ABC transporters are ubiquitous in the human body and are responsible for the efflux of drugs. They are present in the placenta, intestine, liver and kidney, which are the major organs that can affect the pharmacokinetic and pharmacologic properties of drugs. P-gp and BCRP transporters are the best-characterized transporters in the ABC superfamily, and they have a pivotal role in the barrier tissues due to their efflux mechanism. Moreover, during pregnancy, drug efflux is even more important because of the developing fetus. Recent studies have shown that placental and intestinal ABC transporters have great importance in drug absorption and distribution. Placental and intestinal P-gp and BCRP show gestational-age-dependent expression changes, which determine the drug concentration both in the mother and the fetus during pregnancy. They may have an impact on the efficacy of antibiotic, antiviral, antihistamine, antiemetic and oral antidiabetic therapies. In this review, we would like to provide an overview of the pharmacokinetically relevant expression alterations of placental and intestinal ABC transporters during pregnancy.

Obesity affects approximately 30% of pregnancies worldwide and is one of the leading metabolic disorders among pregnant women. Maternal obesity is often associated with placental dysfunction and structural alterations, which increase the risk of developing complications. Efflux transporters, including P-glycoprotein (P-gp), may impact placental function and fetal development. Consequently, our research examined the effects of obesity on P-glycoprotein expression in both a rat model and human placental tissue. P-gp expression was measured by RT-PCR and Western blot techniques in human and rat placental tissues. Moreover, we further characterized the high-fat and high-sugar diet (HFHSD)-induced gestational obesity rat model by measuring tissue weights. Significant decreases were observed in fetal, placental, and uterus weights in the obese animals near the end of pregnancy. In obese rats, mRNA and protein expression of placental P-gp showed a reduction on gestation days 15, 20, and 22. A similar P-gp reduction was observed in the term placenta in obese women in mRNA and protein levels. We hypothesize that the reduced expression of P-gp may heighten the susceptibility of both the fetus and placenta to P-gp substrates. This alteration could potentially result in an increased risk of pregnancy complications and obesity-related drug contraindications linked to P-gp transport during pregnancy.

Ovulation is a critical event in mammalian reproduction, a complex process that involves the release of a mature oocyte from the ovaries for fertilization. Hormonal shifts are the driving force of the ovulation cycle; however, several other factors are able to fine-tune the occurrence of follicular rupture. Prior to the follicular rupture, the pre-ovulatory luteinizing hormone (LH) surge triggers a self-generating local inflammatory and redox cascade, which is responsible for the release of several inflammatory and redox signaling mediators. Eicosanoids are one of the key regulators of the initiation of the local inflammation within the follicle, while the balance of reactive oxygen species and antioxidants is fundamental to maintaining the physiologically coordinated redox state during the ovulation process. In this review, we aim to provide a summary of the human menstrual and rat estrus cycles and demonstrate the LH-induced inflammatory and redox cascade involved in follicle rupture through the details of lipid-derived and redox signaling mediators.

Objectives: Obesity and the associated metabolic dysfunction influence fertility performance at molecular levels and ABC transporters are considered as potential molecular factors affecting fertility both in the testis and sperm; therefore, we aimed to examine the effect of a short-term diet-induced obesity on testicular and spermatic ABC transporters in a rat model focusing on the expressions of P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (BCRP, Abcg2). The testicular androgen state involving aromatase enzyme (Cyp19a1), androgen receptor (Ar), and testosterone levels were also evaluated. Methods: Obesity was induced in male Sprague Dawley rats by feeding a high-fat, high-sugar diet (HFHSD) for 10 weeks, and metabolic status was evaluated using a glucose tolerance test. The weight and size of reproductive organs were measured, and Abcb1a/1b, Abcg2, Cyp19a1, and Ar expression in testes or sperm was determined by RT-PCR and Western blotting. At the same time, testosterone levels were measured by ELISA. Results: HFHSD successfully induced higher weight gain with glucose intolerance and reduced reproductive organ size. In obese rats, testicular Abcb1a and Abcb1b mRNA and P-gp protein expression were significantly higher, whereas testicular Abcg2 mRNA levels decreased. Spermatic Abcb1a, Abcb1b and Abcg2 mRNA expression also reduced in obesity. Neither testicular testosterone concentration nor Cyp19a1 and Ar mRNA expression levels changed after the 10-week obesogenic diet compared with controls. Conclusions: Overall, our study revealed infertility-related ABC transporter changes in obese male rats, suggesting that these alterations may predispose obese males to fertility impairments, even before the obesity-induced androgen dysregulation.

Background: Calonysterone (CAL) is a natural derivative of 20-hydroxyecdysone (20E) with enhanced bioactivity on skeletal muscle cells in vitro, but its in vivo physiological actions remain less well characterized. This study aimed to compare the effects of 20E and CAL on metabolic, muscular, and endocrine parameters in normal and obese male rats, with a particular focus on androgen balance. Methods: Male rats were treated with 20E or CAL under normal (ND) or high-fat, high-sugar dietary (HFHSD) conditions for 12 weeks. Body weight, food intake, skeletal and androgen-sensitive muscle mass, and testicular weight were measured. Testicular expression of androgen receptor (Ar) and aromatase (Cyp19a1) mRNA was assessed by RT-PCR. ELISA was used to determine the plasma corticosterone, testosterone and ERβ level in testes. Results: 20E and CAL prevented HFHSD-induced weight gain and skeletal muscle atrophy. CAL uniquely preserved testicular and levator ani muscle mass in obese rats. CAL increased the expression of Cyp19a1 and ERβ in testicles. Decreased Ar mRNA expression was regulated in 20E- and CAL-treated obese animals. While 20E treatment significantly reduced plasma testosterone levels in the normal diet group compared to controls, both 20E and CAL interventions elicited significant reductions in the obese group relative to both the ND and HFHSD groups. HFHSD-induced increase in plasma corticosterone levels was normalized by 20E or CAL treatment. Conclusions: 20E and CAL exhibit beneficial metabolic and anabolic effects by preventing HFHSD-induced obesity and consequential muscle atrophy. CAL counteracts obesity-induced testicular atrophy in terms of tissue mass. Based on our results, we hypothesized that CAL enhances testicular aromatase levels, which may lead to increased compensatory androgen receptor mRNA expression and increased ERβ levels. These complex, not yet fully understood results underscore the need for caution in the use of phytoecdysteroids as dietary supplements.