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Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation., Introduction In mammals, the reproductive system is initially indistinguishable between the two sexes but is predetermined to develop along the female pathway. To become a male requires modification of this [...]

Background: Phthalate exposure induces germ cell effects in the fetal rat testis. Although experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells have been less explored. OBJECTIVES: We sought to identify the effects of phthalate exposure on human fetal germ cells in a dynamic model and to establish whether the rat is an appropriate model for investigating such effects. METHODS: We used immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction to examine Sertoli and germ cell markers on rat testes and human fetal testis xenografts after exposure to vehicle or di(n-butyl) phthalate (DBP). Our study included analysis of germ cell differentiation markers, proliferation markers, and cell adhesion proteins. RESULTS: In both rat and human fetal testes, DBP exposure induced similar germ cell effects, namely, germ cell loss (predominantly undifferentiated), induction of multinucleated gonocytes (MNGs), and aggregation of differentiated germ cells, although the latter occurred rarely in the human testes. The mechanism for germ cell aggregation and MNG induction appears to be loss of Sertoli cell--germ cell membrane adhesion, probably due to Sertoli cell microfilament redistribution. CONCLUSIONS: Our findings provide the first comparison of DBP effects on germ cell number, differentiation, and aggregation in human testis xenografts and in vivo in rats. We observed comparable effects on germ cells in both species, but the effects in the human were muted compared with those in the rat. Nevertheless, phthalate effects on germ cells have potential implications for the next generation, which merits further study. Our results indicate that the rat is a human-relevant model in which to explore the mechanisms for germ cell effects. http://dx.doi.org/10.1289/ehp.1408248, Introduction In utero exposure of rats to high doses of certain phthalate esters, such as diethylhexyl phthalate (DEHP) or di(n-butyl) phthalate (DBP), impairs steroidogenesis by the fetal testis, resulting in [...]

Abstract Background Following exposure via inhalation, intratracheal instillation or ingestion some nanomaterials (NM) have been shown to translocate to the liver. Since oxidative stress has been implicated as a possible mechanism for NM toxicity this study aimed to investigate the effects of various materials (five titanium dioxide (TiO2), two zinc oxide (ZnO), two multi-walled carbon nanotubes (MWCNT) and one silver (Ag) NM) on oxidative responses of C3A cell line as a model for potential detrimental properties of nanomaterials on the liver. Results We noted a dose dependant decrease in the cellular glutathione content following exposure of the C3A cells to Ag, the ZnO and the MWCNTs. Intracellular ROS levels were also measured and shown to increase significantly following exposure of the C3A to the low toxicity NMs (MWCNT and TiO2). The antioxidant Trolox in part prevented the detrimental effect of NMs on cell viability, and decreased the NM induced IL8 production after exposure to all but the Ag particulate. Following 4 hr exposure of the C3A cells to sub-lethal levels of the NMs, the largest amount of DNA damage was induced by two of the TiO2 samples (7 nm and the positively charged 10 nm particles). Conclusions All ten NMs exhibited effects on the hepatocyte cell line that were at least in part ROS/oxidative stress mediated. These effects included mild genotoxicity and IL8 production for all NM except the Ag possibly due to its highly cytotoxic nature.

Abstract This review focuses on outlining the toxicity of titanium dioxide (TiO2) particulates in vitro and in vivo, in order to understand their ability to detrimentally impact on human health. Evaluating the hazards associated with TiO2 particles is vital as it enables risk assessments to be conducted, by combining this information with knowledge on the likely exposure levels of humans. This review has concentrated on the toxicity of TiO2, due to the fact that the greatest number of studies by far have evaluated the toxicity of TiO2, in comparison to other metal oxide particulates. This derives from historical reasons (whereby the size dependency of particulate toxicity was first realised for TiO2) and due to its widespread application within consumer products (such as sunscreens). The pulmonary and dermal hazards of TiO2 have been a particular focus of the available studies, due to the past use of TiO2 as a (negative) control when assessing the pulmonary toxicity of particulates, and due to its incorporation within consumer products such as sunscreens. Mechanistic processes that are critical to TiO2 particulate toxicity will also be discussed and it is apparent that, in the main, the oxidant driven inflammatory, genotoxic and cytotoxic consequences associated with TiO2 exposure, are inherently linked, and are evident both in vivo and in vitro. The attributes of TiO2 that have been identified as being most likely to drive the observed toxicity include particle size (and therefore surface area), crystallinity (and photocatalytic activity), surface chemistry, and particle aggregation/agglomeration tendency. The experimental set up also influences toxicological outcomes, so that the species (or model) used, route of exposure, experiment duration, particle concentration and light conditions are all able to influence the findings of investigations. In addition, the applicability of the observed findings for particular TiO2 forms, to TiO2 particulates in general, requires consideration. At this time it is inappropriate to consider the findings for one TiO2 form as being representative for TiO2 particulates as a whole, due to the vast number of available TiO2 particulate forms and large variety of potential tissue and cell targets that may be affected by exposure. Thus emphasising that the physicochemical characteristics are fundamental to their toxicity.

Abstract Background In the year 2000 Corus closed its steel plant operations in Redcar, NE of England temporarily for refurbishment of its blast furnace. This study investigates the impact of the closure on the chemical composition and biological activity of PM10 collected in the vicinity of the steel plant. Methods The metal content of PM10 samples collected before during and after the closure was measured by ICP-MS in order to ascertain whether there was any significant alteration in PM10 composition during the steel plant closure. Biological activity was assessed by instillation of 24 hr PM10 samples into male Wistar rats for 18 hr (n = 6). Inflammation was identified by the cellular and biochemical profile of the bronchoalveolar lavage fluid. Metal chelation of PM10 samples was conducted using Chelex beads prior to treatment of macrophage cell line, J774, in vitro and assessment of pro-inflammatory cytokine expression. Results The total metal content of PM10 collected before and during the closure period were similar, but on reopening of the steel plant there was a significant 3-fold increase (p < 0.05) compared with the closure and pre-closure samples. Wind direction prior to the closure was predominantly from the north, compared to south westerly during the closure and re-opened periods. Of metals analysed, iron was most abundant in the total and acid extract, while zinc was the most prevalent metal in the water-soluble fraction. Elevated markers of inflammation included a significant increase (p < 0.01) in neutrophil cell numbers in the bronchoalveolar lavage of rats instilled with PM10 collected during the reopened period, as well as significant increases in albumin (p < 0.05). Extracts of PM10 from the pre-closure and closure periods did not induce any significant alterations in inflammation or lung damage. The soluble and insoluble extractable PM10 components washed from the reopened period both induced a significant increase in neutrophil cell number (p < 0.05) when compared to the control, and these increases when added together approximately equalled the inflammation induced by the whole sample. PM10 from the re-opened period stimulated J774 macrophages to generate TNF-α protein and this was significantly prevented by chelating the metal content of the PM10 prior to addition to the cells. Conclusion PM10-induced inflammation in the rat lung was related to the concentration of metals in the PM10 samples tested, and activity was found in both the soluble and insoluble fractions of the particulate pollutant.