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About 1-6% of the genetic ancestry of modern humans today originates from admixture with archaic humans. It has recently been shown that autosomal genomic regions with a reduced proportion of Neanderthal and Denisovan ancestries (NA and DA) are significantly enriched in genes that are more expressed in testis than in other tissues. To determine whether a cellular segregation pattern would exist, we combined maps of archaic introgression with a cross-analysis of three transcriptomic datasets deciphering the transcriptional landscape of human gonadal cell types. We reveal that the regions deficient in both NA and DA contain a significant enrichment of genes transcribed in meiotic germ cells. The interbreeding of anatomically modern humans with archaic humans may have introduced archaic-derived alleles that contributed to genetic incompatibilities affecting meiosis that were subsequently purged by natural selection.

Thyroperoxidase (TPO) is central in thyroid hormone (TH) synthesis and inhibition can lead to TH deficiency. Many chemicals can inhibit TPO activity in vitro, but how this may manifest in the developing thyroid gland at the molecular level is unclear. Here, we characterized the thyroid gland transcriptome of male rats developmentally exposed to the in vitro TPO-inhibitors amitrole, 2-mercaptobenzimidazole (MBI), or cyanamide by use of Bulk-RNA-Barcoding (BRB) and sequencing. Amitrole exposure caused TH deficiency and 149 differentially expressed genes in the thyroid gland. The effects indicated an activated and growing thyroid gland. MBI caused intermittent changes to serum TH concentrations in a previous study and this was accompanied by 60 differentially expressed genes in the present study. More than half of these were also affected by amitrole, indicating that they could be early effect biomarkers of developmental TH system disruption due to TPO inhibition. Further work to validate the signature is needed, including assessment of substance independency and applicability domain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Thyroid hormone (TH) system disrupting compounds can impair brain development by perturbing TH action during critical life stages. Human exposure to TH system disrupting chemicals is therefore of great concern. To better protect humans against such chemicals, sensitive test methods that can detect effects on the developing brain are critical. Worryingly, however, current test methods are not sensitive and specific towards TH-mediated effects. To address this shortcoming, we performed RNA-sequencing of rat brains developmentally exposed to two different thyroperoxidase (TPO) inhibiting compounds, the medical drug methimazole (MMI) or the pesticide amitrole. Pregnant and lactating rats were exposed to 8 and 16 mg/kg/day(d) MMI or 25 and 50 mg/kg/d amitrole from gestational day 7 until postnatal day 16. Bulk-RNA-seq was performed on hippocampus from the 16-day old male pups. MMI and amitrole caused pronounced changes to the transcriptomes; 816 genes were differentially expressed, and 425 gene transcripts were similarly affected by both chemicals. Functional terms indicate effects from key cellular functions to changes in cell development, migration and differentiation of several cell populations. Of the total number of DEGs, 106 appeared to form a consistent transcriptional fingerprint of developmental hypothyroidism as they were similarly and dose-dependently expressed across all treatment groups. Using a filtering system, we identified 20 genes that appeared to represent the most sensitive, robust and dose-dependent markers of altered TH-mediated brain development. These markers provide inputs to the adverse outcome pathway (AOP) framework where they, in the context of linking TPO inhibiting compounds to adverse cognitive function, can be used to assess altered gene expression in the hippocampus in rat toxicity studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The use of millimeter waves (MMW) will exponentially grow in the coming years due to their future utilization in 5G/6G networks. The question of possible biological effects at these frequencies has been raised. In this present study, we aimed to investigate gene expression changes under exposure to MMW using the Bulk RNA Barcoding and sequencing (BRB-seq) technology. To address this issue, three exposure scenarios were performed aiming at: i) comparing the cellular response of two primary culture of keratinocytes (HEK and NHEK) and one keratinocyte derivate cell line (HaCaT) exposed to MMW; ii) exploring the incident power density dose-effect on gene expression in HaCaT cell line; and, iii) studying the exposure duration at the new ICNIRP exposure limit for the general population. With the exception of heat effect induced by high power MMW (over 10 mW/cm 2 ), those exposure scenarios have not enabled us to demonstrate important gene expression changes in the different cell populations studied. Very few differentially genes were observed between MMW exposed samples and heat shock control, and most of them were significantly associated with heat shock response that may reflect small differences in the heat generation. Together these results show that acute exposure to MMW has no effects on the transcriptional landscape of human keratinocyte models under athermal conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The prevalence of hormone-related health issues caused by exposure to endocrine disrupting chemicals (EDCs) is a significant, and increasing, societal challenge. Declining fertility rates together with rising incidence rates of reproductive disorders and other endocrine-related diseases underscores the urgency in taking more action. Addressing the growing threat of EDCs in our environment demands robust and reliable test methods to assess a broad variety of endpoints relevant for endocrine disruption. EDCs also require effective regulatory frameworks, especially as the current move towards greater reliance on non-animal methods in chemical testing puts to test the current paradigm for EDC identification, which requires that an adverse effect is observed in an intact organism. Although great advances have been made in the field of predictive toxicology, disruption to the endocrine system and subsequent adverse health effects may prove particularly difficult to predict without traditional animal models. The MERLON project seeks to expedite progress by integrating multispecies molecular research, new approach methodologies (NAMs), human clinical epidemiology, and systems biology to furnish mechanistic insights and explore ways forward for NAM-based identification of EDCs. The focus is on sexual development and function, from foetal sex differentiation of the reproductive system through mini-puberty and puberty to sexual maturity. The project aims are geared towards closing existing knowledge gaps in understanding the effects of EDCs on human health to ultimately support effective regulation of EDCs in the European Union and beyond., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Svingen T et al.)

Background: An important issue for young men affected by testicular germ cell tumor (TGCT) is how TGCT and its treatment will affect, transiently or permanently, their future reproductive health. Previous studies have reported that xenobiotics can induce changes on human sperm epigenome and have the potential to promote epigenetic alterations in the offspring., Objectives: Here, we report the first longitudinal DNA methylation profiling of frozen sperm from a TGCT patient before and up to 2 years after a bleomycin, etoposide, and cisplatin (BEP) chemotherapy., Materials and Methods: A TGCT was diagnosed in a 30-year-old patient. A cryopreservation of spermatozoa was proposed before adjuvant BEP treatment. Semen samples were collected before and after chemotherapy at 6, 9, 12, and 24 months. The DNA methylation status was determined by RRBS to detect DNA differentially methylated regions (DMRs)., Results: The analysis revealed that among the 74 DMRs showing modified methylation status 6 months after therapy, 17 remained altered 24 months after treatment. We next associated DMRs with differentially methylated genes (DMGs), which were subsequently intersected with loci known to be important or expressed during early development., Discussion and Conclusion: The consequences of the cancer treatment on the sperm epigenome during the recovery periods are topical issues of increasing significance as epigenetic modifications to the paternal genome may have deleterious effects on the offspring. The altered methylated status of these DMGs important for early development might modify their expression pattern and thus affect their function during key stages of embryogenesis, potentially leading to developmental disorders or miscarriages., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

The evolution and development of the head have long captivated researchers due to the crucial role of the head as the gateway for sensory stimuli and the intricate structural complexity of the head. Although significant progress has been made in understanding head development in various vertebrate species, our knowledge of early human head ontogeny remains limited. Here, we used advanced whole-mount immunostaining and 3D imaging techniques to generate a comprehensive 3D cellular atlas of human head embryogenesis. We present detailed developmental series of diverse head tissues and cell types, including muscles, vasculature, cartilage, peripheral nerves, and exocrine glands. These datasets, accessible through a dedicated web interface, provide insights into human embryogenesis. We offer perspectives on the branching morphogenesis of human exocrine glands and unknown features of the development of neurovascular and skeletomuscular structures. These insights into human embryology have important implications for understanding craniofacial defects and neurological disorders and advancing diagnostic and therapeutic strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

To investigate the role of the nuclear receptor NR5A1 in the testis after sex determination, we analyzed mice lacking NR5A1 in Sertoli cells (SCs) from embryonic day (E) 13.5 onwards. Ablation of Nr5a1 impaired the expression of genes characteristic of SC identity (e.g. Sox9 and Amh), caused SC death from E14.5 onwards through a Trp53-independent mechanism related to anoikis, and induced disorganization of the testis cords. Together, these effects caused germ cells to enter meiosis and die. Single-cell RNA-sequencing experiments revealed that NR5A1-deficient SCs changed their molecular identity: some acquired a 'pre-granulosa-like' cell identity, whereas other reverted to a 'supporting progenitor-like' cell identity, most of them being 'intersex' because they expressed both testicular and ovarian genes. Fetal Leydig cells (LCs) did not display significant changes, indicating that SCs are not required beyond E14.5 for their emergence or maintenance. In contrast, adult LCs were absent from postnatal testes. In addition, adult mutant males displayed persistence of Müllerian duct derivatives, decreased anogenital distance and reduced penis length, which could be explained by the loss of AMH and testosterone synthesis due to SC failure., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary development, respectively. Although the Y-linked testis-determining gene Sry has been identified, the ovarian-determining factor remains unknown. In this study, we identified -KTS, a major, alternatively spliced isoform of the Wilms tumor suppressor WT1, as a key determinant of female sex determination. Loss of - KTS variants blocked gonadal differentiation in mice, whereas increased expression, as found in Frasier syndrome, induced precocious differentiation of ovaries independently of their genetic sex. In XY embryos, this antagonized Sry expression, resulting in male-to-female sex reversal. Our results identify -KTS as an ovarian-determining factor and demonstrate that its time of activation is critical in gonadal sex differentiation.

Valproic acid (VPA) has long been the most widely used antiepileptic drug (AED) for the treatment of epilepsy, bipolar psychiatric disorders, and migraine. However, long-term VPA treatment has several adverse effects on the male reproductive system notably on endocrine functions and/or spermatic parameters. In utero exposure of the fetus to VPA is well known to be associated with a higher risk of several congenital malformations including those of male reproductive organs. Subsequent generations of AEDs, such as carbamazepine (CARB) and lamotrigine (LAM), are considered safer and are currently recommended for women of child-bearing age with epilepsy. Because anomalies of the male genital tract mostly result from endocrine imbalance during fetal life, we hypothesized that AEDs could directly impair testis differentiation. We thus aimed at identifying and characterizing the effects of VPA, CARB, and LAM on the differentiation and function of the different testicular cell types, and at understanding the mechanisms underlying these effects. By using ex vivo culture of first-trimester human fetal testes, we show that VPA induces multiple endocrine disruptive effects, compared with the milder ones caused by CARB and LAM. AED also subtly altered the germ cell lineage in distinct manners. Transcriptomic analysis of VPA-induced alterations highlighted a very broad range of effects on the fetal testis. Overall, our results show that AEDs can behave as endocrine disruptors for the human fetal testis ex vivo. This is consistent with, and likely underlies, the VPA-induced male genital tract masculinization abnormalities observed in patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Clear cell Renal Cell Carcinoma (ccRCC) is one of the most prevalent kidney cancers, which is often asymptomatic and thus discovered at a metastatic state (mRCC). mRCC are highly heterogeneous tumors composed of subclonal populations that lead to poor treatment response rate. Several recent works explored the potential of ccRCC tumoroids culture derived from patients. However, these models were produced following a scaffold-based method using collagen I or Matrigel that exhibit lot variability and whose complexity could induce treatment response modifications and phenotypic alterations. Following the observation that ccRCC tumoroids can create their own niche by secreting extracellular matrix components, we developed the first scaffold-free tumoroid model of ccRCC tumors. Tumoroids from mice as well as from human tumors were generated with high success rate (≥90%) using a magnetic suspension method and standard culture media. Immunofluorescence analysis revealed their self-organization capacities to maintain multiple tumor-resident cell types, including endothelial progenitor cells. Transcriptomic analysis showed the reproducibility of the method highlighting that the majority of gene expression patterns was conserved in tumoroids compared to their matching tumor tissue. Moreover, this model enables to evaluate drug effects and invasiveness of renal cancer cells in a 3D context, providing a robust preclinical tool for drug screening and biomarker assessment in line with alternative ex vivo methods like tumor tissue slice culture or in vivo xenograft models., (© 2023. The Author(s).)