to promote the epigenetic transgenerational inheritance of disease.

A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans.

Renal agenesis (RA) is one of the more extreme examples of congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis is almost invariably fatal at birth, and unilateral renal agenesis can lead to future health issues including end-stage renal disease. Genetic investigations have identified several gene variants that cause RA, including EYA1, LHX1, and WT1 However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we carried out whole exome sequence analysis of two families showing inheritance of an RA phenotype, and in both identified a single candidate gene, GREB1L Analysis of a zebrafish greb1l loss-of-function mutant revealed defects in the pronephric kidney just prior to death, and F0 CRISPR/Cas9 mutagenesis of Greb1l in the mouse revealed kidney agenesis phenotypes, implicating Greb1l in this disorder. GREB1L resides in a chromatin complex with RAR members, and our data implicate GREB1L as a coactivator for RARs. This study is the first to associate a component of the RAR pathway with renal agenesis in humans.

Simple inheritance of a complex trait: figured wood in curly birch is caused by one semi-dominant and lethal Mendelian factor?

Even though individuals with a deviant morphology have been elemental in genetics of model species, they have thus far been largely ignored in the studies of forest trees. Here we studied the inheritance of curly-grained and brown-figured wood phenotype in curly birch (Betula pendula var. carelica (Mercklin) Hämet-Ahti). In addition of the figured wood, curly birches display reduced and aberrant growth, indicating that the causative locus (loci) is (are) vital for normal tree development. To explore the genetic basis of this mutation, we studied the inheritance of the curly birch phenotype in a progeny trial (crosses between curly birch parent trees, between curly and normal phenotypes, and from selfings of curly trees). Based on the external morphology, the phenotypes of 11-year-old progeny trees were scored as either curly or wild. Based on the phenotypic segregation ratios, we postulate a simple Mendelian inheritance model for curliness: (i) a one-locus, two-allele model in which the allele coding for curly phenotype is dominant over the allele coding for normal phenotype and (ii) the semi-dominant curly allele is lethal when homozygous. We expect that further studies on the molecular genetic basis of the curly birch phenotype will provide valuable information on the developmental pathways involved in wood formation.

Grandpaternal-induced transgenerational dietary reprogramming of the unfolded protein response in skeletal muscle

ObjectiveParental nutrition and lifestyle impact the metabolic phenotype of the offspring. We have reported that grandpaternal chronic high-fat diet (HFD) transgenerationally impairs glucose metabolism in subsequent generations. Here we determined whether grandpaternal diet transgenerationally impacts the transcriptome and lipidome in skeletal muscle. Our aim was to identify tissue-specific pathways involved in transgenerational inheritance of environmental-induced phenotypes. MethodsF0 male Sprague–Dawley rats were fed a HFD or chow for 12 weeks before breeding with chow-fed females to generate the F1 generation. F2 offspring were generated by mating F1 males fed a chow diet with an independent line of chow-fed females. F1 and F2 offspring were fed chow or HFD for 12 weeks. Transcriptomic and LC-MS lipidomic analyses were performed in extensor digitorum longus muscle from F2-females rats. Gene set enrichment analysis (GSEA) was performed to determine pathways reprogrammed by grandpaternal diet. ResultsGSEA revealed an enrichment of the unfolded protein response pathway in skeletal muscle of grand-offspring from HFD-fed grandfathers compared to grand-offspring of chow-fed males. Activation of the stress sensor (ATF6α), may be a pivotal point whereby this pathway is activated. Interestingly, skeletal muscle from F1-offspring was not affected in a similar manner. No major changes were observed in the skeletal muscle lipidome profile due to grandpaternal diet. ConclusionsGrandpaternal HFD-induced obesity transgenerationally affected the skeletal muscle transcriptome. This finding further highlights the impact of parental exposure to environmental factors on offspring's development and health.

The Pea (Pisum sativum L.) Rogue Paramutation is Accompanied by Alterations in the Methylation Pattern of Specific Genomic Sequences

The spontaneous emergence among common pea (Pisum sativum L.) cultivars of off-type rogue plants exhibiting leaves with narrower and pointed leaflets and stipules and the non-Mendelian inheritance of this new phenotype were first described in the early 20th century. However, so far, no studies at the molecular level of this first identified case of paramutation have been carried out. In this study, we show for the first time that the pea rogue paramutation is accompanied by alterations in the methylation status of specific genomic sequences. Although, no significant differences were observed in the genome-wide DNA methylation in leaves of non-rogue cv. Onward in comparison to its rogue paramutant line JI2723, 22 DNA sequences were identified by methylation-sensitive amplified fragment length polymorphisms (MS-AFLP) analysis as differentially methylated in the two epigenomes. Mitotically inherited through all leaf tissues, the differential methylation patterns were also found to be meiotically inherited and conserved in pollen grains for 12 out of the 22 sequences. Fourteen of the sequences were successfully amplified in cDNA but none of them exhibited significant differential expression in the two contrasting epigenotypes. The further exploitation of the present research results on the way towards the elucidation of the molecular mechanisms behind this interesting epigenetic phenomenon is discussed.

Inheritance of brewing-relevant phenotypes in constructed Saccharomyces cerevisiae\xa0\xd7\xa0Saccharomyces eubayanus hybrids

BackgroundInterspecific hybridization has proven to be a potentially valuable technique for generating de novo lager yeast strains that possess diverse and improved traits compared to their parent strains. To further enhance the value of hybridization for strain development, it would be desirable to combine phenotypic traits from more than two parent strains, as well as remove unwanted traits from hybrids. One such trait, that has limited the industrial use of de novo lager yeast hybrids, is their inherent tendency to produce phenolic off-flavours; an undesirable trait inherited from the Saccharomyces eubayanus parent. Trait removal and the addition of traits from a third strain could be achieved through sporulation and meiotic recombination or further mating. However, interspecies hybrids tend to be sterile, which impedes this opportunity.ResultsHere we generated a set of five hybrids from three different parent strains, two of which contained DNA from all three parent strains. These hybrids were constructed with fertile allotetraploid intermediates, which were capable of efficient sporulation. We used these eight brewing strains to examine two brewing-relevant phenotypes: stress tolerance and phenolic off-flavour formation. Lipidomics and multivariate analysis revealed links between several lipid species and the ability to ferment in low temperatures and high ethanol concentrations. Unsaturated fatty acids, such as oleic acid, and ergosterol were shown to positively influence growth at high ethanol concentrations. The ability to produce phenolic off-flavours was also successfully removed from one of the hybrids, Hybrid T2, through meiotic segregation. The potential application of these strains in industrial fermentations was demonstrated in wort fermentations, which revealed that the meiotic segregant Hybrid T2 not only didn’t produce any phenolic off-flavours, but also reached the highest ethanol concentration and consumed the most maltotriose.ConclusionsOur study demonstrates the possibility of constructing complex yeast hybrids that possess traits that are relevant to industrial lager beer fermentation and that are derived from several parent strains. Yeast lipid composition was also shown to have a central role in determining ethanol and cold tolerance in brewing strains.

Embryonic environment and transgenerational effects in quail

BackgroundEnvironmental exposures, for instance to chemicals, are known to impact plant and animal phenotypes on the long term, sometimes across several generations. Such transgenerational phenotypes were shown to be promoted by epigenetic alterations such as DNA methylation, an epigenetic mark involved in the regulation of gene expression. However, it is yet unknown whether transgenerational epigenetic inheritance of altered phenotypes exists in birds. The purpose of this study was to develop an avian model to investigate whether changes to the embryonic environment had a transgenerational effect that could alter the phenotypes of third-generation offspring. Given its impact on the mammalian epigenome and the reproductive system in birds, genistein was used as an environment stressor.ResultsWe compared several third-generation phenotypes of two quail “epilines”, which were obtained from genistein-injected eggs (Epi+) or from untreated eggs (Epi−) from the same founders. A “mirrored” crossing strategy was used to minimize between-line genetic variability by maintaining similar ancestor contributions across generations in each line. Three generations after genistein treatment, a significant difference in the sexual maturity of the females, which, after three generations, could not be attributed to direct maternal effects, was observed between the lines, with Epi+ females starting to lay eggs later. Adult body weight was significantly affected by genistein treatment applied in a previous generation, and a significant interaction between line and sex was observed for body weight at 3 weeks. Behavioral traits, such as evaluating the birds’ reaction to social isolation, were also significantly affected by genistein treatment. Yet, global methylation analyses revealed no significant difference between the epilines.ConclusionsThese findings demonstrate that embryonic environment affects the phenotype of offspring three generations later in quail. While one cannot rule out the existence of some initial genetic variability between the lines, the mirrored animal design should have minimized its effects, and thus, the observed differences in animals of the third generation may be attributed, at least partly, to transgenerational epigenetic phenomena.

Environmentally toxicant exposures induced intragenerational transmission of liver abnormalities in mice.

Environmental toxicants such as chemicals, heavy metals, and pesticides have been shown to promote transgenerational inheritance of abnormal phenotypes and/or diseases to multiple subsequent generations following parental and/or ancestral exposures. This study was designed to examine the potential transgenerational action of the environmental toxicant trichloroethane (TCE) on transmission of liver abnormality, and to elucidate the molecular etiology of hepatocyte cell damage. A total of thirty two healthy immature female albino mice were randomly divided into three equal groups as follows: a sham group, which did not receive any treatment; a vehicle group, which received corn oil alone, and TCE treated group (3 weeks, 100 μg/kg i.p., every 4th day). The F0 and F1 generation control and TCE populations were sacrificed at the age of four months, and various abnormalities histpathologically investigated. Cell death and oxidative stress indices were also measured. The present study provides experimental evidence for the inheritance of environmentally induced liver abnormalities in mice. The results of this study show that exposure to the TCE promoted adult onset liver abnormalities in F0 female mice as well as unexposed F1 generation offspring. It is the first study to report a transgenerational liver abnormalities in the F1 generation mice through maternal line prior to gestation. This finding was based on careful evaluation of liver histopathological abnormalities, apoptosis of hepatocytes, and measurements of oxidative stress biomarkers (lipid peroxidation, protein carbonylation, and nitric oxide) in control and TCE populations. There was an increase in liver histopathological abnormalities, cell death, and oxidative lipid damage in F0 and F1 hepatic tissues of TCE treated group. In conclusion, this study showed that the biological and health impacts of environmental toxicant TCE do not end in maternal adults, but are passed on to offspring generations. Hence, linking observed liver abnormality in the offspring to environmental exposure of their parental line. This study also illustrated that oxidative stress and apoptosis appear to be a molecular component of the hepatocyte cell injury.

The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy.

Autism spectrum disorder (ASD) is a heterogeneously pervasive developmental disorder in which various genetic and environmental factors are believed to underlie its development. Recently, epigenetics has been suggested as a novel concept for ASD aetiology with a proposition that epigenetic marks can be transgenerationally inherited. Based on this assumption of epigenetics, we investigated the transgenerational inheritance of ASD-like behaviours and their related synaptic changes in the VPA animal model of ASD. The first generation (F1) VPA-exposed offspring exhibited autistic-like impaired sociability and increased marble burying. They also showed increased seizure susceptibility, hyperactivity and decreased anxiety. We mated the VPA-exposed F1 male offspring with naïve females to produce the second generation (F2), and then similarly mated the F2 to deliver the third generation (F3). Remarkably, the autism-like behavioural phenotypes found in F1 persisted to the F2 and F3. Additionally, the frontal cortices of F1 and F3 showed some imbalanced expressions of excitatory/inhibitory synaptic markers, suggesting a transgenerational epigenetic inheritance. These results open the idea that E/I imbalance and ASD-like behavioural changes induced by environmental insults in mice can be epigenetically transmitted, at least, to the third generation. This study could help explain the unprecedented increase in ASD prevalence.