Exposure to BPA and BPS during pregnancy disrupts the bone mineralization in the offspring.

Exposure to plastic-derived estrogen-mimicking endocrine-disrupting bisphenols can have a long-lasting effect on bone health. However, gestational exposure to bisphenol A (BPA) and its analogue, bisphenol S (BPS), on offspring's bone mineralization is unclear. The effects of in-utero bisphenol exposure were examined on the offspring's bone parameters. BPA and BPS (0.0, 0.4 µg/kg bw) were administered to pregnant Wistar rats via oral gavage from gestational day 4 to 21. Maternal exposure to BPA and BPS increased bone mineral content and density in the offspring aged 30 and 90 days (P<0.05). Plasma analysis revealed that alkaline phosphatase, and Gla-type osteocalcin were significantly elevated in the BPS-exposed offspring (P<0.05). The expression of BMP1, BMP4, and their signaling mediators SMAD1 mRNAs were decreased in BPS-exposed osteoblast SaOS-2 cells (P<0.05). The expression of extracellular matrix proteins such as ALPL, COL1A1, DMP1, and FN1 were downregulated (P<0.05). Bisphenol co-incubation with noggin decreased TGF-ß1 expression, indicating its involvement in bone mineralization. Altered mineralization could be due to dysregulated expression of bone morphogenetic proteins and signalling mediators in the osteoblast cells. Thus, bisphenol exposure during gestation altered growth and bone mineralization in the offspring, possibly by modulating the expression of Smad-dependent BMP/TGF-ß1 signalling mediators.

Modulation of fetoplacental growth, development and reproductive function by endocrine disrupters.

Maternal endocrine homeostasis is vital to a successful pregnancy, regulated by several hormones such as human chorionic gonadotropin, estrogen, leptin, glucocorticoid, insulin, prostaglandin, and others. Endocrine stress during pregnancy can modulate nutrient availability from mother to fetus, alter fetoplacental growth and reproductive functions. Endocrine disrupters such as bisphenols (BPs) and phthalates are exposed in our daily life's highest volume. Therefore, they are extensively scrutinized for their effects on metabolism, steroidogenesis, insulin signaling, and inflammation involving obesity, diabetes, and the reproductive system. BPs have their structural similarity to 17-ß estradiol and their ability to bind as an agonist or antagonist to estrogen receptors to elicit an adverse response to the function of the endocrine and reproductive system. While adults can negate the adverse effects of these endocrine-disrupting chemicals (EDCs), fetuses do not equip themselves with enzymatic machinery to catabolize their conjugates. Therefore, EDC exposure makes the fetoplacental developmental window vulnerable to programming in utero. On the one hand prenatal BPs and phthalates exposure can impair the structure and function of the ovary and uterus, resulting in placental vascular defects, inappropriate placental expression of angiogenic growth factors due to altered hypothalamic response, expression of nutrient transporters, and epigenetic changes associated with maternal endocrine stress. On the other, their exposure during pregnancy can affect the offspring's metabolic, endocrine and reproductive functions by altering fetoplacental programming. This review highlights the latest development in maternal metabolic and endocrine modulations from exposure to estrogenic mimic chemicals on subcellular and transgenerational changes in placental development and its effects on fetal growth, size, and metabolic & reproductive functions.

Gestational exposure to bisphenol S induces microvesicular steatosis in male rat offspring by modulating metaflammation.

Prenatal exposure to endocrine-disrupting bisphenol A (BPA) shows a long-lasting programming effect on an organ's metabolic function and predisposes it to the risk of adult metabolic diseases. Although a reduced contaminant risk due to "BPA-free" exposure is proposed, limited data on a comparative assessment of gestational exposure to BPS and BPA and their effects on metaflammation in predisposing liver metabolic disease is reported. Pregnant Wistar rats were exposed to BPS and BPA (0.0, 0.4, 4.0 µg/kg bw) via gavage from gestational day 4 to 21, and effects were assessed in the 90 d male offspring. Prenatal BPS-exposed offspring showed a more obesogenic effect than BPA, including changes in body fat distribution, feed efficiency, and leptin signalling. The BPS exposure induced the adipocyte hypertrophy of visceral adipose to a greater extent than BPA. The adipose hypertrophy was augmented by tissue inflammation, endoplasmic reticulum (ER) stress, and apoptosis due to increased expression of pro-inflammatory (IL6, IL1ß, CRP, COX2) cytokines, ER stress modulator (CHOP), and apoptotic effector (Caspase 3). The enlarged, stressed, inflamed adipocytes triggered de novo lipogenesis in the bisphenol-exposed offspring liver due to increased expression of cholesterol and lipid biogenesis mediators (srebf1, fasn, acaca, PPARα) concomitant with elevated triacylglycerol (TG) and cholesterol (TC), resulted in impaired hepatic clearance of lipids. The lipogenic effects were also promoted by increased expression of HSD11ß1. BPS exposure increased absolute liver weight, discoloration, altered liver lobes more than in BPA. Liver histology showed numerous lipid droplets, and hepatocyte ballooning, upregulated ADRP expression, an increased expression of pro-inflammatory mediators (IL6, CRP, IL1ß, TNFα, COX2), enhanced lipid peroxidation in the BPS-exposed offspring's liver suggest altered metaflammation leads to microvesicular steatosis. Overall, gestational BPS exposure demonstrated a higher disruption in metabolic changes than BPA, involving excess adiposity, liver fat, inflammation, and predisposition to steatosis in the adult male offspring.

Dietary omega-3 fatty acid deficiency from pre-pregnancy to lactation affects expression of genes involved in hippocampal neurogenesis of the offspring.

Maternal n-3 PUFA (omega-3) deficiency can affect brain development in utero and postnatally. Despite the evidence, the impacts of n-3 PUFA deficiency on the expression of neurogenesis genes in the postnatal hippocampus remained elusive. Since postnatal brain development requires PUFAs via breast milk, we examined the fatty acid composition of breast milk and hippocampal expression of neurogenesis genes in n-3 PUFA deficient 21d mice. In addition, the expression of fatty acid desaturases, elongases, free fatty acids signaling receptors, insulin and leptin, and glucose transporters were measured. Among the genes involved in neurogenesis, the expression of brain-specific tenascin-R (TNR) was downregulated to a greater extent (∼31 fold), followed by adenosine A2A receptor (A2AAR), dopamine receptor D2 (DRD2), glial cell line-derived neurotrophic factor (GDNF) expression in the n-3 PUFA deficient hippocampus. Increasing dietary LA to ALA (50:1) elevated the ARA to DHA ratio by ∼8 fold in the n-3 PUFA deficient breast milk, with an overall increase of total n-6/n-3 PUFAs by ∼15:1 (p<0.05) compared to n-3 PUFA sufficient (LA to ALA: 2:1) diet. The n-3 PUFA deficient mice exhibited upregulation of FADS1, FADS2, ELOVL2, ELOVL5, ELOVL6, GPR40, GPR120, LEPR, IGF1 and downregulation of GLUT1, GLUT3, and GLUT4 mRNA expression in hippocampus (p<0.05). Maternal n-3 PUFA deficiency affects the hippocampal expression of key neurogenesis genes in the offspring with concomitant expression of desaturase and elongase genes, suggesting the importance of dietary n-3 PUFA for neurodevelopment.

Fetal Exposure to Endocrine Disrupting-Bisphenol A (BPA) Alters Testicular Fatty Acid Metabolism in the Adult Offspring: Relevance to Sperm Maturation and Quality.

Daily exposure to bisphenols can affect reproductive functions due to their pseudo-estrogenic and/or anti-androgenic effects. Testicular lipids contain high levels of polyunsaturated fatty acids necessary for sperm maturity, motility, and spermatogenesis. Whether prenatal exposure to bisphenols alters testicular fatty acid metabolism in adult offspring is unknown. Pregnant Wistar rats were gavaged from gestational day 4 to 21 with BPA and BPS (0.0, 0.4, 4.0, 40.0 µg/kg bw/day). Despite increased body and testis weight, the total testicular cholesterol, triglyceride, and plasma fatty acids were unaffected in the offspring. Lipogenesis was upregulated by increased SCD-1, SCD-2, and expression of lipid storage (ADRP) and trafficking protein (FABP4). The arachidonic acid, 20:4 n-6 (ARA) and docosapentaenoic acid, 22:5 n-6 (DPA) levels were decreased in the BPA-exposed testis, while BPS exposure had no effects. The expression of PPARα, PPARγ proteins, and CATSPER2 mRNA were decreased, which are important for energy dissipation and the motility of the sperm in the testis. The endogenous conversion of linoleic acid,18:2 n-6 (LA), to ARA was impaired by a reduced ARA/LA ratio and decreased FADS1 expression in BPA-exposed testis. Collectively, fetal BPA exposure affected endogenous long-chain fatty acid metabolism and steroidogenesis in the adult testis, which might dysregulate sperm maturation and quality.

Maternal omega-3 fatty acid deficiency affects fetal thermogenic development and postnatal musculoskeletal growth in mice.

Maternal omega-3 (n-3) polyunsaturated fatty acids (PUFAs) deficiency can affect offspring's adiposity and metabolism by modulating lipid and glucose metabolism. However, the impact of n-3 PUFA deficiency on the development of fetal thermogenesis and its consequences is not reported. Using an n-3 PUFA deficient mice, we assessed fetal interscapular brown adipose tissue (iBAT), body fat composition, insulin growth factor-1 (IGF-1), glucose transporters (GLUTs), and expression of lipid storage & metabolic proteins in the offspring. The n-3 PUFA deficiency did not change the pups' calorie intake, organ weight, and body weight. However, the offspring's skeletal growth was altered due to excess fat to lean mass, reduced tibia & femur elongation, dysregulated IGF-1 in the mother and pups (P< .05). Localization of uncoupling protein 1 (UCP1) in iBAT exhibited a reduced expression in the deficient fetus. Further, UCP1, GLUT1, GPR120 were downregulated while FABP3, ADRP, GLUT4 expressions were upregulated in the BAT of the deficient offspring (P< .05). The deficiency decreased endogenous conversion of the n-3 LCPUFAs from their precursors and upregulated SCD1, FASN, and MFSD2A mRNAs in the liver (P< .05). An altered musculoskeletal growth in the offspring is associated with impaired browning of the fetal adipose, dysregulated thermogenesis, growth hormone, and expression of glucose and fatty acid metabolic mediators due to maternal n-3 PUFA deficiency. BAT had higher metabolic sensitivity compared to WAT in n-3 PUFA deficiency. Maternal n-3 PUFA intake may prevent excess adiposity by modulating fetal development of thermogenesis and skeletal growth dynamics in the mice offspring.

Prenatal exposure to bisphenol S and bisphenol A differentially affects male reproductive system in the adult offspring.

Early exposure to bisphenol may result in adverse reproductive health in later life. The use of bisphenol S (BPS) has increased considerably after bisphenol A (BPA) is regulated worldwide. However, little is known about the fetal exposure to BPS compared with BPA and its effects on the reproductive system in the adult male offspring. Here, we investigated the effects of orally administered BPS and BPA (0.4, 4.0, 40.0 µg/kg bw/d) during gestation (gD4-21) on testicular development by evaluating the sperm DNA damage & methylation and testicular functions in the 90 d Wistar rats. Male offspring prenatally exposed to BPS (0.4 µg/kg) had higher plasma testosterone than BPA and control. The testis histology reveals thickened membrane by producing a wide interstitial gap between seminiferous tubules, increased testicular inflammation, oxidative stress, TIMP-1 expression, and decreased VCAM-1 expression. BPS promotes apoptosis by up-regulating IL-6, cleaved caspases, and a spike in sperm DNA fragmentation. Prenatal BPS exposure reduces sperm motility mediated via impaired PI3K-AKT signaling and increases testicular TEX11 expression in the offspring. Exposure of the fetus to BPS interferes developmental programming of the male reproductive system in the offspring. BPS could be an equally potent endocrine disruptor affecting male reproductive functions.