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Phthalates are used as plasticizers in soft polyvinyl chloride (PVC) and in a large number of consumer products. Because of reported health risks, diisononyl phthalate (DiNP) has been introduced as a replacement for di(2-ethylhexyl) phthalate (DEHP) in soft PVC. This raises concerns because animal data suggest that DiNP may have antiandrogenic properties similar to those of DEHP. The anogenital distance (AGD)--the distance from the anus to the genitals--has been used to assess reproductive toxicity. The objective of this study was to examine the associations between prenatal phthalate exposure and AGD in Swedish infants. AGD was measured in 196 boys at 21 months of age, and first-trimester urine was analyzed for 10 phthalate metabolites of DEP (diethyl phthalate), DBP (dibutyl phthalate), DEHP, BBzP (benzylbutyl phthalate), as well as DiNP and creatinine. Data on covariates were collected by questionnaires. The most significant associations were found between the shorter of two AGD measures (anoscrotal distance; AGDas) and DiNP metabolites and strongest for oh-MMeOP [mono-(4-methyl-7-hydroxyloctyl) phthalate] and oxo-MMeOP [mono-(2-ethyl-5-oxohexyl) phthalate]. However, the AGDas reduction was small (4%) in relation to more than an interquartile range increase in DiNP exposure. These findings call into question the safety of substituting DiNP for DEHP in soft PVC, particularly because a shorter male AGD has been shown to relate to male genital birth defects in children and impaired reproductive function in adult males and the fact that human levels of DiNP are increasing globally.

The genitalia of Lepidoptera are complex structures that evolve rapidly and divergently. The endophallus of many lepidopterans is ornamented with elaborate sclerotized structures known as cornuti. In some species, the cornuti are deciduous and remain within the female genital tract after copulation; the function of these structures is virtually unknown. These structures are a peculiar potential type of secondary “socially transferred material” (the primary materials are spermatozoids, i.e., genetic material), because they probably influence the physiology and behaviour of receivers (i.e., females) but are not molecules that function as allohormones. Such influence could be achieved by acting as mating plugs or via mechanical stimulation of females. The most intriguing and bizarre deciduous cornuti are the so-called caltrop cornuti, star-shaped structures, composed of several rays radiating from a central mass. Despite the presence of caltrop cornuti in at least 400 species, there are no studies of their microscopic structure and mechanism of dislodgement and transference to the female. In this study, we describe in detail the general and microscopic structure of the caltrop cornuti and associated structures of the prominent moth Peridea anceps (Notodontidae). We provide quantitative data of the cornuti and, for the first time, we explain the processes of detachment and transference to the female genital tract; we also describe their distribution inside the female genitalia. We discuss the possibility that one of the functions of deciduous caltrop cornuti is protection against sperm competition, as well as their potential influence on other aspects of the behaviour and physiology of females via mechanical stimulation.

Male genitalia exhibit patterns of divergent evolution driven by sexual selection. In contrast, for many taxonomic groups, female genitalia are relatively uniform and their patterns of evolution remain largely unexplored. Here we quantify variation in the shape of female genitalia across onthophagine dung beetles, and use new comparative methods to contrast their rates of divergence with those of male genitalia. As expected, male genital shape has diverged more rapidly than a naturally selected trait, the foretibia. Remarkably, female genital shape has diverged nearly three times as fast as male genital shape. Our results dispel the notion that female genitalia do not show the same patterns of divergent evolution as male genitalia, and suggest that female genitalia are under sexual selection through their role in female choice. Although male genital shape is known to evolve rapidly in response to sexual selection, relatively little is known about the evolution of female genital shape. Here, the authors show that across onthophagine dung beetles, female genital shape has diverged much more rapidly than male genital shape.

The testis is a reservoir for viruses that can cause persistent infection and adversely affect male reproductive health, an observation commonly attributed to deficiencies in inducible antiviral defence mechanisms. In this study, we demonstrate that interferon-epsilon (IFNε), a type I interferon initially discovered in female reproductive epithelia, is constitutively expressed by meiotic and post-meiotic spermatogenic cells, Leydig cells and macrophages in mouse testes. A similar distribution pattern was observed in human testes. Mice lacking IFNɛ were more susceptible to Zika virus-induced inflammation and damage of the testis and epididymis compared to wild-type mice. Exogenous IFNε treatment reduced the viral infection burden in cultured human testicular cells by inducing interferon-stimulated gene expression, and reducing inflammatory gene expression and cell damage. Treatment was more effective when administered prior to infection. These data indicate a critical role for constitutively-expressed IFNɛ in limiting viral infection and inflammatory damage in the male reproductive tract.

Background The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically recognized for its role in the regulation of toxicity mediated by environmental chemicals. Recent research points to AhR’s critical participation in male reproductive physiology, particularly in spermatogenesis, hormone signaling, and the maintenance of sperm quality. Both endogenous ligands (e.g., dietary and gut microbiota-derived metabolites) and exogenous pollutants (e.g., dioxins and benzo-α-pyrene) influence AhR-mediated pathways, making it a key link between environmental exposures and male fertility. Results This review highlights AhR’s influence on the male reproductive system, emphasizing the role of endogenous AhR ligands and AhR expression in the maturation and function of male reproductive organs. Environmental AhR agonists have been shown to induce oxidative stress, hormonal imbalance, and sperm DNA damage, which impact harmfully on the spermatogenesis process, which leads to reproductive abnormalities. Conversely, certain natural compounds such as resveratrol, curcumin, and lycopene appear to antagonize AhR activation and reduce its negative effects, thus offering potential protective benefits against male reproductive toxicity. Nevertheless, discrepancies persist regarding the exact interplay between AhR signaling and critical reproductive hormones such as testosterone and LH, and it remains unclear how transgenerational epigenetic changes triggered by AhR activation might affect long-term male fertility. Conclusion AhR is pivotal in male reproductive physiology, influencing spermatogenesis, sperm quality, and hormone regulation through its interactions with both endogenous and environmental ligands. Persistent pollutants such as dioxins and polycyclic aromatic hydrocarbons cause oxidative damage and hormonal disturbances via AhR, contributing to reduced sperm quality and fertility. Graphical Abstract The Impact of ligands of Aryl Hydrocarbon Receptor (AhR) on Male Reproductive Health. →, activation;  ⊣ , inhibition; DEHP, Di(2-ethylhexyl) phthalate; I3C, indole-3-carbinol; PAH, polycyclic aromatic hydrocarbon; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin (Created by Biorender.com).

Many pesticides can antagonize the androgen receptor (AR) or inhibit androgen synthesis but their potential to cause reproductive toxicity related to disruption of androgen action during fetal life is difficult to predict. Currently no approaches for using data to anticipate such effects exist. Prioritization schemes that limit unnecessary testing are urgently needed. The aim was to develop a quantitative to extrapolation (QIVIVE) approach for predicting anti-androgenicity arising from gestational exposures and manifesting as a shortened anogenital distance (AGD) in male rats. We built a physiologically based pharmacokinetic (PBK) model to simulate concentrations of chemicals in the fetus resulting from maternal dosing. The predicted fetal levels were compared with analytically determined concentrations, and these were judged against active concentrations for AR antagonism and androgen synthesis suppression. We first evaluated our model by using and anti-androgenic data for procymidone, vinclozolin, and linuron. Our PBK model described the measured fetal concentrations of parent compounds and metabolites quite accurately (within a factor of five). We applied the model to nine current-use pesticides, all with evidence for anti-androgenicity but missing data. Seven pesticides (fludioxonil, cyprodinil, dimethomorph, imazalil, quinoxyfen, fenhexamid, -phenylphenol) were predicted to produce a shortened AGD in male pups, whereas two ( , pyrimethanil) were anticipated to be inactive. We tested these expectations for fludioxonil, cyprodinil, and dimethomorph and observed shortened AGD in male pups after gestational exposure. The measured fetal concentrations agreed well with PBK-modeled predictions. Our QIVIVE model newly identified fludioxonil, cyprodinil, and dimethomorph as anti-androgens. With the examples investigated, our approach shows great promise for predicting anti-androgenicity (i.e., AGD shortening) for chemicals with activity and for minimizing unnecessary testing. https://doi.org/10.1289/EHP6774.

The diversity, variability, and apparent rapid evolution of animal genitalia are a vivid focus of research in evolutionary biology, and studies exploring genitalia have dramatically increased over the past decade. These studies, however, exhibit a strong male bias, which has worsened since 2000, despite the fact that this bias has been explicitly pointed out in the past. Early critics argued that previous investigators too often considered only males and their genitalia, while overlooking female genitalia or physiology. Our analysis of the literature shows that overall this male bias has worsened with time. The degree of bias is not consistent between subdisciplines: studies of the lock-and-key hypothesis have been the most male focused, while studies of cryptic female choice usually consider both sexes. The degree of bias also differed across taxonomic groups, but did not associate with the ease of study of male and female genital characteristics. We argue that the persisting male bias in this field cannot solely be explained by anatomical sex differences influencing accessibility. Rather the bias reflects enduring assumptions about the dominant role of males in sex, and invariant female genitalia. New research highlights how rapidly female genital traits can evolve, and how complex coevolutionary dynamics between males and females can shape genital structures. We argue that understanding genital evolution is hampered by an outdated single-sex bias.

Male genital structures are among the most rapidly evolving morphological traits and are often the only features that can distinguish closely related species. This process is thought to be driven by sexual selection and may reinforce species separation. However, while the genetic bases of many phenotypic differences have been identified, we still lack knowledge about the genes underlying evolutionary differences in male genital organs and organ size more generally. The claspers (surstyli) are periphallic structures that play an important role in copulation in insects. Here, we show that divergence in clasper size and bristle number between Drosophila mauritiana and Drosophila simulans is caused by evolutionary changes in tartan (trn), which encodes a transmembrane leucine-rich repeat domain protein that mediates cell–cell interactions and affinity. There are no fixed amino acid differences in trn between D. mauritiana and D. simulans, but differences in the expression of this gene in developing genitalia suggest that cis-regulatory changes in trn underlie the evolution of clasper morphology in these species. Finally, analyses of reciprocal hemizygotes that are genetically identical, except for the species from which the functional allele of trn originates, determined that the trn allele of D. mauritiana specifies larger claspers with more bristles than the allele of D. simulans. Therefore, we have identified a gene underlying evolutionary change in the size of a male genital organ, which will help to better understand not only the rapid diversification of these structures, but also the regulation and evolution of organ size more broadly.

The study of genital diversity has experienced rapidly burgeoning attention over the past few decades. This research has shown that male genitalia in internally fertilizing animals exhibit remarkably rapid and complex evolution. In recent years, a consensus has emerged that sexual selection is responsible for much of the observed genital diversity, with natural selection largely playing a subsidiary role. Despite enhanced understanding of the key proximate forms of selection responsible for genital evolution, we still have a poor grasp of the broader, ultimate causes and consequences of the striking diversity of genitalia. Here, we highlight three topics that have so far received comparatively little attention and yet could prove critically important. First, we encourage investigation of ecology’s direct and indirect roles in genital diversification, as ecological variation can influence selection on genitalia in several ways, perhaps especially by influencing the context of sexual selection. Second, we need more research into the effects of genital divergence on speciation, as genital differences could enhance reproductive isolation through either a lock-and-key process (where selection directly favors reproductive isolation) or as an incidental by-product of divergence. Third, we echo recent calls for increased research on female genitalia, as non-trivial female genital diversity exists, and multiple mechanisms can lead to rapid diversification of female genitalia. For all three topics, we review theory and empirical data, and describe specific research approaches for tackling these questions. We hope this work provides a roadmap toward increased understanding of the causes and consequences of the conspicuous diversity of primary sexual traits, and thus toward new insights into the evolution of complex traits and the phenotypic causes of speciation.

CBLB502, a Toll-like receptor (TLR)5 agonist derived from Salmonella flagellin, was shown to protect mammalian hematopoietic and gastrointestinal systems from acute irradiation syndrome and to stimulate regeneration. To explore whether CBLB502 can improve testicular injuries caused by irradiation, mice were intraperitoneally injected with 0.2 mg/kg CBLB502 or vehicle control 30 min prior to applying 5.0 Gy ionizing radiation (IR). We observed these mice for the following 120 days and determined that CBLB502 pretreatment alleviated IR-induced oxidative stress, alleviated the distorted architecture of seminiferous tubules, reversed the decline of sperm quantity and quality, and helped recover male mouse fertility. Additionally, CBLB502 efficiently reduced DNA damage and chromosomal aberrations in IR-treated mice and their offspring. Due to the suppression of p53-dependent apoptosis, in IR-treated mice, CBLB502 was shown to significantly activate the nuclear factor kappa B (NFκB) pathway and reduce the apoptotic rate in association with an increase in anti-apoptotic B-cell lymphoma 2 levels and a decrease in the levels of DNA repair protein and proliferating cell nuclear antigen. Moreover, an IR-induced reduction in serum testosterone and superoxide dismutase levels and an increase in malondialdehyde levels were considerably reversed in CBLB502-pretreated mice. No significant reverse effects were found in Tlr5 knockout mice, suggesting that protection of the testis against IR by CBLB502 is primarily dependent on the TLR5 signaling pathway. Our results may help further investigations into potential CBLB502 applications for the protection of the male reproductive system during radiotherapy. Summary Sentence CBLB502, an agonist of Toll-like receptor 5, offers protection against ionizing radiation-induced male reproductive system damage in mice.