Effects Of 4-Phenylbutyric Acid On Cadmium-induced Placental Endoplasmic Reticulum Stress And Fetal Growth Restriction In Mice

Objective:This study was to investigate the effect of endoplasmic reticulum molecular chaperone 4-phenylbutyrate?4-PBA?on placental endoplasmic reticulum stress and fetal growth restriction in mice exposed to cadmium by drinking water during pregnancy.Method:This study consisted mainly of two experiments.Experiment 1,to observe the effects of different concentrations of cadmium on the growth and development of the fetuses,when maternal mice exposed to drinking water during pregnancy.Eighteen pregnant mice were divided into three groups:control group,low concentration cadmium group?150 ppm?,and high concentration cadmium group?300 ppm?.The two cadmium groups were exposed to different concentrations of CdCl₂?150 ppm and 300 ppm?via drinking water during the whole pregnancy,and the control group was given reverse osmosis?RO?water.The changes in body weight,water intake and food intake were recorded.The mice were sacrificed on the 18th day of conception,and the growth and development of the fetuses were evaluated.HE staining was performed after placental tissue fixation to examine the vascular structure of the placental labyrinth.In Experiment 2,to observe the effect of 4-PBA on cadmium-induced fetal growth restriction.Eighty pregnant mice were divided into four groups:control group,PBA group?500 mg/kg?,cadmium group?150 ppm?,and PBA+cadmium group.Pregnant mice in the cadmium group were exposed to CdCl₂?150 ppm?through drinking water during the whole pregnancy.The pregnant mice in the PBA+cadmium group were exposed to CdCl₂?150 ppm?in drinking water and4-PBA?500 mg/kg?by oral gavage during the whole pregnancy.Pregnant mice in the PBA group were given oral 4-PBA?500 mg/kg?once a day during the whole pregnancy,and pregnant mice in the control group were given reverse osmosis?RO?water during the whole pregnancy.The changes of body weight,water intake and food intake were recorded.The mice were sacrificed on the 18th day of pregnancy to evaluate the growth and development of the fetuses.HE staining was performed after placental tissue fixation to examine the vascular structure of the placental labyrinth;The level of endoplasmic reticulum stress-related proteins was detected by Western blotting.Results:Maternal exposure to different concentrations of cadmium?150 ppm and 300ppm?during pregnancy caused significant weight loss and body length,and the body weight and body length of high-concentration cadmium group?300 ppm?were significantly lower than those of low-concentration cadmium group?150 ppm?.However,the low exposure and high concentration of cadmium in the maternal drinking water during pregnancy had no effect on the average number of live fetuses,the number of absorbed fetuses,the number of stillbirths and the number of implantations;the placental weight and diameter of mice with high concentration of cadmium were lower than those of the control group.However,the ratio of body weight to placental weight in the high concentration cadmium group was not different from that in the control group.Further studies found that endoplasmic reticulum molecular chaperone PBA combined with cadmium treatment increased cadmium treatment?150 ppm?to reduce fetal body weight,but there was no difference between placental weight,diameter and fetal weight/placental weight in each group.Placental HE staining analysis showed that the cadmium?150 ppm and 300 ppm?exposure of the maternal drinking water during pregnancy caused a significant decrease in the mean sinusoidal area of the mouse placental labyrinth,and the mean sinusoids of the placental labyrinth in the high concentration cadmium group?300 ppm?.The area of the lower concentration cadmium group?150 ppm?was significantly reduced,and the4-PBA treatment further aggravated the cadmium?150 ppm?exposure of the maternal during drinking water to reduce the sinusoidal area of the placental labyrinth.Western blot analysis showed that cadmium exposure to drinking water?150 ppm?during pregnancy significantly up-regulated the expression of endoplasmic reticulum stress-related proteins GRP78,CHOP and pJNK1/2 in placenta,while 4-PBA treatment significantly inhibited cadmium up-regulation of placental endoplasmic reticulum stress-related protein expression.Conclusion:Under the conditions of this experiment,endoplasmic reticulum molecular chaperone 4-PBA treatment inhibits cadmium-induced placental endoplasmic reticulum stress and aggravates cadmium-induced fetal growth restriction.