Insights into pH-dependent transformation of gibberellic acid in aqueous solution: Transformation pathway, mechanism and toxicity estimation.

Gibberellic acid (GA3) is widely used in agriculture and maybe transfer with groundwater flow, which is an endocrine disruptor, but few studies have focused on the transformation pathway and toxicity assessment of GA3 and its products. Here, GA3 and its transformation products in aqueous solution were identified and quantified by liquid chromatography mass spectrometry hybrid ion trap time-of-flight (LCMS-IT-TOF) and high-performance liquid chromatography (HPLC), respectively. The results showed that the half-life of GA3 transformation in ultrapure water was 16.1-24.6 days at pH=2.0-8.0, with the lowest half-life occurring at pH=8.0 and highest half-life occurring at pH=3.3. Isomerized gibberellic acid (Iso-GA3) and gibberellenic acid (GEA) were the main transformation products with a little hydroxy gibberellic acid (OH-GA3). In North China groundwater, the mass balance of GA3 and its products was 76.2%, including Iso-GA3 (58%), GEA (7.9%), GA3 (7.3%) and OH-GA3 (3%) after reaching transformation equilibrium. Using Gaussian 09 for chemical computation, it was found that the transformation mechanism of GA3 was dependent upon the bond energy and the stereochemical feature of its molecular structure. GA3 always isomerized from the γ-lactone ring due to the lowest bond energy between the oxygen terminus of the γ-lactone ring and A ring. While GA3 and its transformation products all had developmental toxicity, the predicated LC50 (96 hr) and LD50 of the main products of GA3 were much lower than those of GA3, indicating GA3 would be transformed into higher toxicity derivatives in water environments, posing a significant health risk to humans and the environment.

Continuous gibberellin A3 exposure from weaning to sexual maturity induces ovarian granulosa cell apoptosis by activating Fas-mediated death receptor signaling pathways and changing methylation patterns on caspase-3 gene promoters.

Information on the effects of gibberellic acid (gibberellin A3, GA3) on ovarian follicle development is limited. In our present study, 21-day-old female Wistar rats were exposed to GA3 by gavage (25, 50, and 100 mg/kg body weight, once per day) for eight weeks to evaluate the influence of GA3 on ovarian follicle development. After treatment, significant (P < 0.05) increases (to 40.17 % and 44.5 %, respectively) in atretic follicle proportions and significant decreases (to 19.49 % and 17.86 %, respectively) in corpus luteum proportions were observed in the 50 and 100 mg/kg treatment groups compared to the control group. Significant (P < 0.05) increases (to 31.3 % and 42.0 %, respectively) in follicle apoptosis were observed in the 50 and 100 mg/kg treatment groups by transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Significantly increased expression of caspase-3, caspase-8, caspase-9 and Fas was observed by real-time PCR and Western blotting. Bisulfite sequencing PCR (BSP) revealed obviously decreased total methylation percentages of the caspase-3 promoter region in the two treatment groups. Real-time quantitative PCR also showed significantly decreased mRNA expression of DNA methyltransferase (Dnmt) 3a and Dnmt3b. Further in vitro studies showed that a DNA methylation inhibitor could enhance the GA3-induced increase in the mRNA expression of caspase-3. Overall, our present study indicates that GA3 administration from weaning until sexual maturity can affect ovarian follicle development by inducing apoptosis and suggests that signaling through the Fas-mediated apoptotic pathway may be an important underlying mechanism of this apoptosis. In addition, GA3-induced aberrant DNA methylation patterns might be partly responsible for upregulation of caspase-3 gene expression.

Residue analysis of gibberellic acid isomer (iso-GA3) in brewing process and its toxicity evaluation in mice.

Gibberellic acid (GA3) is an efficient plant growth regulator, which could speed up barley germination in the brewing industry. However, the residue of GA3 in malt gets denatured into an isomer, termed iso-GA3. In this study, the concentration of iso-GA3 and the conversion rate of GA3 to iso-GA3 during the brewing process was studied by high performance liquid chromatography and the potential toxicity of iso-GA3 was evaluated in ICR mice. The concentration of iso-GA3 increased in the saccharification and wort boiling processes while its concentration was stable during fermentation. The maximum conversion rates of GA3 to iso-GA3 in Canadian malt, Australian malt SCO and Australian malt FAQ were 88%, 87% and 87%, respectively. In the acute oral toxicity study, the median lethal dose (LD50) of iso-GA3 was 2.82 g/kg body weight (BW). In the 28-day repeated dose toxicity study, the iso-GA3 could cause weight loss in mice. And the mice of high-dose group showed a slight decrease in food consumption. Moreover, inflammation and cell necrosis were found in kidney and liver tissue, which were alleviated during the recovery phase. These results establish a practical reference for food safety in products, in which GA3 is added as a food additive.

Histological and biochemical changes induced by gibberellic acid in the livers of pregnant albino rats and their offspring: ameliorative effect of Nigella sativa.

Gibberellic acid (GA3), a plant growth regulator, is widely used in agriculture in many countries to accelerate the growth of fruits and vegetables. We designed histological, immunohistochemical, and biochemical studies to evaluate the deleterious effects of GA3 on the livers of adult pregnant rats and their offspring and to assess the possible ameliorative effect of Nigella sativa Linn. (NsL.oil) against these effects. Twenty-four pregnant albino rats were utilized, randomly divided into four groups: The first group was used as a negative control group, while the second group (positive control group) was provided NsL.oil at a dose of 100 mg/kg of bodyweight. Animals in the third group (GA3 group) were provided 200 ppm of GA3 dissolved in distilled water from the 7th day of pregnancy until 1 day after delivery. Animals in the last group (GA3 + NsL.oil group) were provided GA3 and NsL-oil at the same doses as mentioned above. One day after delivery, each group of lactating mothers and their pups were sacrificed. Liver specimens were subjected to histopathological, immunohistochemical, and biochemical examinations. The livers of rats from the GA3 group showed various degenerative changes, being predominant in the livers of the mothers compared with the offspring. The pathological changes in the livers of the offspring suggested transplacental passage of GA3. The results reveal that GA3 ingestion induced a significant increase in alanine aminotransferase (ALT) and aspartate transaminase (AST) activities in the serum of both groups of mothers and their pups, with a significant increment in lipid peroxidation as evidenced by enhanced malondialdehyde (MDA) levels with significant decrements in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) enzymatic activities in comparison with control groups in the liver of mothers and their offspring. Histopathological examination showed hydropic degeneration and inflammatory cellular infiltration. Additionally, there was fibrosis around the portal area. Moreover, immunolocalization revealed downregulation of the expression of the antiapoptotic marker Bcl-2 in hepatocytes and upregulation of the expression of the apoptotic marker Bax in the treated group. Concomitant use of NsL.oil along with GA3 exerted a considerable reversing effect on histopathological and biochemical changes in the livers of mother groups and their pups. The results of the present study highlight the consequences of exposure to GA3 during pregnancy on hepatic tissue in both mothers and their offspring. Furthermore, the study suggests use of NsL.oil as a potential protective strategy against GA3-induced liver toxicity.

A histological, immunohistochemical and biochemical study of the effects of pomegranate peel extracts on gibberellic acid induced oxidative stress in adult rat testes.

Gibberellins are commonly used plant growth regulators that exhibit deleterious effects on various animal tissues. We investigated the histological, immunohistochemical and biochemical effects of gibberellic acid (GA3) on rat testes as well as the possible protective role of pomegranate peel extract (PPE). We used 28 adult male rats divided into control, PPE treated, GS3 treated and GA3 + PPE treated groups. Testis specimens were analyzed for superoxide dismutase (SOD) and catalase (CAT) activity, and examined histologically. We also investigated the androgen receptor using immunohistochemistry. The GA3 treated group exhibited significantly decreased SOD and CAT levels and area percent of androgen receptor. Seminiferous tubules (ST) were widely separated and the germinal epithelium was separated from the basement membrane in some tubules. Areas of vacuolation, degenerated germ cells with pyknotic nuclei and large multinucleated cells were observed. Ultrastructurally, primary spermatocytes exhibited vacuolated cytoplasm, degenerated mitochondria and hyperchromatic nuclei. Degenerated early spermatids with a ruptured or hyperchromatic nucleus were found. Spermatozoa exhibited abnormalities of the head and tail. The cytoplasm of Sertoli and Leydig cells exhibited dilated smooth endoplasmic reticulum. A significant improvement of the biochemical, histological and immunohistochemical alterations was observed in the GA3 + PPE treated group compared to the GA3 treated group.

The in vitro effects of gibberellin on human sperm motility.

Gibberellin, a plant growth regulator, is widely used to increase the shelf life and quality of fruits and vegetables. In this study, human semen samples were exposed to different concentrations of gibberellin, which reduced spermatozoa motility in vitro. Gibberellin exposure also increased levels of reactive oxygen species and the protein levels of apoptosis markers in human sperm. Gibberellin inhibited the activity of Na+/K+-adenosine triphosphatase (ATPase) and Ca2+-ATPase, which maintain the stability of ions inside and outside the membranes of spermatozoa. Moreover, gibberellin exposure suppressed adenosine triphosphate production and reduced the protein levels of adenosine triphosphate synthases, which may have induced the protein expression of adenosine 5'-monophosphate-activated protein kinase (AMPK) and its phosphorylated form. These results suggest that gibberellin reduces human sperm motility in vitro by increasing reactive oxygen species levels and reducing ATPase activity, which may upregulate AMPK and consequently reduce the fertilization potential of spermatozoa.

Assessments of Algal Toxicity and PBT Behaviour of Pesticides with No Eco-toxicological Data: Predictive Ability of QSA/(T)R Models.

In the present study, the effect of eight pesticides with no ecotoxicological data on the growth rate of Chlorella vulgaris was measured. The selected pesticides are acetochlor, acetamiprid, boscalid diphenamid, gibberellic acid, ioxynil, diclofop and 2,4,5-T. The algal toxicity (IC50 ) of boscalid could not be determined within its solubility limit. Acetamiprid, diphenamid and gibberellic acid revealed IC50 values>100 mg/L. Among the others, the order of 96-h IC50 of pesticides was found as acetochlor>ioxynil>diclofop>2,4,5-T. The IC50 values were also predicted by using four Quantitative Structure-Activity/(Toxicity) Relationship (QSA/(T)R) models selected from the literature. The predictions of the models provided by QSARINS-Chem module of QSARINS as well as those obtained in our previous studies were compared with the results of experimental algal toxicity tests that were performed in our laboratory. The QSTR model generated for the toxicity of diverse chemicals to freshwater algae was able to correctly predict the toxicity order of the pesticides tested in the present study, confirming the utility of the QSA/(T)R approach. Additionally, Persistence, Bioaccumulation and Toxicity (PBT) Index model provided via the software QSARINS was employed and boscalid and diclofop were found to be PBT chemicals based on the PBT model. The present study will be very helpful when a more holistic approach applied to understand the fate of these chemicals in the environment.

Tailoring of a Potential Nanoformulated Form of Gibberellic Acid: Synthesis, Characterization, and Field Applications on Vegetation and Flowering.

Nanoformulation of agrochemicals has become a potential choice to improve the physicochemical properties, enhance the utilization efficiency, and reduce the side effects and ecotoxicity of many hazardous chemicals. Here, we tailored a new formulation platform for gibberellic acid (GA) using the layered double hydroxides (LDH) as a potential carrier. Typically, we synthesized, characterized, and potentially applied the newly nanoformulated form of GA on the quantity and quality properties of Dendranthema grandiflorum cultivar. We also evaluated the synergetic effect of the carrier LDH on the release behavior of GA, showing a remarkable impact on the utilization efficiency of GA. The nanohybrid structure of GA also showed an enhanced thermal stability and safe preservation for the incorporated moieties. Taking into account the hazardous effect of free GA on the environment and human health, the hybrid technique of GA is one of the best choices among all of the studied protocols.

Possible ameliorative effect of Vitamin C on cerebellar toxicity induced by gibberellic acid during late pregnancy and early postnatal periods in albino rats

Gibberellic acid (GA3) is a plant growth regulator, widely used in agriculture in Egypt. The goal of this study was to illustrate the histopathological effects of (GA3) on the growing cerebellar cortex and the possible ameliorative effect of vitamin C. Fifty female Sprague-Dawly rats were classified into the following groups: Group I (control group); Group II (GA3-treated group), which received intra-gastric daily dose of GA3 55 mg/kg from the 14th day of pregnancy until the day 14 after delivery; Group III (GA3 & Vitamin C treated group), which received intra-gastric daily dose GA3, 55 mg/kg simultaneously with 100 mg of Vitamin C /kg from the 14th day of pregnancy till day 14 after delivery; and Group IV (Vitamin C-treated group), which received intra-gastric daily dose 100 mg of Vitamin C / kg from the 14th day of pregnancy till day 14 after delivery. One month after delivery, cerebella of pups from all groups were extracted and examined. The cerebellar cortex of GA3-treated group revealed degenerated and displaced Purkinje and granular nerve cells with prominent spongiosis in the molecular layer. Vitamin C administration resulted in marked regression of the previously mentioned neurotoxic effects. In conclusion: results of the current study revealed that maternal exposure to GA3 during pregnancy and lactation caused delayed development of the offsprings' cerebellar cortex. The co-administration of Vitamin C greatly reduced these neuro-toxic effects of GA3 exposure

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Effects of co-exposure to imidacloprid and gibberellic acid on redox status, kidney variables and histopathology in adult rats.

Data on the individual nephrotoxic effects of imidacloprid (IMI) and gibberellic acid (GA3) are scarce. Moreover, there is a lack of information about their combined effects on the renal tissue. Our study investigated the effects of IMI and GA3 separately or together on rats kidney. IMI (64 mg/kg bw) was given for 3 weeks by gavage either individually or in combination with GA3 (200 mg/L) via drinking water. IMI associated or no with GA3 increased the levels of kidney malondialdehyde, advanced oxidation protein products, protein carbonyls and metallothionein, plasma creatinine, urea, blood urea nitrogen and lactate dehydrogenase activity. A decline of kidney uric acid level and antioxidant status was also observed. All these changes were supported by histopathological observations. Our results highlighted the role of IMI and/or GA3-induced nephrotoxicity. Co-exposure to IMI and GA3 exhibited synergism in biochemical kidney variables and histopathology and antagonism in physical and morphological parameters.

Ameliorative effects of phycocyanin against gibberellic acid induced hepatotoxicity.

Gibberellic acid (GA3) was used extensively unaware in agriculture in spite of its dangerous effects on human health. The current study was designed to investigate the ameliorative effects of the co-administration of phycocyanin with GA3 induced oxidative stress and histopathological changes in the liver. Forty male albino rats were randomly divided into four groups. Group I (control group) received normal saline for 6 weeks, Group II (GA3 treated group) received 3.85 mg/kg body weight GA3 once daily for 6 weeks, Group III (phycocyanin treated group) received Phycocyanin 200 mg/kg body weight/day for 6 weeks orally dissolved in distilled water and Group IV was treated with GA3 and phycocyanin at the same doses as groups 2 and 3. All treatments were given daily using intra-gastric intubation and continued for 6 weeks. Our results revealed significant downregulation of antioxidant enzyme activities and their mRNA levels (CAT, GPx and Cu-Zn, SOD) with marked elevation of liver enzymes and extensive fibrous connective tissue deposition with large biliary cells in hepatic tissue of GA3 treated rats, while treatment with phycocyanin improved the antioxidant defense system, liver enzymes and structural hepatocytes recovery in phycocyanin treated group with GA3. These data confirm the antioxidant potential of Phycocyanin and provide strong evidence to support the co-administration of Phycocyanin during using GA3.

Investigation of neurotoxic and immunotoxic effects of some plant growth regulators at subacute and subchronic applications on rats.

The present study was aimed to investigate the effects of subacute and subchronic treatment of some plant growth regulators (PGRs), such as abscisic acid (ABA) and gibberellic acid (GA3), on neurological and immunological biomarkers in various tissues of rats. The activities of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) were selected as biomarkers for neurotoxic biomarkers. Adenosine deaminase (ADA) and myeloperoxidase (MPO) were measured as indicators for immunotoxic investigation purpose. Wistar albino rats were orally administered with 25 and 50 ppm of PGRs ad libitum for 25-50 days continuously with drinking water. The treatment of PGRs caused different effects on the activities of enzymes. Results showed that the administrations of ABA and GA3 increased AChE and BChE activities in some tissues of rats treated with both the dosages and periods of ABA and GA3. With regard to the immunotoxic effects, ADA activity fluctuated, while MPO activity increased after subacute and subchronic exposure of treated rat tissues to both dosages when compared with the controls. The observations presented led us to conclude that the administrations of PGRs at subacute and subchronic exposure increased AChE, BChE, and MPO activities, while fluctuating the ADA activity in various tissues of rats. This may reflect the potential role of these parameters as useful biomarkers for toxicity of PGRs.

Gibberellic acid induces α-amylase expression in adipose-derived stem cells.

Salivary α-amylase is the most important enzyme for oral digestion of dietary starch. Therefore, regeneration of the salivary glands via a tissue engineering approach is clearly required for patients with salivary gland dysfunction. Early during seed germination, the embryo synthesizes gibberellic acid (GA3), a plant hormone that activates the synthesis and secretion of α-amylase. The purpose of this study was to explore an approach for differentiation of stem cells into salivary glands using GA3. We isolated adipose-derived stem cells (ASCs), which are positive for mesenchymal stem cell markers (CD73, CD90 and CD105) and possess pluripotency to osteoblasts, adipocytes and neural cells, from human buccal fat pads, which are a readily available source for dentists and oral surgeons. In addition, we investigated the cytotoxicity of GA3 for human ASCs. GA3 neither affects cell morphology nor cell viability in a dose- or time-dependent manner. ASCs were incubated with GA3 to assess mRNA and protein expression of α-amylase by reverse transcriptase-polymerase chain reaction and western blot analyses. α-amylase mRNA expression on 21 days after treatment with GA3 (1 mM) was seven times greater than that in resting condition (Day 0). While we did not detect α-amylase bands on Day 0, α-amylase protein was detectable 7 days after treatment with GA3, reaching a maximal level on Day 21. Our results indicated that GA3 can increase cellular α-amylase expression and that our induction method would be useful for therapeutic application for salivary gland regeneration.

Antitumor and antiangiogenic effects of GA-13315, a gibberellin derivative.

This study showed that 13-chlorine-3,15-dioxy-gibberellic acid methyl ester (GA-13315), a gibberellin derivative, possessed high antitumor and antiangiogenic activity in vitro and in vivo. Cytotoxicity assays showed that GA-13315 was a potential and efficient antitumor compound, with inhibitory concentration 50 (IC(50)) values ranging from 0.13 to 30.28 µg/ml in 12 human tumor cell lines, and it showed moderate toxicity to peripheral blood mononuclear cells with an IC(50) value of 14.2 µg/ml. Administration of 0.5 or 2.5 mg/kg GA-13315 for 23 days significantly inhibited tumor growth of human non-small cell lung tumor (A549) xenografts, with relative growth rates ranging from 29.91% to 35.05%. Acute toxicity was determined in ICR mice, and the lethal dose 50 (LD(50)) was 4.19 g/kg after intragastric administration. The high antitumor potency of GA-13315 occurred in parallel with its antiangiogenic activity. In vitro, GA-13315 inhibited recombinant human epithelial growth factor-induced chemotactic motility and capillary-like tube formation of primary cultured human endothelial cells. Furthermore, GA-13315 decreased the factor VIII(+) microvessel density and vascular endothelial growth factor expression in A549 tumors, indicating its antiangiogenic efficacy in vivo. These results indicate that the antiangiogenic activity of GA-13315 contributes to its anticancer properties. Further studies are needed to investigate the use of GA-13315 as an anticancer drug.

Neurotoxicity and oxidative stress induced by gibberellic acid in rats during late pregnancy and early postnatal periods: biochemical and histological changes.

Gibberellic acid (GA(3)) is an endogenous plant growth regulator used worldwide in agriculture; however, little is known about its biochemical and physiological effects on mammals. This study investigated possible neurotoxic effects of GA(3) on the cerebrum and cerebellum of suckling rats. Female Wistar rats were given daily 200 ppm GA(3) in drinking water from the 14th day of pregnancy until day 14 after delivery. Acetylcholinesterase activity in both cerebellum and cerebrum was inhibited after treatment with GA(3). Neurotoxicity was demonstrated by a significant increase in malondialdehyde level and a decrease in the antioxidant enzyme activities of catalase, superoxide dismutase, glutathione peroxidase in the cerebrum and cerebellum of suckling pups. A significant decline of glutathione content and vitamin C was also observed. The biochemical parameters were correlated histologically with an abnormal development of the external granular layer and a loss of Purkinje cells in the cerebellum of GA(3)-treated suckling rats.

Oxidative damage in erythrocytes of adult rats and their suckling pups exposed to gibberellic acid.

Gibberellic acid (GA(3)) is a plant growth regulator used in agriculture worldwide. The present study investigated the propensity of GA(3) to induce hematological disorders. Pregnant Wistar rats were randomly divided into two groups: group I served as controls; group II received orally GA(3) (200 ppm) from the 14th day of pregnancy until day 14 after delivery. GA(3) reduced the number of red blood cells, hemoglobin concentration, and hematocrit in suckling rats, while these parameters remained unchanged in their mothers. White blood cells increased in mothers and were unchanged in their pups. Several studies have associated these hematological disorders with oxidative stress. In fact, GA(3) treatment revealed in erythrocytes a significant increase in malondialdehyde levels and a decrease in antioxidant enzyme activities such as superoxide dismutase, catalase, and glutathione peroxidase. Moreover, a significant decline was observed in acetylcholinesterase activity, glutathione, nonprotein thiols, and vitamin C levels.

Oxidative stress and thyroid impairment after gibberellic acid treatment in pregnant and lactating rats and their offspring.

Gibberellic acid (GA3) has been worldwide used in agriculture as a plant growth regulator. The purpose of this study is to assess the effects of GA3 on the morphology and the thyroid hormone levels in adult rats and their suckling pups. Animals were given daily 200 ppm GA3 in drinking water from the 14th day of pregnancy until day 14 after delivery. Compared with a control group, GA3-treated mothers and pups showed an increase in body and thyroid weights, a decrease in plasma FT4 and FT3 levels, which were more pronounced in pups than in their mothers. Thyroid iodine content was also decreased in pups. These biochemical modifications corresponded histologically; the majority of follicles had cubical epithelial cells, which surrounded empty vesicular cavities. Toxicity was objectified by a significant increase in plasma malondialdehyde, protein carbonyls, and advanced oxidation protein products levels in GA3-treated dams and their suckling pups; while, the activities of superoxide dismutase, catalase, and glutathione peroxidase were decreased in plasma of both dams and their pups. Moreover, a significant decline was observed in plasma glutathione, nonprotein thiols, and vitamin C levels. We conclude that GA3 treatment affects thyroid function and plasma antioxidant status in adult rats and their progeny.

Oxidative stress induced by gibberellic acid on kidney tissue of female rats and their progeny: biochemical and histopathological studies.

Gibberellic acid (GA(3)) is an endogenous plant growth regulator used worldwide in agriculture. The objective of this study was to investigate the effects of GA(3) on the kidney function of adult rats and their pups. Female Wistar rats were given daily 200 ppm GA(3) in drinking water from the 14th day of pregnancy until day 14 after delivery. GA(3) induced nephrotoxicity, as evidenced by a reduction in the 24-h urine volume and an increase in plasma creatinine, urea and uric acid levels. Nephrotoxicity was objectified by a significant increase of malondialdehyde level and a decrease of antioxidant enzyme activities like catalase, superoxide dismutase, glutathione peroxidase and glutathione content in kidneys of suckling pups and their mothers. Kidney histological studies confirmed biochemical parameters. We concluded that the exposure of rats to GA(3) induced oxidative stress and histopathological changes in kidneys of suckling rats and their mothers during late pregnancy and early postnatal periods.

Oxidative stress induced by gibberellic acid in bone of suckling rats.

The present study investigates the bone maturity of suckling rats whose mothers were treated with gibberellic acid (GA(3)). Female Wistar rats were divided into two groups: group I that served as controls and group II that received orally GA(3) (200 ppm) from the 14th day of pregnancy until day 14 after delivery. In the GA(3) group, an increase in body and femur weights as well as in femur length of pups was noted when compared to controls. Lipid peroxidation was demonstrated by high femur malondialdehyde levels, while superoxide dismutase, catalase, glutathione peroxidase activities, glutathione and vitamin C levels in femur decreased. GA(3) caused a decrease in calcium and phosphorus levels in bone. The calcium concentration in plasma increased and the phosphorus concentration decreased, while urinary levels of calcium decreased and those of phosphate increased. Moreover, plasma total tartrate-resistant acid phosphatase and total alkaline phosphatase increased. Bone disorders were confirmed by femur histological changes.

Hepatotoxicity induced by gibberellic acid in adult rats and their progeny.

Gibberellic acid (GA(3)), a plant growth regulator, was largely used in agriculture of many countries including Tunisia. However, its potential hazardous effects on human health were relatively unexplored. The purpose of this study was to investigate the effects of GA(3) on hepatic function in female rats and their pups. Animals were given daily 200 ppm GA(3) in drinking water from the 14th day of pregnancy until day 14 after delivery. It was found that GA(3) induced liver damages as evidenced by the elevation of plasma aminotransferases (ALT, AST), lactate dehydrogenase activities, bilirubin and albumin levels. Hepatotoxicity was objectified by the significant increase of malondialdehyde (MDA) level and a decrease of antioxidant enzyme activities such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione content in liver of suckling pups and their mothers. Impairment of hepatic function corresponded histologically. We have observed blood vessels congestion and leucocytes infiltration, which were more pronounced in hepatocytes of dams than those of suckling pups. Results of this current study suggest that exposure rats to GA(3) induces hepatotoxicity and histopathological changes in liver of female rats and their progeny.