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The current generation of carcinogenicity tests is often insufficient to predict cancer outcomes from pesticide exposures. In order to facilitate health risk assessment, The International Agency for Research on Cancer identified 10 key characteristics which are commonly exhibited by human carcinogens. The ToxTracker panel of six validated GFP-based mouse embryonic stem reporter cell lines is designed to measure a number of these carcinogenic properties namely DNA damage, oxidative stress and the unfolded protein response. Here we present an evaluation of the carcinogenic potential of the herbicides glyphosate, 2,4-D and dicamba either alone or in combination, using the ToxTracker assay system. The pesticide 2,4-D was found to be a strong inducer of oxidative stress and an unfolded protein response. Dicamba induced a mild oxidative stress response, whilst glyphosate did not elicit a positive outcome in any of the assays. The results from a mixture of the three herbicides was primarily an oxidative stress response, which was most likely due to 2,4-D with dicamba or glyphosate only playing a minor role. These findings provide initial information regarding the risk assessment of carcinogenic effects arising from exposure to a mixture of these herbicides., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Common waterhemp emerges throughout the crop growing season in the Midwestern United States, and as a result, the seedlings are exposed to a wide range of temperature regimes. Typically, 2,4-D is used in the Midwest to control winter annual broad-leaf weeds before planting soybean and in an early post-emergence application in corn and sorghum; however, the evolution of 2,4-D-resistant common waterhemp in several Midwestern states may limit the use of 2.4-D for controlling this problem weed. Moreover, temperature is one of the crucial factors affecting weed control efficacy of 2,4-D. This research investigated the effect of temperature on efficacy of 2,4-D to control 2,4-D susceptible (WHS) and -resistant (WHR) common waterhemp. Do se-response of WHS and WHR to 2,4-D was assessed at two temperature regimes, high (HT; 34/20 °C, d/n) and low (LT; 24/10 °C, d/n). Whole plant dose response study indicated an increased level of 2,4-D resistance in WHR at HT compared to LT. Additional investigation of the physiological mechanism of this response indicated that both WHS and WHR common waterhemp plants rapidly metabolized 14 C 2,4-D at HT compared to LT. In conclusion, a rapid metabolism of 2,4-D conferred increased level of resistance to 2,4-D in WHR at HT. Therefore, application of 2,4-D when temperatures are cooler can improve control of 2,4-D resistant common waterhemp.

The gut microbiota critically confers various health benefits, whereas environmental chemicals can affect its constitution and functionality thereby increasing disease risk. In the present study, we aim to evaluate the toxic effects of a wildly-used herbicide 2,4-D (2,4-dichlorophenoxyacetic acid) on the gut microbiome and host using an occupationally relevant dose. A mouse model was used combined with metagenomic sequencing and metabolomic profiling to examine the alterations induced by subchronic low-dose 2,4-D exposure in fecal and plasma samples. The metagenomics results revealed a distinct gut microbial community with profound changes in diverse microbial pathways including urea degradation, amino acid and carbohydrate metabolism in 2,4-D-treated mice. Moreover, the metabolomics results revealed that the metabolic profiles in treatment group were differentiated from control group in both fecal and plasma samples. Toxic effects on the host of 2,4-D at an occupationally relevant dose were observed indicated by decreased acylcarnitine levels in plasma. These findings indicated that 2,4-D can cause toxicity and substantially impact the gut microbiome in mice at occupationally relevant doses, inferring that the relationship between environmental contaminants and microbiota is largely underestimated calling for more comprehensive consideration of the toxicity of occupational exposures.

Prior studies have shown that applications of the synthetic auxin 2,4-dichlorophenoxyacetic acid (2,4-D) to the foliage of potato plants can reduce common scab. Here field and glasshouse trials suggest that 2,4-D foliar treatments may also reduce the biologically distinct tuber disease, powdery scab. Significant correlations between suppression of common and powdery scab from the field trials suggested an interaction between the two diseases or possible additional broad spectrum mechanisms of enhanced defence against pathogen invasion provided by 2,4-D treatment.

We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

This study aims to assess effects of 96 h goldfish exposure to 1, 10 and 100 mg/L of the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), on metabolic indices and free radical process markers in white muscle of a commercial fish, the goldfish Carassius auratus L. Most oxidative stress markers and antioxidant enzymes were not affected at 2,4-D fish treatment. 2,4-D fish exposure induced the elevated levels of total (by 46% and 40%) and reduced (by 77% and 73%) glutathione in muscles of goldfish of 10 mg/L 2,4-D and recovery (after 100 mg/L of 2,4-D exposure) groups, respectively. However, in muscles of 100 mg/L 2,4-D exposed goldfish these parameters were depleted (by 47% and 64%). None of investigated parameters of protein and carbohydrate metabolisms changed in white muscles of 2,4-D exposed fish, with exception of lactate dehydrogenase activity, which was slightly (by 11-15%) elevated in muscles of goldfish exposed to 10-100 mg/L of 2,4-D, but also recovered. Thus, the short term exposure of goldfish to the selected concentrations of 2,4-D does not substantially affect their white muscle, suggesting the absence of any effect under the environmentally relevant concentrations., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

J. curcas has been studied in different countries and some interesting agronomic, pharmacological and industrial properties have been reported. More recently, it has been considered an important alternative source for biofuel production. The objective of this study was to establish a long-term method for the maintenance of calli and cell suspension cultures of the local species J. curcas and J. gossypifolia, in order to allow future studies for novel compounds with pharmaceutical or industrial applications. For this, friable calli were successfully induced from hypocotyl segments of.. curcas and J. gossypifolia that were cultured in semisolid MS media supplemented with 1.5 mg/L, and 0.5 mg/L of 2,4-D, respectively. Cell suspension cultures of J. curcas were established using 1 g of 35 and 60-day calli, in 50 mL of liquid MS media supplied with 1.5 mg/L of 2,4-D; sucrose and maltose were additionally evaluated as carbon sources. After 35 days, cell suspension cultures initiated with 35-day calli, showed greater cell growth with a maximum biomass of 194.9 g/L fresh weight, 6.59 g/L dry weight and 17.3% packed volume. The exponential phase ended at day 35 for cultures initiated with 35-day calli, and at day 21 for cultures initiated with 60-day calli. Higher biomass production was obtained with sucrose. Cell cultures were established with 35-day calli in MS media with the same 2,4-D concentration used for calli induction and 30g/L sucrose. This medium was considered optimum for the maintenance and growth of cell suspensions for both species, with sub-cultures every 20 days. The biotechnological potential for the production of bioactive compounds in these species for pharmacological, agricultural and industrial applications is being evaluated.

The accumulation of 2,4-dichlorophenoxyacetic acid (2,4-D) and its metabolite 2,4-dichlorophenol (2,4-DCP) in the kidneys of rats was investigated. Male and female Sprague-Dawley rats were given 2,4-D in drinking water and food for 30 days. Group A (control group) was fed a normal diet, Group B was fed 50 ppm 2,4-D in 15 g food, Group C received 100 ppm 2,4-D in 15 g food, Group D received 25 ppm 2,4-D in 15 ml drinking water and Group E was given 50 ppm 2,4-D in 15 ml of drinking water. Levels of 2,4-D and 2,4-DCP in kidneys were determined using high performance liquid chromatography (HPLC). It was observed that at low doses of 2,4-D, the metabolite, 2,4-DCP found in the kidneys.

2,4-dichlorophenoxyacetic acid and monosodium methanearsonate are often sold in commercial mixtures. Bioconcentration studies have been performed for each of these herbicides individually, but little information exists concerning long-term exposure to a mixture of these herbicides. The following study examined the uptake of arsenic in crawfish after long-term exposure to this mixture, and the health risks associated with consumption of these crawfish. Bioconcentration and depuration experiments using a 50:50 by concentration mixture of the two herbicides, with and without surfactant, were performed to quantify how much arsenic is concentrated in the edible tissue of the crawfish. Of the three tissues (muscle, gill, and hepatopancreas) sampled hepatopancreas bioconcentrated the highest amount of arsenic. Surfactant significantly reduced this uptake but did not affect bioconcentration of arsenic into other tissues. Surfactant had no effect on depuration of arsenic from any of the tissues. Cooking lowered hepatopancreatic arsenic content, possibly as a result of structural changes in the hepatopancreas. Assessment of the human health risk associated with consuming these crawfish showed an exposure dose at the high end of consumption that was approximately twice the reference dose for arsenic. Cancer risks were averaged at approximately 7 extra tumors in a population of 10,000 and 6 extra tumors in a population of 10,000 resulting from a lifetime consumption of crawfish exposed to the herbicide mixture without and with surfactant, respectively.

In cultured Bright Yellow-2 tobacco (Nicotiana tabacum) cells, the depletion of 2,4-dichlorophenoxyacetic acid (2,4-D) in the culture medium induces amyloplast development. This differentiation also includes a decrease in cell multiplication, and an increase in cell size. These changes were primarily triggered by the depletion of 2,4-D, and accelerated by the addition of benzyladenine (BA). Three cDNAs were identified whose transcript levels are specifically increased during differentiation of starch-storing cells using the differential display method, and designated as starch-storing cell induced genes (SCI genes). One of these cDNAs, SCI2 encodes a 285 amino acids long protein with a KH RNA-binding domain. A database search revealed that this protein showed similarity to respective domains of mammalian quaking proteins. 2,4-D addition, which can convert starch-storing cells into dividing cells, to starch-storing BY-2 cells, immediately decreases the SCI2 transcript level, suggesting that SCI2 may have some role in starch-storing cell differentiation in BY-2 cells.

Peroxisome proliferators are non-mutagenic carcinogens in the liver of rodents, acting both as initiators and promoters. The National Toxicology Program (NTP) conducted a study of several peroxisome proliferators (PPs), including Wyeth (WY)-14643 as a prototypical PP and 2,4-dichlorophenoxyacetic acid (2,4-D) as a weak PP, in Sprague-Dawley rats. B6C3F1 mice, and Syrian hamsters. In the kidney, an unusual change was observed in the outer stripe of the outer medulla, especially in rats treated with 2,4-D or WY-14643. This change was characterized by foci of tubules that were partially or completely lined by basophilic epithelial cells with decreased cytoplasm and high nuclear density. Changes typical of chronic nephropathy such as interstitial fibrosis or basement membrane thickening were not associated with these foci. Results of immunohistochemical staining for catalase and cytochrome P-450 4A in the kidney indicated increased staining intensity in renal tubular epithelial cells primarily in the region where the affected tubules were observed: however, the altered cells were negative for both immunohistochemical markers. Ultrastructurally, affected cells had long brush borders typical of the P3 tubule segment. The most distinguishing ultrastructural change was a decreased amount of electronlucent cytoplasm that contained few differentiated organelles and, in particular, a prominent reduced volume and number of mitochondria; changes in peroxisomes were not apparent. In addition to the lesion in rats, mice treated with the highest dose of 2,4-D, but not WY-14643, manifested similar renal tubular changes as seen by light microscopy. Neither chemical induced renal tubular lesions in hamsters. Hepatocellular changes characteristic of PPs were present in all 3 species treated with WY-14643, but not 2,4-D. These results indicate that the rat is the species most sensitive to the nephrotoxic effects of PPs and there is a site specificity to this toxicity related to areas of PP-related enzyme induction. Although 2,4-D is considered a weak PP for the liver, it was the most effective at inducing renal lesions, indicating that the toxic potency of various PPs will depend on the target organ.

The acute toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D), a herbicide, was studied in chicks dosed with 100, 300, 500, or 600 mg 2,4-D/kg BW, by the oral route. Clinical, laboratory, and histopathological methods were used as indicators of toxicity. After acute exposure, the herbicide decreased motor activity and induced muscular weakness and motor incoordination; decreased weight gain; increased serum creatine kinase (CK) and alkaline phosphatase (AP) activities and serum uric acid (UA), creatinine (CR), and total proteins (TP) levels; and did not change serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) activities. These changes were time- and dose-dependent and reversible. The LD50 (lethal dose 50%) calculated for oral 2,4-D in chicks was 420 mg/kg BW (385 to 483). Chromatographic analysis of the serum of the intoxicated chicks showed the presence of the herbicide; the amount found was dose- and time-dependent, increasing from 2 to 8 h after exposure and decreasing afterwards. Histopathological post-mortem studies conducted on intoxicated chicks showed hepatic (vacuolar degeneration of the hepatocytes), renal (tubular nephrosis), and intestinal (hemorrhagic) lesions. Taken together, the observed alterations mainly reflected kidney and muscle tissue damage, although hepatic toxicity may also have occurred after acute 2,4-D intoxication.

Forms of 2,4-dichlorophenoxyacetic acid (2,4-D) are herbicides used in the control of a wide variety of broadleaf and woody plants. Subchronic toxicity studies in dogs were conducted on three forms of 2,4-D: the parent form, 2,4-D acid (ACID); 2,4-D dimethylamine salt (DMA); and 2,4-D 2-ethylhexyl ester (2-EHE). The three studies were designed to allow for comparison of the toxicity of the three forms. Doses in the subchronic studies, on an acid equivalent basis, were 0, 0.5 (ACID only), 1.0, 3.75, and 7.5 mg/kg/day. Treatment related findings in the three studies included reductions in body weight gain, and food consumption, and minor increases in blood urea nitrogen, creatinine, and alanine aminotransferase. The data from the three subchronic studies demonstrated the comparable toxicity of ACID, DMA, and 2-EHE and support a subchronic no observed adverse effect level (NOAEL) of 1.0 mg/kg/day for all three forms. Due to the similarity in toxicity of the three forms of 2,4-D, a 1-year chronic toxicity study was performed on the parent ACID to fully characterize the potential toxicity of 2,4-D in the dog. ACID was well tolerated at doses of 0, 1.0, 5.0, and 7.5 mg/kg/day. The clinical pathology alterations were similar to those seen in the subchronic studies and were not progressive. The histopathology alterations observed were not severe in nature and the no observed effect level in the chronic study was determined to be 1.0 mg/kg/day. There was no indication of any immunotoxic or oncogenic response in the studies. In conclusion, the findings of these studies indicate comparable toxicity among representative forms of 2,4-D and their generally low toxicity following subchronic and chronic dietary exposure in the dog.