Effects Of T-2 Toxin Exposure To Late Gestation And Lactation In Mice And Its Impact On Growth,development And Onset Of Puberty In Offspring

T-2 toxin is a fungal mycotoxin naturally occurring mold byproduct of Fusarium spp,which contaminates cereals cultured in wide areas due to high temperature and increased level of moisture content,monsoons,unseasonal rains during harvesting and flash floods.The biosynthetic pathway of trichothecenes mycotoxins produced in isolated species specific manner by cereals pathogens includes T-2 toxin,deoxynivalenol,nivalenol and diacetoxyscripenol.T-2 toxin can contaminate a wide array of feed such as barley,milo,corn gluten feed,corn gluten meal,corn,and bran.T-2 toxin has been associated with impaired health of an individual.Trichothecenes have been recognized to possess several inhibitory effects on eukaryotic cells,such as it inhibits protein synthesis,RNA and DNA synthesis,impede mitochondrial function,effect the cell division and multiplication and impairs the membrane integrity.Furthermore it induces apoptosis and programmed cell death.Gross toxic effects of T-2 toxin contaminated feed offered to the farm animals are as feed intake refusal,vomiting,growth retardation,alimentary toxic aleukia(ATA),gastroenteritis,immune-compromiszation,reduced ovarian function and reproductive disorders.T-2 toxin induced toxicity depends on the route,dose and duration of exposure.The dietary intake during gestation and lactation is widely supported by the most recent scientific literature to ensure well-being of mother and offspring.Overall,of the most existing discoveries studying T-2 toxin based on in-vitro or in-vivo have been conducted on variety of animals.Previous studies have reported effects of T-2 toxin on pregnant mice,on embryo and fetus,but there is gape to study the effect of T-2 toxin during late gestation and entire lactation in dams and their next generation performance from birth to weaning and weaning to maturity.Therefore,present study was designed for the first time on the basis of exposure time during late gestation(GD 14)upto entire lactation(LD 21)to investigate the effect of T-2 toxin on mother and offspring to explore the potential toxic effects in mice.1.Effect of T-2 toxin exposure to gestation and lactation on liver oxidative damage and early acini involution in mother miceThis experiment was designed to evaluate the toxic effects of T-2 toxin on late gestation and whole lactation period.In total,30 ICR strain pregnant mice were equally distributed into three groups(n=10/group)0,0.005 and 0.05 mg/kg.Pregnant mice allocated for gestation(GD 14)and lactation(LD 21)received T-2 toxin at 0,0.005 and 0.05 mg/kg/bw daily through oral gavage.Results showed that T-2 toxin significantly decreased feed intake and body weights.Absolute and relative body and organ weights significantly decreased in treatment groups.Additionally,T-2 toxin induced oxidative stress by generating free radicals,it increased lipid peroxidation biomarker,malondialdehyde(MDA),decreased antioxidant enzymes such as catalase(CAT),superoxide dismutase(SOD),glutathione peroxidase(GSH-Px)and total antioxidant capacity(T-AOC)in serum and liver.Consequently,T-2 toxin resulted in elevated levels of liver metabolizing enzymes such as glutamic oxaloacetic transaminase(GOT)and glutamic pyruvic transaminase(GPT).Histomorphology of liver showed cellular injury and apoptosis,spleen showed extensive areas of apoptotic tissues,kidney demonstrating extensive epithelial cell necrosis,hyaline formation and early involution of mammary glandular acini.It was concluded that gestational and lactational exposure with T-2 toxin caused obvious toxicity to the mothers by oxidative damage,decreased feed intake and body weight.The toxic effects caused early involution of mammary gland acini possibly decreasing milk production,which directly affected their offspring.2.Maternal exposure to T-2 toxin affects growth and development in male and female mice offspringIn this experiment,thirty pregnant mice were randomly divided into three groups(n=10/group).The dams were orally administered with T-2 toxin at the doses of 0,0.005 and 0.05 mg/kg from late gestation(GD 14)up to the end of lactation(LD 21).The male(n=5/group)and female(n=5/group)mice offspring was randomly collected from each group and euthanized at five different time points,postnatal day 01,07,21,28 and 56.After weaning postnatal day 21 the feed intake and body weight was recorded weekly.Body weight and feed intake was decreased significantly at T-2 toxin treated offspring.T-2 toxin decreased absolute and relative organs weights of male and female offspring at each harvesting time point.Additionally,it induced free radicals by increasing levels of lipid peroxidation biomarker,malondialdehyde(MDA)which ultimately decreased antioxidant enzymes such as catalase(CAT),superoxide dismutase(SOD),glutathione peroxidase(GSH-Px)and total antioxidant capacity(T-AOC)in serum and liver.Consequently,liver metabolizing enzymes,glutamic oxaloacetic transaminase(GOT)and glutamic pyruvic transaminase(GPT)were increased.Histomorphology showed cell apoptosis in hepatocytes,kidney showed interstitial fibrosis tubular degeneration,spleen showed cellular fragments apoptotic cells.Serum insulin like growth factor-1(IGF-1)also decreased significantly,which could have possibly decreased somatic cells growth,bone growth and organ development,consequently decreasing body weight and length in male offspring.Thus,it was concluded that prenatal and postnatal exposure with T-2 toxin delayed offspring growth and development in male and female mice offspring.3.Maternal exposure to T-2 toxin affects on the onset of puberty and delays estrus cycle in female mice offspringDams were treated with T-2 toxin at 0,0.005 and 0.05 mg/kg BW per day from gestational day 14(GD-14)upto lactational day 21(LD 21).Female mice offspring(n=5)were randomly selected at the weaning age from each group.The results of this experiment showed that T-2 toxin exposure caused significant decrease in the absolute and relative body weights.It also affected reproductive organ such as decreased length,width and weight of the uterus and ovaries compared with control.Vaginal opening timing increased significantly in T-2 toxin treated group.First di-estrus was delayed significantly along with obvious decrease in body weight gain.In the length of estrus cycle after measuring three consecutive estrus,first di-estrus and normal cyclicity of estrus were delayed with prolong di-estrus.Serum concentrations of estrogen(E2),progesterone(P4),luteinizing hormone(LH)and follicle stimulating hormone(FSH)markedly decreased following T-2 toxin during early developmental exposure.T-2 toxin induced free radicals,increased lipid peroxidation biomarker,malondialdehyde(MDA),consequently decreased antioxidant enzymes such as catalase(CAT),superoxide dismutase(SOD),glutathione peroxidase(GSH-Px)and total antioxidant capacity(T-AOC)in serum and ovary.Decrease in hypothalamic mRNA expression of GnRH and in pituitary GnRHR,LH and FSH.Ovarian mRNA level of FSHR and LHR decreased significantly compared to the control.T-2 toxin induced oxidative damage and decreased level of serum sex steroids,estrogen and progesterone;caused damage to the protective cornified epithelial layer and deteriorated the vaginal epithelium which has important role in balancing vaginal environment.Thus,the results of this experiment lead to conclude that early exposure to T-2 toxin delayed maturity and induced ovarian damage.