Effects of non-inherited ancestral genotypes on offspring phenotypes

2021 ◽  
Author(s):  
Sean M Cullen ◽  
Nora Hassan ◽  
Matthew Smith-Raska
Keyword(s):  
Germ Cells ◽  
Disease Risk ◽  
Environmental Exposures ◽  
In Utero ◽  
Genetic Aberration ◽  
Alternate Routes

Abstract It is well established that environmental exposures can modify the profile of heritable factors in an individual’s germ cells, ultimately affecting the inheritance of phenotypes in descendants. Similar to exposures, an ancestor’s genotype can also affect the inheritance of phenotypes across generations, sometimes in offspring who do not inherit the genetic aberration. This can occur via a variety of prenatal, in utero, or postnatal mechanisms. In this review, we discuss the evidence for this process in mammals, with a focus on examples that are potentially mediated through the germline, while also considering alternate routes of inheritance. Non-inherited ancestral genotypes may influence descendant’s disease risk to a much greater extent than currently appreciated, and focused evaluation of this phenomenon may reveal novel mechanisms of inheritance.

scholarly journals The influence of birth weight and genetic factors on lipid levels: a study in adult twins

2006 ◽  
Vol 95 (3) ◽  
pp. 504-510 ◽  
Author(s):  
Chuluuntulga Tuya ◽  
William J. Mutch ◽  
Paul Haggarty ◽  
Doris M. Campbell ◽  
Alastair Cumming ◽  
...  
Keyword(s):  
Birth Weight ◽  
Disease Risk ◽  
Adult Life ◽  
In Utero ◽  
Growth Restriction ◽  
Inverse Association ◽  
Lipid Levels ◽  
Cholesterol Levels ◽  
Atherogenic Lipid Profile ◽  
Adult Twins

Twins can be used to investigate the biological basis for observed associations between birth weight and later disease risk, as they experiencein uterogrowth restriction compared with singletons, which can differ in magnitude within twin pairs despite partial or total genetic identity. In the present study, sixty monozygotic and seventy-one dizygotic same-sex twin pairs aged 19–50 years and eighty-nine singleton controls matched for age, gestational age, sex, maternal age and parity were recruited from an obstetric database. Associations between fasting lipid levels and birth weight were assessed by linear regression with adjustment for possible confounding factors. Twins were significantly lighter at birth but were not significantly different in adult height, weight or lipid levels from the singleton controls. There was a significant inverse association between birth weight and both total and LDL-cholesterol levels among singleton controls (−0·53mmol/l per kg (95% CI −0·97, −0·09),P=0·02 and −0·39mmol/l per kg (95% CI −0·76, −0·02),P=0·04, respectively), but there was no significant association between birth weight and lipid levels in either unpaired or within-pair analysis of twins. The results suggest that thein uterogrowth restriction and early catch-up growth experienced by twins does not increase the risk of an atherogenic lipid profile in adult life.

scholarly journals Factors Determining the Risk of Inadvertent Retroviral Transduction of Male Germ Cells After In Utero Gene Transfer in Sheep

2009 ◽  
Vol 20 (3) ◽  
pp. 201-215 ◽  
Author(s):  
Paul J. Park ◽  
Evan Colletti ◽  
Ferhat Ozturk ◽  
Josh A. Wood ◽  
Joe Tellez ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Germ Cells ◽  
In Utero ◽  
Male Germ Cells ◽  
Retroviral Transduction

scholarly journals The mitochondrial-dependent pathway is chronically affected in testicular germ cell death in adult rats exposed in utero to anti-androgens

2004 ◽  
Vol 183 (1) ◽  
pp. 79-90 ◽  
Author(s):  
A Bozec ◽  
F Chuzel ◽  
S Chater ◽  
C Paulin ◽  
R Bars ◽  
...  
Keyword(s):  
Germ Cells ◽  
Sertoli Cells ◽  
In Utero ◽  
Testicular Germ Cell ◽  
Adult Rats ◽  
Wide Range ◽  
Mrna And Protein Expression ◽  
Related Proteins ◽  
Dependent Pathway

In utero exposure to exogenous anti-androgenic compounds induces a wide range of abnormalities of the reproductive system, including hypospermatogenesis, cryptorchidism and hypospadias. By using rats exposed in utero to the anti-androgenic compound flutamide (0.4, 2 or 10 mg/kg per day), it has been shown that hypospermatogenesis in adult testes could be related to (i) a long-term apoptosis in germ cells but not in somatic Leydig and Sertoli cells as evidenced by the TUNEL approach and (ii) alterations in the mRNA and protein expression of pro- (Bax, Bak, Bid) and anti-apoptotic (Bcl-2, Bcl-w) members of the Bcl-2 family. Indeed, the number of apoptotic germ cells increased with the dose of flutamide administered and the apoptotic germ cells were mainly detected at androgen-dependent stages VII–VIII. Moreover, for the Bcl-2-related proteins that were expressed mainly in the germ cells, a decrease in the levels of anti-apoptotic peptides Bcl-w (60%, P=0.003) and Bcl-2 (90%, P=0.0001) was observed at 2 mg/kg per day flutamide and an increase in levels of the pro-apoptotic Bax (2.3-fold, P=0.0004) was detected at 10 mg/kg per day. In contrast, the levels of pro-apoptotic peptide Bak that was mainly expressed in somatic cells decreased (70%, P=0.0008) at 10 mg/kg per day. Such alterations in Bcl-2-related peptides occurred mainly at the protein level except for Bcl-2 (72%, P=0.0001) and Bak (43%, P=00002) transcripts. Together, these results showed that the apoptosis observed in adult germ cells from rats exposed in utero to flutamide may result from a long-term alteration in the balance between pro- and anti-apoptotic Bcl-2-related molecules in favour of pro-apoptotic proteins. These data further supported the concept of an androgen-dependent fetal programming that is in relation with an alteration of the expression of Bcl-2-related genes/proteins promoting apoptosis in testicular germ cells of adult rats with fetal androgen disruption.

The Epigenome and In-Utero Environmental Exposures

2018 ◽  
Vol 2018 (1) ◽  
Author(s):  
Mariona Bustamante ◽  
Todd M Everson ◽  
Marta Vives ◽  
Johanna Lepeule ◽  
Martine Vrijheid ◽  
...  
Keyword(s):  
Environmental Exposures ◽  
In Utero

scholarly journals Gestational hypercholesterolemia alters fetal hepatic lipid metabolism and microRNA expression in Apo-E-deficient mice

2019 ◽  
Vol 317 (5) ◽  
pp. E831-E838 ◽  
Author(s):  
Jerad H. Dumolt ◽  
Min Ma ◽  
Joyce Mathew ◽  
Mulchand S. Patel ◽  
Todd C. Rideout
Keyword(s):  
Lipid Metabolism ◽  
Mirna Expression ◽  
Molecular Mechanisms ◽  
Disease Risk ◽  
Pathological Condition ◽  
In Utero ◽  
In Utero Exposure ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Apo E

Maternal hypercholesterolemia (MHC) is a pathological condition characterized by an exaggerated rise in maternal serum cholesterol during gestation, which can alter offspring hepatic lipid metabolism. However, the extent that these maladaptations occur during gestation and the molecular mechanisms involved remain unknown. MicoRNAs (miRNA) are small, noncoding RNAs that contribute to the development and progression of nonalcoholic fatty liver disease. Therefore, we sought to determine the degree to which in utero exposure to excessive cholesterol affects fetal hepatic lipid metabolism and miRNA expression. Twelve female apoE−/− mice were randomly assigned to two different chow-based diets throughout gestation: control (CON) or the CON diet with cholesterol (0.15%). MHC reduced maternal fecundity and reduced litter size and weight. On gestational day 18, fetuses from MHC dams possessed increased placental cholesterol and hepatic triglycerides (TG), which were accompanied by a downregulation in the expression of hepatic lipogenic and TG synthesis and transport genes. Furthermore, fetal livers from MHC mothers showed increased miRNA-27a and reduced miRNA-200c expression. In summary, in utero exposure to MHC alters fetal lipid metabolism and lends mechanistic insight that implicates early changes in miRNA expression that may link to later-life programming of disease risk.

scholarly journals Environmental exposures in utero and microRNA

2014 ◽  
Vol 26 (2) ◽  
pp. 243-251 ◽  
Author(s):  
Maya Kappil ◽  
Jia Chen
Keyword(s):  
Environmental Exposures ◽  
In Utero

scholarly journals Alteration of Transforming Growth Factor-β Signaling System Expression in Adult Rat Germ Cells with a Chronic Apoptotic Cell Death Process after Fetal Androgen Disruption

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5135-5143 ◽  
Author(s):  
Magali Maire ◽  
Anne Florin ◽  
Krisztian Kaszas ◽  
Daniel Regnier ◽  
Pierre Contard ◽  
...  
Keyword(s):  
Cell Death ◽  
Germ Cell ◽  
Germ Cells ◽  
Apoptotic Cell ◽  
In Utero ◽  
Apoptotic Cell Death ◽  
Death Process ◽  
Rat Testis ◽  
Adult Rat ◽  
Cell Death Process

In utero exposure to chemicals with antiandrogen activity induces undescended testis, hypospadias, and sub- or infertility. The hypospermatogenesis observed in the adult rat testis exposed in utero to the antiandrogen flutamide has been reported to be a result of a long-term apoptotic cell death process in mature germ cells. However, little if anything is known about the upstream signaling mechanisms controlling this apoptosis. In the present study, we have investigated the possibility that the TGF-β signaling pathway may be at play in this control of the apoptotic germ cell death process. By using a model of adult rat exposed in utero to 0, 0.4, 2, or 10 mg/kg·d flutamide, we observed that pro-TGF-β signaling members, such as the three isoforms of TGF-β ligands (TGF-β1–3), the two TGF-β receptors (TGF-βRI and -RII) and the R-Smads Smad 1, Smad 2, Smad 3, and Smad 5 were inhibited at the mRNA and protein levels, whereas the anti-TGF-β signaling member Smad 7 was overexpressed. Furthermore, we report that the overexpression of Smad 7 mRNA could induce an activation of c-Jun N-terminal kinase, because of the observed c-Jun overexpression, activation, and nuclear translocation leading to an increase in the transcription of the proapoptotic factor Fas-L. Together, the alterations of TGF-β signaling may represent upstream mechanisms underlying the adult germ cell apoptotic process evidenced in adult rat testis exposed in utero to antiandrogenic compounds such as flutamide.

scholarly journals Nutritional adversity, sex and reproduction: 30 years of DOHaD and what have we learned?

2019 ◽  
Vol 242 (1) ◽  
pp. T51-T68 ◽  
Author(s):  
Patrycja A Jazwiec ◽  
Deborah M Sloboda
Keyword(s):  
Germ Cells ◽  
Early Life ◽  
Disease Risk ◽  
Primordial Germ Cells ◽  
Reproductive Function ◽  
Postnatal Life ◽  
Early Life Adversity ◽  
Increased Risk ◽  
Health And Disease

It is well established that early life environmental signals, including nutrition, set the stage for long-term health and disease risk – effects that span multiple generations. This relationship begins early, in the periconceptional period and extends into embryonic, fetal and early infant phases of life. Now known as the Developmental Origins of Health and Disease (DOHaD), this concept describes the adaptations that a developing organism makes in response to early life cues, resulting in adjustments in homeostatic systems that may prove maladaptive in postnatal life, leading to an increased risk of chronic disease and/or the inheritance of risk factors across generations. Reproductive maturation and function is similarly influenced by early life events. This should not be surprising, since primordial germ cells are established early in life and thus vulnerable to early life adversity. A multitude of ‘modifying’ cues inducing developmental adaptations have been identified that result in changes in reproductive development and impairments in reproductive function. Many types of nutritional challenges including caloric restriction, macronutrient excess and micronutrient insufficiencies have been shown to induce early life adaptations that produce long-term reproductive dysfunction. Many pathways have been suggested to underpin these associations, including epigenetic reprogramming of germ cells. While the mechanisms still remain to be fully investigated, it is clear that a lifecourse approach to understanding lifetime reproductive function is necessary. Furthermore, investigations of the impacts of early life adversity must be extended to include the paternal environment, especially in epidemiological and clinical studies of offspring reproductive function.

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