There is growing concern regarding the health and safety issues of endocrine-disrupting chemicals (EDCs). Long-term exposure to EDCs has serious adverse health effects through both hormone-direct and hormone-indirect ways. Accordingly, some EDCs can be a pathogen and an inducer to the susceptibility of disease, even if they have a very low affinity on the estrogen receptor, or no estrogenic effect. Endoplasmic reticulum (ER) stress recently attracted attention in this research area. Because ER and ER stress could be key regulators of the EDC’s adverse effects, such as the malfunction of the organ, as well as the death, apoptosis, and proliferation of a cell. In this review, we focused on finding evidence which shows that EDCs could be a trigger for ER stress and provide specific examples of EDCs, which are known to cause ER stress currently.

Arsenic in inorganic form is a known human carcinogen; even low levels of arsenic can interfere with the endocrine system. In mammalian development, arsenic exposure can cause a malformation of fetuses and be lethal. This study examined the effects of sodium arsenite (SA) as the inorganic form of arsenic in embryonic bodies (EBs) with three germ layers in the developmental stage. This condition is closer to the physiological condition than a 2D cell culture. The SA treatment inhibited EBs from differentiating into cardiomyocytes. A treatment with 1 μM SA delayed the initiation of beating, presenting successful cardiomyocyte differentiation. In particular, mitochondria function analysis showed that SA downregulated the transcription level of the Complex IV gene. SA increased the fission form of mitochondrion identified by the mitochondria number and length. In addition, a treatment with D-penicillamine, an arsenic chelator, restored the beat of EBs against SA, but not mitochondrial dysfunction. These findings suggest that SA is a toxicant that induces mitochondrial damage and interferes with myocardial differentiation and embryogenesis. This study suggests that more awareness of SA exposure during pregnancy is required because even minuscule amounts have irreversible adverse effects on embryogenesis through mitochondria dysfunction.

The female reproductive system becomes fertile through the action of hormones involved in the hypothalamic-pituitary-ovarian axis. On the other hand, estrogen-like endocrine disruptors released into the environment come into contact with humans by various routes and affect the reproductive system. Exposure to these chemicals can cause problems with the reproductive process, from egg ovulation to implantation, or cause female reproductive diseases. These reproductive problems cause infertility. Decamethylcyclopentasiloxane (D5) is used for lubrication in silicone polymers, households, and personal care products. In the case of D5, it is discharged through factory wastewater and can bioaccumulate. Therefore, it accumulates in the human body. In this study, D5 was administered orally for four weeks to determine the effects of D5 on the reproductive process. As a result, D5 increases the number of follicles in the ovary and suppresses the expression of genes related to the growth of follicles. In addition, it increases the gonadotropin hormone, inducing estradiol enhancement and progesterone reduction. Because of these changes in the reproductive system when exposed to D5, the industry should reconsider using D5.

A real-life environment during pregnancy involves multiple and simultaneous exposures to toxic chemicals. Perinatal exposures to toxic chemicals have been reported to exert an inhibitory effect on mouse neural development and behaviors. However, the effect of combined exposures of organophosphate and nicotine has not been previously reported. In this study, we investigated whether a combined exposure of diazinon and nicotine can have a synergistic effect. The effects of the combined chemical exposure on cell viability and neuronal differentiation were examined using mouse Sox1-GFP cells. Additionally, mice were maternally administered 0.18 mg/kg diazinon, a no adverse effect level (NOAEL) dose, combined with 0.4, 1, and 2 mg/kg nicotine. Mice offspring underwent behavior tests to assess locomotor, depressive, cognitive, and social behaviors. Morphological change in the brain was investigated with immunolocalization. We revealed that the combined exposure to diazinon and nicotine can have a synergistic adverse effect in vitro. In addition, the chemical-treated mouse offspring showed abnormalities in motor learning, compulsive-like behaviors, spatial learning, and social interaction patterns. Moreover, 0.18 mg/kg diazinon and 2 mg/kg nicotine co-exposure resulted in an increase in tyrosine hydroxylase (TH)-positive dopaminergic neurons. Thus, the findings suggest that perinatal co-exposure to nicotine and diazinon can result in abnormal neurodevelopment and behavior, even at low-level administration.

Valproic acid (VPA) is a histone deacetylase inhibitor that is used mainly as an antiepileptic and anticonvulsant drug. The side effects of VPA usually appears as hepatic injury and various metabolic disorders. On the other hand, it is rarely reported to cause kidney injury. Despite the many studies on the influence of VPA exposure on the kidneys, the specific mechanism remains unclear. This study examined the changes after VPA treatment to the mouse kidney stem cells (mKSCs). VPA triggers an increase in mitochondrial ROS, but there was no change in either mitochondrial membrane potential or the mitochondrial DNA copy number in mKSCs. The VPA treatment increased the mitochondrial complex III but decreased complex V significantly compared to the DMSO treatment as a control. The inflammatory marker (IL-6) and the expression of the apoptosis markers (Caspase 3) and were increased by VPA. In particular, the expression of the podocyte injury markers (CD2AP) was increased significantly. In conclusion, VPA exposure has adverse effects on mouse kidney stem cells.

D5, a member of the cyclic siloxane family, is widely used in personal care products such as shampoo, cosmetics, and deodorant and as an industrial intermediate. D5 can mainly be absorbed orally or through inhalation. Through these routes, people are exposed to D5 daily. However, the risk of prenatal exposure to D5 has not been fully elucidated. In this study, the effect of D5 on neural development was established through behavioral tests on offspring mice. The result confirmed that the maternal administration of 12 mg/kg of D5 showed depression in tail suspension and decreased performance in the forced swimming test as well as an increase in repetitive activity in both the marble-burying test and grooming test compared to the vehicle group. Furthermore, the 12 mg/kg group showed a decrease in cognitive ability and social behavior in the three-chamber test. In the novel object recognition test, memory impairment and a lack of exploring ability were found in the 12 mg/kg group. In conclusion, it is suggested that maternal D5 exposure has developmental neurotoxicity and can cause behavioral disorders in the offspring of mice. Thus, the usage of D5 needs to be considered carefully.