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The present study identified a critical role of Cx43 in LYC maintaining BTB integrity, which is a prerequisite for normal spermatogenesis. This study reveals the role of Cx43 in LYC preventing phthalate-induced spermatogenic disorders, and Cx43 regulation may provide the basis for future therapeutic male infertility. [Display omitted] • Phthalate induced spermatogenic disorders and destroyed BTB integrity. • Phthalate caused cell migration capacity decline and cytoskeletal disorganization. • LYC alleviated DEHP-induced disruption of intercellular junctions in mouse testes. • LYC improved DEHP-induced spermatogenic disorders by regulating BTB integrity. • LYC ameliorated DEHP-induced BTB disruption by modulating Cx43 expression. Male infertility is a multifactorial pathological condition and may be a harbinger of future health. Phthalates are ubiquitous environmental contaminants that have been implicated in the global decline in male fertility. Among them, di-(2-ethylhexyl) phthalate (DEHP) is the most prevalently used. Lycopene (LYC) is a possible preventive and therapeutic agent for male infertility owing to its antioxidant properties. The blood-testis barrier (BTB) is formed between Sertoli cells where it creates a unique microenvironment for spermatogenesis. We hypothesize that phthalate caused male infertility and LYC plays an important role in phthalate-induced male fertility disorders. Hematoxylin-eosin (H&E) staining, ultrastructure observation, and fluorescence microscopy were used to examine the morphological changes. RNA-Seq, and western blotting were conducted to detect gene and protein levels. Routine testing for sperm morphology and sperm-egg binding assay were conducted to examine the morphological structure and function of sperm. Cell scratch assay and transepithelial electrical resistance (TER) were used to detect cell migration capacity and barrier integrity. In vivo experiments, we showed that LYC prevented DEHP-induced impairment of BTB integrity, which provided a guarantee for the smooth progress of spermatogenesis. LYC improved DEHP-induced change in sperm parameters and fertilization ability. Subsequent in vitro experiments, LYC alleviated MEHP-induced disruption of intercellular junctions in mouse Spermatogonia cells (GC-1 cells) and mouse Sertoli cells (TM4 cells). In MEHP-induced BTB impairment models of Sertoli cells, treatment with LYC or overexpressing connexin-43 (Cx43) promoted cell migration capacity and normalized BTB integrity. Cx43 knockdown inhibited cell migration capacity and perturbed BTB reassembly in LYC preventing DEHP-induced BTB impairment. Our study provides evidence for the role of LYC in phthalates-induced spermatogenic disorders and points to Cx43 as a potential target for male fertility. [ABSTRACT FROM AUTHOR]

Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer that is easily found in the environment. Excessive daily exposure of it may lead to an increased risk of cardiovascular disease (CVD). Lycopene (LYC), as a natural carotenoid, has been shown to have the potential to prevent CVD. However, the mechanism of LYC on cardiotoxicity caused by DEHP exposure is unknown. The research was aimed to investigate the chemoprotection of LYC on the cardiotoxicity caused by DEHP exposure. Mice were treated with DEHP (500 mg/kg or 1,000 mg/kg) and/or LYC (5 mg/kg) for 28 d by intragastric administration, and the heart was subjected to histopathology and biochemistry analysis. The results indicated that DEHP caused cardiac histological alterations and enhanced the activity of cardiac injury indicators, and interfered with mitochondrial function and activating mitophagy. Notably, LYC supplementation could inhibit DEHP-induced oxidative stress. The mitochondrial dysfunction and emotional disorder caused by DEHP exposure were significantly improved through the protective effect of LYC. We concluded that LYC enhances mitochondrial function by regulating mitochondrial biogenesis and dynamics to antagonize DEHP-induced cardiac mitophagy and oxidative stress. DEHP exposure can cause heart damage and destroy the pathophysiological integrity of the mouse heart. LYC can alleviate this phenomenon. LYC can alleviate the heart oxidative stress damage induced by the imbalance of mitochondrial biogenesis and mitochondrial dynamics disorder DEHP. This study provides new insights and shows that LYC can prevent DEHP-induced heart damage by activating mitophagy, which may be the target molecule of DEHP toxicity and LYC effect mechanism in the future. [Display omitted] [ABSTRACT FROM AUTHOR]

The burden and morbidity of environmental nephrosis is increasing globally. Atrazine (ATR) and degradation products in the environment are considered key determinants of nephrosis. However, the lack of highly effective treatments for environmental nephrosis creates an urgent need to better understand the preventive strategies and mechanisms. This study aimed to highlight the mechanism of ATR-induced environmental nephrosis and the chemoprotective potential of lycopene (LYC) against the renal injury and nephrosis. Male mice were treated with LYC (5 mg/kg) and/or ATR (50 mg/kg or 200 mg/kg) by gavage administration for 21 days. Histopathological changes and biochemical function, cytochrome P450 enzymes system (CYP450s), nuclear xenobiotic receptors (NXRs) response and the transcription of CYP isoforms (CYPs) were detected. ATR exposure caused the changes of the histopathological and biochemical function, activated the NXR response and disturbed the CYP450s homeostasis. Supplementary LYC significantly prevented ATR-induced nephrotoxicity and alleviated the alternation of histopathological and biochemical function via modulating the CYP450s homeostasis and the NXR response. The results demonstrated AHR, CAR, PXR, PPAR (α, γ), CYP1, CYP2, CYP3 and CYP4 superfamily play a vital role in LYC-ATR interaction. Our findings provide new evidence that ATR exposure can cause the environmental nephrosis via inducing the kidney injury. Supplementary LYC showed significant chemoprotective potential against ATR-induced renal injury and environmental nephrosis via regulating the NXR response and the CYP450s homeostasis. [ABSTRACT FROM AUTHOR]

Atrazine (ATR) is a commercially available herbicide that is used worldwide. The intensive use of ATR poses potential risks to animals' and humans' health. Lycopene (LYC) is an anti-oxidative phytochemical that normalizes health hazards triggered by environmental factors. In this study, we aimed to investigate the toxic effects of ATR on the hippocampus and its amelioration by LYC. Male mice were exposed to ATR (50 mg/kg/day or 200 mg/kg/d) and/or LYC (5 mg/kg/d) for 21 days. The results showed that ATR exposure induced hippocampus-dependent learning and memory impairments. ATR-induced ferroptosis in hippocampal cells affects the homeostasis of lipid metabolism, whereas LYC ameliorates the neurotoxic effects of ATR in the hippocampus. LYC inhibited ATR-induced ferroptosis by increasing the expression of HO-1, Nrf2 and SLC7A11. Therefore, this study established that LYC ameliorates ATR-induced spatial learning and memory impairments by inhibiting ferroptosis in the hippocampus and also provides a novel approach for the treatment in contradiction of environmental pollutants. ATR is a kind of herbicide that spreads throughout the environment. Because of its biological activity, particularly antioxidant properties, LYC has attracted a lot of interest. According to our findings, LYC ameliorates ATR-induced spatial learning and memory impairments by inhibiting ferroptosis in the hippocampus of mice. This research may lead to a plausible molecular mechanism for LYC therapy of ATR-induced neurological damage. [Display omitted] • ATR caused spatial learning and memory impairments. • ATR induced ferroptosis in the hippocampus. • LYC can prevent ferroptosis and promote nerve cell repair. • LYC mitigated ATR-induced spatial learning and memory impairments. [ABSTRACT FROM AUTHOR]

Di (2-ethylhexyl) phthalate (DEHP) is commonly used as a plasticizer in plastic products, and due to its unique chemical composition, it frequently dissolves and enters the environment. Lycopene as a natural carotenoid has been shown to have powerful antioxidant capacity and strong kidney protection. This study aimed to investigate the role of the interplay between oxidative stress and the classical pyroptosis pathway in LYC alleviating DEHP-induced renal injury. ICR mice were given DEHP (500 mg/kg/d or 1000 mg/kg/d) and/or LYC (5 mg/kg/d) for 28 days to explore the underlying mechanisms of this hypothesis. Our results indicated that DEHP caused the shedding of renal tubular epithelial cells, increased the content of kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL) in the tissue, the decrease of antioxidant activity markers and the increase of oxidative stress indexes. It is gratifying that LYC alleviates DEHP-induced renal injury. The expression of nuclear factor erythrocyte 2-related factor 2 (Nrf2) and its downstream target genes is improved in DEHP induced renal injury through LYC mediated protection. Meanwhile, LYC supplementation can inhibit DEHP-induced Caspase-1/NLRP3-dependent pyroptosis and inflammatory responses. Taken together, DEHP administration resulted in nephrotoxicity, but these changes ameliorated by LYC may through crosstalk between the Nrf2/Keap-1/NLRP3/Caspase-1 pathway. Our study provides new evidence that LYC protects against kidney injury caused by DEHP. [Display omitted] [ABSTRACT FROM AUTHOR]

Phthalates are extensively used in the production of plastics products and have been verified to induce lung injury. Lycopene (LYC) has proved an effective preventive and can be utilized to prevent phthalates-induced toxicity. However, the role of phthalate in pathogenesis of lung injury remain poorly researched, and little work has been devoted whether LYC could alleviate phthalate-induced lung toxicity via modulating nuclear xenobiotic receptors (NXRs) response. Here, di (2-ethylhexyl) phthalate (DEHP) is used as the representative of phthalates for further studies on toxicity of phthalates and the antagonistic role of LYC in phthalates-induced lung injury. We found that DEHP exposure caused alveoli destruction and alveolar epithelial cells type II damage. Mechanistically, DEHP exposure increased nuclear accumulation of aryl hydrocarbon receptor (AHR) and its downstream genes level, including cytochrome P450-dependent monooxygenase (CYP) 1A1 and CYP1B1. Constitutive androstane receptor (CAR) and their downstream gene level, including CYP2E1 are also increased after phthalates exposure. Significantly, LYC supplementation relieves lung injury from DEHP exposure by inhibiting the activation of NXRs. We confirm that NXRs plays a key role in phthalates-induced lung injury. Our study showed that LYC may have a positive role in alleviating the toxicity effects of phthalates, which provides an effective strategy for revising phthalates-induced injury. DEHP activates xenobiotic-sensing nuclear receptors AHR and CAR signaling pathway, and thereby resulted in lung injury. LYC supplementation is a potential therapeutic strategy to attenuates phthalates-induced lung injury (By Figdraw). [Display omitted] • DEHP causes lung injury via activating AHR/CAR signaling pathway. • DEHP increases the nuclear accumulation of AHR and CAR. • DEHP causes vacuolization and electron density reduced of lamellar bodies. • AHR and CAR can be used as targets for LYC to attenuate DEHP-induced lung injury. [ABSTRACT FROM AUTHOR]

Atrazine (ATR) is a widely used herbicide with biologically toxic effects that can lead to neurotoxicity. Lycopene (LYC) is an antioxidant with chemoprotective properties. However, little know about the mechanisms of preventative interventions about LYC alleviated ATR-induced neurotoxicity. Male mice were treated with distilled water (C), 5 mg/kg BW/day LYC (L), 50 and 200 mg/kg BW/day ATR (A1, A2), respectively and LYC + ATR (A1+L, A2+L). ATR promoted oxidative stress and inflammatory damage, as showed by the effects on MDA, H 2 O 2 , IL-6 and TNF-α accumulation, and IL-10, SOD, CAT and GSH depletion, which caused neuronal swelling and mitochondrial vacuolar degeneration. ATR disrupted the CYP450s balance via increasing contents of CYP450 and cytochrome B5, enhancing activities of NCR and ERND and activating NXRs and NXRs-related transcription factors. However, all these effects were reversed by LYC pretreatment. Collectively, these data indicated that LYC inhibited ATR-induced oxidative damage through modulating xenobiotic-sensing nuclear receptors and CYP450s. [Display omitted] • LYC inhibits ATR exposure-induces neurotoxicity. • LYC alleviates ATR exposure-induces AHR/PXR/CAR pathway responses. • LYC alleviates ATR-induces the CYP450 homeostasis disorders and CYPs transcription. • LYC alleviates ATR exposure triggers oxidative stress and inflammatory response. [ABSTRACT FROM AUTHOR]

Male infertility is an attracting growing concern owing to decline in sperm quality of men worldwide. Phthalates, in particular to di (2-ethylhexyl) phthalate (DEHP) or its main metabolite mono-2-ethylhexyl phthalate (MEHP), affect male reproductive development and function, which mainly accounts for reduction in male fertility. Lycopene (LYC) is a natural antioxidant agent that has been recognized as a possible therapeutic option for treating male infertility. Testosterone (T)/androgen receptor (AR) signaling pathway is involved in maintaining spermatogenesis and male fertility. How DEHP causes spermatogenesis disturbance and whether LYC could prevent DEHP-induced male reproductive toxicity have remained unclear. Using in vivo and vitro approaches, we demonstrated that DEHP caused T biosynthesis reduction in Leydig cell and secretory function disorder in Sertoli cell, and thereby resulted in spermatogenic impairment. Results also showed that MEHP caused mitochondrial damage and oxidative damage, which imposes a serious threat to the progress of spermatogenesis. However, LYC supplement reversed these changes. Mechanistically, DEHP contributed to male infertility via perturbing T/AR signaling pathway during spermatogenesis. Overall, our study reveals critical role for T/AR signal transduction in male fertility and provides promising insights into the protective role of LYC in phthalate-induced male reproductive disorders. [Display omitted] • DEHP caused testosterone synthesis decline in Leydig cells. • DEHP resulted in secretory function disorder in Sertoli cells. • DEHP led to spermatogenic disorders by disrupting testosterone/androgen pathway. • LYC prevented DEHP-induced sperm parameters decline and spermiogenesis impairment. [ABSTRACT FROM AUTHOR]

Di(2-ethylhexyl) phthalate (DEHP) is an omnipresent environmental pollutant. It has been determined that DEHP is involved in multiple health disorders. Lycopene (Lyc) is a natural carotenoid pigment, with anti-inflammatory and antioxidant properties. However, it is not clear whether Lyc can protect the spleen from DEHP-induced oxidative damage. A total of 140 mice were randomly divided into seven groups (n = 20) and continuously gavaged with corn oil, distilled water, DEHP (500 or 1000 mg/kg BW/day) and/or Lyc (5 mg/kg BW/day) for 28 days. Histopathological and ultrastructural results showed a DEHP-induced inflammatory response and mitochondrial injuries. Moreover, DEHP exposure induced redox imbalance, which resulted in the up-regulation of ROS activity and MDA content, and the down-regulation of T-AOC, T-SOD and CAT in the DEHP groups. Simultaneously, our results also demonstrated that DEHP-induced kelch-like ECH-associated protein 1 (Keap1) expression was downregulated, and the expression levels of P62, nuclear factor erythroid 2-related factor (NRF2) and their downstream target genes were up-regulated. However, the supplementary Lyc reverted these changes to normal levels. Together, Lyc prevented DEHP-induced splenic injuries by regulating the P62-Keap1-NRF2 signaling pathway. Hence, the protective effects of Lyc might be a therapeutic strategy to ameliorate DEHP-induced splenic damage. Exposure to persistent environmental pollutants such as di(2-ethylhexyl) phthalate (DEHP) has been involved in multiple health disorders, including splenic diseases. In this study, we clarified the potential protective effect of lycopene on DEHP-induced splenic injury. The results showed that Lyc inhibited DEHP induced oxidative damage by regulating the P62-Keap1-NRF2 signaling pathway, indicating that Lyc could alleviate the toxic effects of DEHP and may be helpful in reducing spleen injury. [Display omitted] • Lyc alleviated DEHP exposure-induced splenic injury. • Lyc alleviated the DEHP exposure-induced redox imbalance. • Lyc mitigated the inhibition of P62-Keap1-NRF2 pathway induced by DEHP exposure. • Lyc alleviated the splenic cell mitochondrial injuries induced by DEHP exposure. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the possible chemoprotective role of lycopene (LYC) against atrazine (ATR)-induced ionic disorder and hepatotoxicity in mice. Male kunming mice were treated with LYC (5mg/kg) and/or ATR (50mg/kg or 200mg/kg) by lavage administration for 21days. Ionic disorder was assessed by determining the Na(+), K(+) and Ca(2+) content and the alteration in ATP enzymes (ATPases) including Na(+)-K(+)-ATPase, Ca(2+)-ATPase, Mg(2+)-ATPase and Ca(2+)-Mg(2+)-ATPase and the mRNA levels of ATPase's subunits in liver. ATR caused the increases of alanine aminotransferase and aspartate aminotransferase activities and histological changes. LYC pretreatment significantly protected liver against ATR-caused alternation. The significant effect of ATR and LYC on the K(+) and Mg(2+) content in liver was not observed, but ATR increased hepatic Na(+)-K(+)-ATPase activity and decreased Mg(2+)-ATPase and Ca(2+)-Mg(2+)-ATPase activity. The mRNA expressions of Na(+)-K(+)-ATPase subunits were regulated significantly by ATR. A significant increase of Ca(2+) content and seven down-regulated mRNA expressions of Ca(2+)-ATPase subunits and a decrease of Ca(2+)-ATPase activity were observed in the ATR-treated mice. Notably, LYC modulated these ATR-induced alterations of ATPase activity and mRNA expression of their subunits. These results suggest that ATR presents hepatotoxicity via regulating hepatic ATPase's activities and their subunit transcriptions and inducing ionic disorder. LYC protects liver against ATR-induced hepatotoxicity, significantly. LYC modulated hepatic ionic homeostasis disturbance via regulation of ATPase activities and their subunits' (1a1, 1b3, 1b4 and 2b4) transcriptions. In summary, these effects play a critical role of LYC-mediated chemoprevention against ATR-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]