Transgenerational BPA exposure may contribute to autism

Transgenerational Bisphenol A Causes Deficits in Social Recognition and Alters Postsynaptic Density Genes in Mice, 2019

According to a recent mouse study, BPA exposure has transgenerational effects on gene linked to autism – social recognition test used for first time in mice showed behavioral deficit – the Endocrine Society reports.

2019 Study Abstract

Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical. Developmental exposure produces changes in behavior and gene expression in the brain. Here, we examined social recognition behaviors in mice from the third familial generation (F3) after exposure to gestational BPA. Second-generation mice were bred in one of four mating combinations to reveal whether characteristics in F3 were acquired via maternal or paternal exposures. After repeated habituation to the same mouse, offspring of dams from the BPA lineage failed to display increased investigation of a novel mouse. Genes involved in excitatory postsynaptic densities (PSDs) were examined in F3 brains using quantitative PCR. Differential expression of genes important for function and stability of PSDs were assessed at three developmental ages. Several related PSD genes―SH3 and multiple ankyrin repeat domains 1 (Shank1), Homer scaffolding protein 1c (Homer1c), DLG associated protein 1 (Gkap), and discs large MAGUK scaffold protein 4 (PSD95)―were differentially expressed in control- vs BPA-lineage brains. Using a second strain of F3 inbred mice exposed to BPA, we noted the same differences in Shank1 and PSD95 expression in C57BL/6J mice. In sum, transgenerational BPA exposure disrupted social interactions in mice and dysregulated normal expression of PSD genes during neural development. The fact that the same genetic effects were found in two different mouse strains and in several brain regions increased potential for translation. The genetic and functional relationship between PSD and abnormal neurobehavioral disorders is well established, and our data suggest that BPA may contribute in a transgenerational manner to neurodevelopmental diseases.

DES and the GENES

Tiny air pollution particles may lead to reduced sperm production

Particulate air pollution linked with reduced sperm production in mice, 2019

New Orleans, LA – Exposure to tiny air pollution particles may lead to reduced sperm production, suggests new research in mice, presented Monday, March 25 at ENDO 2019, the Endocrine Society’s annual meeting.

“Infertility rates are increasing around the world, and air pollution may be one of the main factors,”

said lead researcher Elaine Maria Frade Costa, M.D., Ph.D., of Sao Paulo University in Sao Paulo, Brazil.

The World Health Organization (WHO) estimates that approximately 15 percent of the global population has difficulty with fertility, and male infertility accounts for about half of those problems.

The study looked at the effect of particulate matter (PM) on sperm production. PM is a mixture of solid particles and liquid droplets found in the air. PM2.5 is a fine inhalable particle with diameters that are 2.5 micrometers or smaller. The average human hair is about 70 micrometers in diameters, making it 30 times larger than the biggest fine particle. PM2.5 is known to disrupt the endocrine system in humans and animals. The endocrine system is involved in reproduction, including the production of sperm.

The study included four groups of mice. One was exposed to PM2.5 from Sao Paolo before and after birth, from the day they were weaned from their mother’s milk until adulthood. The second group was exposed only during gestation. The third group was exposed after birth from weaning until adulthood; and the fourth group was exposed only to filtered air during gestation and from the time they were weaned until adulthood.

The researchers analyzed the testes of the mice and their production of sperm. DNA tests were used to evaluate gene expression, the process by which genes in DNA provide instructions for proteins.

The tubes in the testes that produce sperm of all the exposed mice showed signs of deterioration. In comparison with the mice not exposed to PM2.5, the sperm of the first group, which was exposed before and after birth, was of significantly worse quality.

The exposure to PM2.5 led to changes in the levels of genes related to testicular cell function. Exposure to PM2.5 after birth seemed to be the most harmful to testicular function, the study found.

Costa said these changes are epigenetic, which means they are not caused by changes in the DNA sequence. Epigenetic changes can switch genes on or off and determine which proteins a gene expresses.

The research demonstrates for the first time that exposure to air pollution of a large city impairs production of sperm through epigenetics, mainly in exposure after birth, Costa said.

“These findings provide more evidence that governments need to implement public policies to control air pollution in big cities,”

she said. Reference. Featured image.

Endocrine disruptors alter female reproduction throughout multiple generations

OR23-1 Transgenerational Effects of Endocrine Disrupting Chemicals on Pubertal Timing through Epigenetic Reprogramming of the Hypothalamus

According to a recent animal study, endocrine disruptors, hormone-altering chemicals that are widespread in our environment, can shape the brain through four generations, altering offspring’s maternal behavior, sexual development and reproduction, The Endocrine Society reports.

Abstract

Endocrine disrupting chemicals (EDCs) are a rising concern for public health due to their ubiquitous presence as complex mixtures affecting development throughout generations. Our goal was to study the effect of a mixture of EDCs on female sexual development during 3 generations. Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. The mixture was composed of plasticizers (BPA, DBP, DEHP), fungicides/pesticides (Vinclozolin, Procymidon, Prochloraz, Epoxynazole, Linurone, p-p’-DDT), UV filters (4-MBC, OMC), Butyl Paraben and the analgesic Acetaminophen. The doses were in the micrograms/kg range in order to represent human exposure. Sexual development (vaginal opening, GnRH interpulse interval and estrous cyclicity) as well as maternal behavior were studied from F1 to F3 generations. At PND21 the mediobasal hypothalamus of the F1 and F3 were removed for gene expression analysis by RNAseq and RT-qPCR as well as for Chromatin Immunoprecipitation of histone modifications at regulatory regions of target genes. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles and decreased GnRH interpulse interval, no such changes were detected in F1 animals. These reproductive phenotypes were associated with alterations in both transcriptional and histone posttranslational modifications of hypothalamic genes involved in reproductive competence and behavior like kisspeptin (Kiss1), oxytocin (Oxt), estrogen (Esr1), glutamate (Grin2d), dopamine signaling (Th and Drd1) as well as glucocorticoid activity (Nr3c1 and Crh). Concomitant with a decrease in transcriptional activity, we have observed either a decrease of active histone marks (H3K4me3, H3K9ac) for Esr1 and Oxt promoter regions, an increase of repressive histone modifications (H3K27me3, H3K9me3) for Grin2D, Th and Nr3c1 promoter regions or both for the Kiss1 promoter. Up-regulated genes (Pomc, and CRH) showed decreased H3K9me3 and increased H3K9ac at their 5’regulatory regions. F1 females that were exposed in utero to the EDC mixture, showed a reduction in Th mRNA expression and decreased grooming/licking behavior while spending more time resting alone. These alterations on maternal behavior are known to cause transgenerational alterations of the development of the corticotropic and gonadotropic axis. Overall, our data shows that gestational and lactational exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development throughout epigenetic reprogramming of the hypothalamus. Such effects could be mediated by alterations of maternal behavior caused by exposure of the first generation to the EDC mixture.

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Glyphosate, Epigenetics and Transgenerational Inheritance of Disease

Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology, 2019

Listen to Dr. Eric Nilsson, Research Assistant Professor in the School of Biological Sciences at Washington State University, presenting a recent study investigating exposure to the herbicide glyphosate in rats. The study found that the exposed rats’ subsequent grand-offspring and un-exposed great grand-offspring had higher rates of disease. Reference.

Abstract

Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations.

Endocrine disruptors have an impact on reproduction for several generations

Endocrine disruptors transgenerationally alters pubertal timing through epigenetic reprogramming of the hypothalamus

2019 Study Abstract

Endocrine disruptors are a rising concern for public health due to their ubiquitous presence affecting reproductive development throughout generations.

We aim at studying the transgenerational effect of an EDC mixture on female sexual development and reproduction.

Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. The mixture was composed of plasticizers (BPA, DBP, DEHP), fungicides/pesticides (Vinclozolin, Procymidon, Prochloraz, Epoxynazole, Linurone, p-p’-DDT), UV filters (4-MBC, OMC), Butylparaben and the analgesic Acetaminophen. Doses were in the human exposure range (μg/kg).

Sexual development and reproductive parameters (vaginal opening, GnRH secretion, estrous cyclicity and folliculogenesis) were studied from F1 to F3 generations. Maternal behavior was measured from F0 to F2 generations. At PND21, mediobasal hypothalamus of the F1 and F3 were removed for gene expression analysis (RNAseq, RT-PCR) as well as for Chromatin Immunoprecipitation of histone modifications at regulatory regions of target genes.

The results show multiple multi- and transgenerational effects after ancestral EDC exposure. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles, decreased GnRH interpulse interval and altered folliculogenesis, no such changes were detected in F1 animals. These alterations were accompanied with transcriptional and histone posttranslational modifications of key hypothalamic genes involved in puberty and reproduction. We observed a downregulation of estrogen signaling (Esr1), genes involved in the GnRH network (Kisspeptin, Grin2d, Tac3R), maternal behavior (Th, Oxt, Avp, Drd1, Drd2) and stress responsiveness (Nr3c1). Upregulated gens involved glucocorticoid activity (Crh) and metabolism (Pomc, Cart). Concomitantly with transcriptional levels, while downregulated genes present higher levels of repressive histone marks (H3K9me3, H3K27me3) and decreased levels of activational histone marks (H3K4me3, H3K9ac), upregulated genes present the opposite pattern. Such histone marks related to changes in the polycomb/thritorax group of protein balance, involved in the control of female puberty. F1 and F2 females displayed decreased licking while spending more time resting alone. F1 RNAseq showed a reduction in Th, Drd1 and Drd2 mRNA expression. These alterations on maternal behavior are known to cause transgenerational alterations of the development of the corticotropic and gonadotropic axis.

In conclusion, exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development and reproduction throughout epigenetic reprogramming of the hypothalamus. While not yet clear, such effects could be mediated by alterations of maternal behavior caused by exposure to the first generation.

ReferenceImage.

DES and the GENES

Comment fonctionnent les perturbateurs endocriniens ?

Le Monde, vidéo publiée le 12 juillet 2017

Ils sont partout ! Comment perturbent-ils ?

Vidéo Le Monde, publiée le 12 juillet 2017

Le Distilbène DES, en savoir plus

Screening for rare epigenetic variations in autism and schizophrenia

Additional evidence that rare epivariations likely contribute to the mutational spectra underlying neurodevelopmental disorders

2019 Study Abstract

While many studies have led to the identification of rare sequence variants linked with susceptibility to autism and schizophrenia, the contribution of rare epigenetic variations (epivariations) in these disorders remains largely unexplored.

Previously we presented evidence that epivariations occur relatively frequently in the human genome, and likely contribute to a subset of congenital and neurodevelopmental disorders through the disruption of dosage-sensitive genes.

Here we extend this approach, studying methylation profiles from 297 samples with autism and 767 cases with schizophrenia, identifying 84 and 268 rare epivariations in these two cohorts, respectively, that were absent from 4,860 population controls.

We observed multiple features associated with these epivariations that support their pathogenic relevance, including

  1. a significant enrichment for epivariations in schizophrenic individuals at genes previously linked with schizophrenia,
  2. increased brain expression of genes associated with epivariations found in autism cases compared with controls,
  3. in autism families, a significant excess of epivariations found specifically in affected versus unaffected sibs,
  4. Gene Ontology terms linked with epivariations found in autism, including “D1 dopamine receptor binding.”

Our study provides additional evidence that rare epivariations likely contribute to the mutational spectra underlying neurodevelopmental disorders. Image credit Brigham and Women’s Hospital.

DES DIETHYLSTILBESTROL RESOURCES

Effects on offspring of epigenetic inheritance via sperm

Sperm-inherited H3K27me3 impacts offspring transcription and development in C. elegans

In experiments with worms, researchers showed that epigenetic marks on sperm chromosomes affect gene expression and development in offspring.

2019 Study Abstract

Paternal epigenetic inheritance is gaining attention for its growing medical relevance. However, the form in which paternal epigenetic information is transmitted to offspring and how it influences offspring development remain poorly understood.

Here we show that in C. elegans, sperm-inherited chromatin states transmitted to the primordial germ cells in offspring influence germline transcription and development. We show that sperm chromosomes inherited lacking the repressive histone modification H3K27me3 are maintained in that state by H3K36me3 antagonism. Inheritance of H3K27me3-lacking sperm chromosomes results in derepression in the germline of somatic genes, especially neuronal genes, predominantly from sperm-inherited alleles.

This results in germ cells primed for losing their germ cell identity and adopting a neuronal fate. These data demonstrate that histone modifications are one mechanism through which epigenetic information from a father can shape offspring gene expression and development.

Reference. Press release.

Offspring whose mothers experienced early life febrile seizures display long term memory deficits

Prolonged febrile seizures induce inheritable memory deficits in rats through DNA methylation

2018 Summary

Aims:
Febrile seizures (FSs) are the most common types of seizures in young children. However, little is known whether the memory deficits induced by early‐life FSs could transmit across generations or not.

Methods:
The memory functions of different generations of FS rats were behaviorally evaluated by morris water maze, inhibitory avoidance task, and contextual fear conditioning task. Meanwhile, molecular biology and pharmacological methods were used to investigate the role of DNA methylation in transgenerational transmission of memory defects.

Results:
Prolonged FSs in infant rats resulted in memory deficits in adult and transgenerationally transmitted to next generation, which was mainly through mothers. For these two generations, DNA methyltransferase (DNMT) was upregulated, leading to transcriptional inhibition of the synaptic plasticity protein reelin but not the memory suppressor protein phosphatase. DNMT inhibitors prevented the high expression of DNMT and hypermethylation of reelin gene and reversed the transgenerationally memory deficits. In addition, enriched environment in juvenile rats rescued memory deficits induced by prolonged FSs.

Conclusions:
Our study demonstrated early experience of prolonged FSs led to memory deficits in adult rats and their unaffected offspring, which involved epigenetic mechanisms, suggesting early environmental experiences had a significant impact on the transgenerational transmission of neurological diseases.

The negative impact of the environment on methylation/epigenetic marking in gametes and embryos

A plea for action to protect the fertility of future generations, 17 January 2019

Abstract

Life expectancy has increased since World War II and this may be attributed to several aspects of modern lifestyles. However, now we are faced with a downturn, which seems to be the result of environmental issues. This paradigm is paralleled with a reduction in human fertility: decreased sperm quality and increased premature ovarian failure and diminished ovarian reserve syndromes.

Endocrine Disruptor Compounds (EDCs) and other toxic chemicals: herbicides, pesticides, plasticizers, to mention a few, are a rising concern in today environment. Some of these are commonly used in the domestic setting: cleaning material and cosmetics and they have a known impact on epigenesis and imprinting via perturbation of methylation processes. Pollution from Poly Aromatic Hydrocarbons (PAH), particulate matter (PM), <10 and <2.5 μm and ozone, released into the air all affect fertility. Poor food processing management is a source DNA adducts formation, impairing gametes quality. An important question to be answered is that of nanoparticles (NPs) that are present in food and which are thought to induce oxidative stress. Now is the time to take a step backwards. Global management of the environment and food production is required urgently in order to protect the fertility of future generations.

Reference.

DES and the GENES