Inter‐ and Transgenerational Effects of Paternal Exposure to Inorganic Arsenic

The rise of metabolic disorders in modern times is mainly attributed to the environment. However, heritable effects of environmental chemicals on mammalian offsprings' metabolic health are unclear. Inorganic arsenic (iAs) is the top chemical on the Agency for Toxic Substances and Disease Registry priority list of hazardous substances. Here, we assess cross‐generational effects of iAs in an exclusive male‐lineage transmission paradigm. The exposure of male mice to 250 ppb iAs causes glucose intolerance and hepatic insulin resistance in F1 females, but not males, without affecting body weight. Hepatic expression of glucose metabolic genes, glucose output, and insulin signaling are disrupted in F1 females. Inhibition of the glucose 6‐phosphatase complex masks the intergenerational effect of iAs, demonstrating a causative role of hepatic glucose production. F2 offspring from grandpaternal iAs exposure show temporary growth retardation at an early age, which diminishes in adults. However, reduced adiposity persists into middle age and is associated with altered gut microbiome and increased brown adipose thermogenesis. In contrast, F3 offspring of the male‐lineage iAs exposure show increased adiposity, especially on a high‐calorie diet. These findings have unveiled sex‐ and generation‐specific heritable effects of iAs on metabolic physiology, which has broad implications in understanding gene‐environment interactions

LncRNA SNHG5 adversely governs follicular growth in PCOS via miR-92a-3p/CDKN1C axis

Summary: Small nucleolar RNA host genes (SNHGs) have been implicated in various biological processes, yet their involvement in polycystic ovary syndrome (PCOS) remains elusive. Specifically, SNHG5, a long non-coding RNA implicated in several human cancers, shows elevated expression in granulosa cells (GCs) of PCOS women and induces PCOS-like features when overexpressed in mice. In vitro, SNHG5 inhibits GC proliferation and induces apoptosis and cell-cycle arrest at G0/G1 phase, with RNA-seq indicating its impact on DNA replication and repair pathways. Mechanistically, SNHG5 acts as a competing endogenous RNA by binding to miR-92a-3p, leading to increased expression of target gene CDKN1C, which further suppresses GC proliferation and promotes apoptosis. These findings elucidate the crucial role of SNHG5 in the pathogenesis of PCOS and suggest a potential therapeutic target for this condition. Additional investigations such as large-scale clinical studies and functional assays are warranted to validate and expand upon these findings

JC-1 staining of different stage early embryos in the HTF-control, PF-control, and PF-E groups.

<p>Rows, from top to bottom, correspond to 2-cell, 4-cell, morula, and blastocyst stages, respectively. Columns, from left to right, correspond to the HTF-control (A, D, G, and J), PF-control (B, E, H, and K), and PF-E (C, F, I, and L) groups, respectively.</p

Genome sequencing analysis of a family with a child displaying severe abdominal distention and recurrent hypoglycemia

Abstract Background Germline mutations in PTEN are associated with the PTEN hamartoma tumor syndrome (PHTS), an umbrella term used to describe a spectrum of autosomal‐dominant disorders characterized by variable phenotypic manifestations associated with cell or tissue overgrowth. We report a boy who developed severe progressive abdominal distention due to a dramatic adipose mass from the age of 7 months and developed recurrent hypoinsulinemic hypoglycemia that led to seizures at the age of 4 years. Methods Trio‐based whole‐genome sequencing was performed by using blood DNA from the child and his parents. The possible pathogenic variants were verified by Sanger sequencing. Functional characterization of the identified variant was completed by western blot. Results The child inherited a single‐nucleotide deletion NM_000314.6:c.849delA (p.Glu284Argfs) in the tumor suppressor gene PTEN from his father. The paternal family members have a history of cancer. It is conceivable that PTEN loss‐of‐function induced the adipose tumor growth and hypoglycemia, although the proband did not meet the usual diagnosis criteria of Cowden syndrome or Bannayan–Riley–Ruvalcaba syndrome that are characterized by germline mutations of PTEN. Conclusion This case underlines the variability of phenotypes associated with PTEN germline mutations and provides useful information for diagnosis and genetic counseling of PTEN‐related diseases for pediatric patients

Sex differences in paternal arsenic-induced intergenerational metabolic effects are mediated by estrogen.

BACKGROUND: Gene-environment interactions contribute to metabolic disorders such as diabetes and dyslipidemia. In addition to affecting metabolic homeostasis directly, drugs and environmental chemicals can cause persistent alterations in metabolic portfolios across generations in a sex-specific manner. Here, we use inorganic arsenic (iAs) as a prototype drug and chemical to dissect such sex differences. METHODS: After weaning, C57BL/6 WT male mice were treated with 250 ppb iAs in drinking water (iAsF0) or normal water (conF0) for 6 weeks and then bred with 15-week-old, non-exposed females for 3 days in cages with only normal water (without iAs), to generate iAsF1 or conF1 mice, respectively. F0 females and all F1 mice drank normal water without iAs all the time. RESULTS: We find that exposure of male mice to 250 ppb iAs leads to glucose intolerance and insulin resistance in F1 female offspring (iAsF1-F), with almost no change in blood lipid profiles. In contrast, F1 males (iAsF1-M) show lower liver and blood triglyceride levels than non-exposed control, with improved glucose tolerance and insulin sensitivity. The liver of F1 offspring shows sex-specific transcriptomic changes, with hepatocyte-autonomous alternations of metabolic fluxes in line with the sex-specific phenotypes. The iAsF1-F mice show altered levels of circulating estrogen and follicle-stimulating hormone. Ovariectomy or liver-specific knockout of estrogen receptor α/β made F1 females resemble F1 males in their metabolic responses to paternal iAs exposure. CONCLUSIONS: These results demonstrate that disrupted reproductive hormone secretion in alliance with hepatic estrogen signaling accounts for the sex-specific intergenerational effects of paternal iAs exposure, which shed light on the sex disparities in long-term gene-environment interactions

Electron microscopy of 2-cell and 4-cell embryos in the HTF-control, PF-control, and PF-E groups.

<p>A) 2-cell embryos in the HTF-control group. The mitochondria were round with few cristae (17,500×). B) 4-cell embryos in the HTF-control group. Several mitochondria with rich cristae were seen (24,000×). C) 2-cell embryos in the PF-control group. Most mitochondria were round with few cristae, and a few mitochondria had a transverse crest (24,000×). D) 4-cell embryos in the PF-control group. Mitochondria with transverse cristae were increased (24,000×). E) 2-cell embryos in the PF-E group. Mitochondria with lamellar transverse cristae were increased significantly (24,000×). F) 4-cell embryos in the PF-E group. Multiple mitochondria with rich transverse cristae were seen (24,000×). (The single arrow indicates mitochondria rich in transverse cristae, and the double arrow indicates the Golgi apparatus.)</p

The Effect of Peritoneal Fluid from Patients with Endometriosis on Mitochondrial Function and Development of Early Mouse Embryos

<div><p>Background</p><p>Peritoneal fluid (PF) from patients with endometriosis can inhibit early embryo development via probable functional changes of embryo mitochondria in the early stage of embryo development. The purpose of this study was to determine the effect of PF from patients with endometriosis on mitochondrial function and development of early mouse embryos.</p><p>Methodology/Principal Findings</p><p>PF was collected from patients with infertility and endometriosis, infertility due to tubal factors, and normal control subjects, and the level of NO was measured. Early murine embryos were then cultured with PF from normal control subjects, those with endometriosis, and with human tubal fluid (HTF), respectively. Cleavage and blastulation rates, mitochondrial DNA (mtDNA) copy numbers, adenosine triphosphate (ATP) level, and mitochondrial membrane potential (ΔΨm) of the different groups were compared. The NO level in the PF of patients with endometriosis was significantly greater than in those without endometriosis and control patients. The embryos cultures with PF from patients with endometriosis had a lower cleavage rate and blastulation rate, and higher ATP and ΔΨm level at the 2- and 4-cell stages. No significant difference was found in mtDNA copies among the 3 groups.</p><p>Conclusions/Significance</p><p>PF from patients with endometriosis can inhibit early embryo development via probable functional changes of embryo mitochondria in the early stage of embryo development. Understanding the effects of PF on embryo development may assist in developing new methods of treatment for infertility.</p></div

Sex differences in paternal arsenic-induced intergenerational metabolic effects are mediated by estrogen

Abstract Background Gene-environment interactions contribute to metabolic disorders such as diabetes and dyslipidemia. In addition to affecting metabolic homeostasis directly, drugs and environmental chemicals can cause persistent alterations in metabolic portfolios across generations in a sex-specific manner. Here, we use inorganic arsenic (iAs) as a prototype drug and chemical to dissect such sex differences. Methods After weaning, C57BL/6 WT male mice were treated with 250 ppb iAs in drinking water (iAsF0) or normal water (conF0) for 6 weeks and then bred with 15-week-old, non-exposed females for 3 days in cages with only normal water (without iAs), to generate iAsF1 or conF1 mice, respectively. F0 females and all F1 mice drank normal water without iAs all the time. Results We find that exposure of male mice to 250 ppb iAs leads to glucose intolerance and insulin resistance in F1 female offspring (iAsF1-F), with almost no change in blood lipid profiles. In contrast, F1 males (iAsF1-M) show lower liver and blood triglyceride levels than non-exposed control, with improved glucose tolerance and insulin sensitivity. The liver of F1 offspring shows sex-specific transcriptomic changes, with hepatocyte-autonomous alternations of metabolic fluxes in line with the sex-specific phenotypes. The iAsF1-F mice show altered levels of circulating estrogen and follicle-stimulating hormone. Ovariectomy or liver-specific knockout of estrogen receptor α/β made F1 females resemble F1 males in their metabolic responses to paternal iAs exposure. Conclusions These results demonstrate that disrupted reproductive hormone secretion in alliance with hepatic estrogen signaling accounts for the sex-specific intergenerational effects of paternal iAs exposure, which shed light on the sex disparities in long-term gene-environment interactions

Cleavage (A) and blastulation (B) rates of HTF-control group and groups cultured with peritoneal fluid from patients with endometriosis (PF-E) and those without endometriosis (PF-control).

<p>^a Indicates a significant difference between the given group and HTF-control group. ^bIndicates a significant difference between the PF-control and PF-E groups.</p

Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection

Nuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus-hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling