An integrated multi-tissue approach for endometriosis candidate biomarkers: a systematic review.

Biomarker identification could help in deciphering endometriosis pathophysiology in addition to their use in the development of non invasive diagnostic and prognostic approaches, that are essential to greatly improve patient care. Despite extensive efforts, no single potential biomarker or combination has been clinically validated for endometriosis.Many studies have investigated endometriosis-associated biological markers in specific tissues, but an integrative approach across tissues is lacking. The aim of this review is to propose a comprehensive overview of identified biomarkers based on tissue or biological compartment, while taking into account endometriosis phenotypes (superficial, ovarian or deep, or rASRM stages), menstrual cycle phases, treatments and symptoms.We searched PubMed and Embase databases for articles matching the following criteria: 'endometriosis' present in the title and the associated term 'biomarkers' found as Medical Subject Headings (MeSH) terms or in all fields. We restricted to publications in English and on human populations. Relevant articles published between 01 January 2005 (when endometriosis phenotypes start to be described in papers) and 01 September 2022 were critically analysed and discussed.Four hundred forty seven articles on endometriosis biomarkers that included a control group without endometriosis and provided specific information on endometriosis phenotypes are included in this review. Presence of information or adjustment controlling for menstrual cycle phase, symptoms and treatments is highlighted, and the results are further summarized by biological compartment. The 9 biological compartments studied for endometriosis biomarker research are in order of frequency: peripheral blood, eutopic endometrium, peritoneal fluid, ovaries, urine, menstrual blood, saliva, feces and cervical mucus. Adjustments of results on disease phenotypes, cycle phases, treatments and symptoms are present in 70%, 29%, 3% and 6% of selected articles, respectively. A total of 1107 biomarkers were identified in these biological compartments. Of these, 74 were found in several biological compartments by at least two independent research teams and only 4 (TNF-a, MMP-9, TIMP-1 and miR-451) are detected in at least 3 tissues with cohorts of 30 women or more.Integrative analysis is a crucial step to highlight potential pitfalls behind the lack of success in the search for clinically relevant endometriosis biomarkers, and to illuminate the physiopathology of this disease.

Epoxiconazole alters the histology and transcriptome of mouse liver in a transgenerational pattern.

BACKGROUND: The use of phytosanitary products is always associated with their safety concern on the environment and on health. The associated adverse effects are very broad and substance-dependent. Among these substances, epoxiconazole (EPOX) is one of the most widely used fungicides, especially in beet crops. Although its use is questionable or even prohibited in the European Union, it is still widely used and its consequences (transgenerational effects) on future generations is unknown. OBJECTIVES: We aimed to investigate the hepatic effects of epoxiconazole in the descendants of perinatally exposed low-dose C57Bl/6J mice, focusing on liver histological and transcriptomic analyses. METHODS: From day 0 of gestation up to day 21 postnatal, only pregnant F0 C57BL6/J mice were exposed to EPOX (1.75 µg/kg bw/day). F1 males and females were mated to obtain the F2 generation and similarly, F2 mice were crossed to obtain F3. Histological and transcriptomic analyses of the liver were performed. Gene set enrichment analysis was realized to determine an a priori defined set of genes with significantly altered mRNA expression. Plasma parameters were also measured. RESULTS AND CONCLUSION: s: Perinatal exposure to EPOX induces transgenerational effects with phenotypic, histological and transcriptomic changes in the liver. These changes are highly dependent on the sex and generation of the animal. All these modifications lead to an alteration of the hepatic metabolism resulting in a difference in the size of the hepatocytes. Beyond these specific mechanisms, EPOX also seems to have a more general impact on hepatic metabolism via the circadian rhythm.

Multigenerational study of the obesogen effects of bisphenol S after a perinatal exposure in C57BL6/J mice fed a high fat diet.

BACKGROUND: Bisphenol S is an endocrine disruptor exhibiting metabolic disturbances, especially following perinatal exposures. To date, no data are available on the obesogen effects of BPS in a mutligenerational issue. OBJECTIVES: We investigated obesogen effects of BPS in a multigenerational study by focusing on body weight, adipose tissue and plasma parameters in male and female mice. METHODS: Pregnant C57BL6/J mice were exposed to BPS (1.5 µg/kg bw/day ie a human equivalent dose of 0.12 µg/kg bw/day) by drinking water from gestational day 0 to post natal day 21. All offsprings were fed with a high fat diet during 15 weeks. Body weight was monitored weekly and fat mass was measured before euthanasia. At euthanasia, blood glucose, insuline, triglyceride, cholesterol and no esterified fatty acid plasma levels were determined and gene expressions in visceral adipose tissue were assessed. F1 males and females were mated to obtain the F2 generation. Likewise, the F2 mice were cross-bred to obtain F3. The same analyses were performed. RESULTS: In F1 BPS induced an overweight in male mice associated to lipolysis gene expressions upregulation. In F1 females, dyslipidemia was observed. In F2, BPS exposure was associated to an increase in body weight, fat and VAT masses in males and females. Several plasma parameters were increased but with a sex related pattern (blood glucose, triglycerides and cholesterol in males and NEFA in females). We observed a down-regulation in mRNA expression of gene involved in lipogenesis and in lipolysis for females but only in the lipogenesis for males. In F3, a decrease in VAT mass and an upregulation of lipogenesis gene expression occurred only in females. CONCLUSIONS: BPS perinatal exposure induced sex-dependent obesogen multigenerational effects, the F2 generation being the most impacted. Transgenerational disturbances persisted only in females.

Transgenerational effects on intestinal inflammation status in mice perinatally exposed to bisphenol S.

Increasing evidence has highlighted the critical role of early life environment in shaping the future health outcomes of individuals in subsequent generations. Bisphenol S (BPS) has been widely used as a substitute for various plastic materials due to the limited application of Bisphenol A (BPA) which is an endocrine disruptor. However, the lack of efficient evaluation of BPS leaves doubts about the relevant substitute of BPA. Few studies of transgenerational inheritance have examined the effects of environmental exposures to endocrine disruptors on the immune system. In this study, we analyzed the transgenerational effects of BPS on intestinal inflammation and its consequence in metabolism. In this study, only F0 pregnant mice were exposed to BPS (1.5 µg/kg bw/day) from gestational day 0 until weaning of offspring. In this work, both F1 and F2 male offspring developed an inflammatory response in the ileum and colon at adulthood after F0 mothers were exposed to BPS; this phenomenon disappeared in F3. This inflammatory response in F1 male offspring is associated with a significant decrease of blood cholesterol without modification of metabolic status. Further, in F3 offspring male, the decrease of gut inflammatory response is associated with a decrease of fat weight and with an increase of blood glucose and cholesterol level. A sex-specific profile is observed in female offspring. We also observed that early life exposure to BPS was associated with strong abnormal intestinal immune status. The study presented here demonstrates that the immune system, like other organ systems, is vulnerable to transgenerational effects caused by environmental exposures.

Hepatic transcriptome and DNA methylation patterns following perinatal and chronic BPS exposure in male mice.

BACKGROUND: Bisphenol S (BPS) is a common bisphenol A (BPA) substitute, since BPA is virtually banned worldwide. However, BPS and BPA have both endocrine disrupting properties. Their effects appear mostly in adulthood following perinatal exposures. The objective of the present study was to investigate the impact of perinatal and chronic exposure to BPS at the low dose of 1.5 µg/kg body weight/day on the transcriptome and methylome of the liver in 23 weeks-old C57BL6/J male mice. RESULTS: This multi-omic study highlights a major impact of BPS on gene expression (374 significant deregulated genes) and Gene Set Enrichment Analysis show an enrichment focused on several biological pathways related to metabolic liver regulation. BPS exposure also induces a hypomethylation in 58.5% of the differentially methylated regions (DMR). Systematic connections were not found between gene expression and methylation profile excepted for 18 genes, including 4 genes involved in lipid metabolism pathways (Fasn, Hmgcr, Elovl6, Lpin1), which were downregulated and featured differentially methylated CpGs in their exons or introns. CONCLUSIONS: This descriptive study shows an impact of BPS on biological pathways mainly related to an integrative disruption of metabolism (energy metabolism, detoxification, protein and steroid metabolism) and, like most high-throughput studies, contributes to the identification of potential exposure biomarkers.

Obesogen effect of bisphenol S alters mRNA expression and DNA methylation profiling in male mouse liver.

Environmental pollution is increasingly considered an important factor involved in the obesity incidence. Endocrine disruptors (EDs) are important actors in the concept of DOHaD (Developmental Origins of Health and Disease), where epigenetic mechanisms play crucial roles. Bisphenol A (BPA), a monomer used in the manufacture of plastics and resins is one of the most studied obesogenic endocrine disruptor. Bisphenol S (BPS), a BPA substitute, has the same obesogenic properties, acting at low doses with a sex-specific effect following perinatal exposure. Since the liver is a major organ in regulating body lipid homeostasis, we investigated gene expression and DNA methylation under low-dose BPS exposure. The BPS obesogenic effect was associated with an increase of hepatic triglyceride content. These physiological disturbances were accompanied by genome-wide changes in gene expression (1366 genes significantly modified more than 1.5-fold). Gene ontology analysis revealed alteration of gene cascades involved in protein translation and complement regulation. It was associated with hepatic DNA hypomethylation in autosomes and hypermethylation in sex chromosomes. Although no systematic correlation has been found between gene repression and hypermethylation, several genes related to liver metabolism were either hypermethylated (Acsl4, Gpr40, Cel, Pparδ, Abca6, Ces3a, Sgms2) or hypomethylated (Soga1, Gpihbp1, Nr1d2, Mlxipl, Rps6kb2, Esrrb, Thra, Cidec). In specific cases (Hapln4, ApoA4, Cidec, genes involved in lipid metabolism and liver fibrosis) mRNA upregulation was associated with hypomethylation. In conclusion, we show for the first time wide disruptive physiological effects of low-dose of BPS, which raises the question of its harmlessness as an industrial substitute for BPA.

Chronic exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces an obesogenic effect in C57BL/6J mice fed a high fat diet.

Contaminant involvement in the pathophysiology of obesity is widely recognized. It has been shown that low dose and chronic exposure to endocrine disruptor compounds (EDCs) potentiated diet- induced obesity. High and acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant (POP) and an EDC with anti-estrogenic property, causes wasting syndrome . However at lower doses, the TCDD metabolic effects remain poorly understood. We investigated the obesogenic effect during chronic exposure of TCDD at 1µg/kg body weight (bw)/week in adult C57BL/6J mice fed with a high fat diet (HFD) and exposed from 10 to 42 weeks old to TCDD or equal volume of vehicle by intragastric gavage. Under these conditions, TCDD was obesogenic in adult mice (7% in males and 8% in females), which was linked to fat mass. A sex effect was observed in the fat mass distribution in adipose tissue and in the hepatic triglyceride content evolution. In visceral fat pad weight, we observed a decrease (11%) in males and an increase (14%) in females. The hepatic triglyceride content increase (41%) in females only. TCDD failed to induce any change in plasma parameters regarding glucose and lipid homeostasis. Messenger ribonucleic acid (mRNA) levels involved in adipose tissue and hepatic metabolism, inflammation, xenobiotic metabolism and endocrine disruption were differently regulated between males and females. In conclusion, these results provide new evidence that dioxin, a POP and EDC can be obesogenic for adult mice with multi-organ effects.