Maternal Mammary Gland Research Articles

In the Murine and Bovine Maternal Mammary Gland Signal Transducer and Activator of Transcription 3 is Activated in Clusters of Epithelial Cells around the Day of Birth

Signal transducers and activators of transcription (STAT) proteins regulate mammary development. Here we investigate the expression of phosphorylated STAT3 (pSTAT3) in the mouse and cow around the day of birth. We present localised colocation analysis, applicable to other mammary studies requiring identification of spatially congregated events. We demonstrate that pSTAT3-positive events are multifocally clustered in a non-random and statistically significant fashion. Arginase-1 expressing cells, consistent with macrophages, exhibit distinct clustering within the periparturient mammary gland. These findings represent a new facet of mammary STAT3 biology, and point to the presence of mammary sub-microenvironments.

In utero, lactational, or peripartal fluoxetine administration has differential implications on the murine maternal skeleton.

The peripartal period is marked by alterations in calcium metabolism to accommodate for embryonic skeletal mineralization and support bone development of offspring in early life, and serotonin plays a critical role in modulating peripartal bone remodeling. Selective serotonin reuptake inhibitors (SSRIs) are commonly used as first-line treatment for psychiatric illness during pregnancy and the postpartum period and considered safe for maternal use during this time frame. In order to evaluate the effect of peripartal alterations of the serotonergic system on maternal skeletal physiology, we treated dams with the SSRI fluoxetine during gestation only, lactation only, or during the entire peripartal period. Overall, we found a low dose of fluoxetine during gestation only had minimal impacts on maternal bone at weaning, but there were implications on maternal skeleton at weaning when dams were exposed during lactation only or during the entire peripartal period. We found that these effects were differential between female mice dosed lactationally or peripartally, and there were also impacts on maternal mammary gland at weaning in both of these groups. Though SSRIs are largely considered safe maternally during the peripartal period, this study raises the question whether safety of SSRIs, specifically fluoxetine, during the peripartal period should be reevaluated.

Effects of silver nanoparticles on maternal mammary glands and offspring development under lactation exposure

The widespread applications of silver nanoparticles (AgNPs) throughout our daily lives have raised concerns regarding their environmental health and safety (EHS). Despite an increasing number of studies focused on the EHS impacts of AgNPs, there remain significant knowledge gaps with respect to their potential health impacts on susceptible populations, such as lactating mothers and infants. Herein, we aimed to investigate the deleterious effects of AgNPs with different sizes (20 and 40 nm) and surface coatings (PVP and BPEI) on maternal mice and their offspring following lactation exposure at doses of 20, 100 and 400 μg/kg body weight. We discovered that AgNPs could accumulate in the maternal mammary glands and disrupt the epithelial barrier in a dose-dependent manner. Notably, BPEI-coated AgNPs caused more damage to the mammary glands than PVP-coated particles. Importantly, we observed that, while AgNPs were distributed throughout the blood and main tissues, they were particularly enriched in the brains of breastfed offspring after maternal exposure during lactation, exhibiting exposure dosage- and particle coating-dependent patterns. Compared to PVP-coated nanoparticles, BPEI-coated AgNPs were more readily transferred to the offspring, possibly due to their enhanced deposition in maternal mammary glands. Moreover, we observed reduced body weight, blood cell toxicity, and tissue injuries in breastfed offspring whose dams received AgNPs. As a whole, these results reveal that maternal exposure to AgNPs results in the translocation of AgNPs into offspring via breastfeeding, inducing developmental impairments in these breastfed offspring. This study provides important new insights into the EHS impacts of AgNP consumption during lactation.

Lactational exposure to Deoxynivalenol causes mammary gland injury via inducing inflammatory response and impairing blood-milk barrier integrity in mice

Lactation is a unique physiological process to produce and secrete milk. Deoxynivalenol (DON) exposure during lactation has been demonstrated to affect adversely the growth development of offspring. However, the effects and potential mechanism of DON on maternal mammary glands remain largely unknown. In this study, we found the length and area of mammary glands were significantly reduced after DON exposure on lactation day (LD) 7 and LD 21. RNA-seq analysis results showed that the differentially expressed genes (DEGs) were significantly enriched in acute inflammatory response and HIF-1 signaling pathway, which led to an increase of myeloperoxidase activity and inflammatory cytokines. Furthermore, lactational DON exposure increased blood-milk barrier permeability by reducing the expression of ZO-1 and Occludin, promoted cell apoptosis by upregulating the expression of Bax and cleaved Caspase-3 and downregulating the expression of Bcl-2 and PCNA. Additionally, lactational DON exposure significantly decreased serum concentration of prolactin, estrogen, progesterone. All these alterations eventually resulted in a decrease of β-casein expression on LD 7 and LD 21. In summary, our findings indicated that lactational exposure to DON caused lactation-related hormone disorder and mammary gland injury induced by inflammatory response and blood-milk barrier integrity impairment, ultimately resulting in lower production of β-casein.

New insights into the effect of bisphenol AF exposure on maternal mammary glands at various stages of gestation in mice

Bisphenol AF (BPAF) is the most estrogenic compound among BPA analogs. Mammary glands (MDs) are special organs that undergo repeated cycles of structural development, metabolism, and functional differentiation. Gestation is a sensitive window for MDs. In the present study, plug-positive CD-1 mice were exposed to vehicle (Veh) or 300 μg/kg BPAF through oral gavage every second day during gestation, and maternal MDs were collected from different developmental windows at 9.5, 13.5, and 18.5 d of gestation (gestation day [GD]9.5, GD13.5 and GD18.5). The results showed that gestational BPAF exposure induced a significantly elevated MD density at GD18.5. Non-target metabolomics analysis was used to screen for tyrosine, valine, ornithine, proline, threonine, phenylalanine and asymmetrical dimethylarginine (ADMA) amino acids, which changed significantly at all time points. Furthermore, the mRNA expression levels of genes related to these amino acids also changed significantly. Additionally, amino acid levels in BPAF-treated MGs at GD18.5 were related to the serum ammonia concentration of the corresponding offspring. These results provide a comprehensive view of the adverse effects of BPAF exposure during gestation on the maternal MG structure and function, which may affect milk components during lactation. Moreover, higher amino acids content may lead to amino acid imbalance or hyperammonemia in newborns.

Parenteral administration of l-arginine to twin-bearing Romney ewes during late pregnancy is associated with reduced milk somatic cell count during early lactation

Maternal milk is the primary source of nutrition for suckling mammals, and its yield and composition are important determinants of survival during the early neonatal period. The objective of this study was to examine whether parenteral administration of l-Arg to twin-bearing ewes, during mid to late pregnancy, influenced prepartum maternal mammary gland development and subsequent lactation performance in the early postpartum period (14 d). At 80 d of pregnancy, multiparous Romney ewes were housed indoors in group pens, split into 2 cohorts, and fed a lucerne-based pellet diet, formulated to meet 100% of National Research Council-recommended requirements for twin-bearing pregnant ewes, once a day. Cohort 1 was administered l-Arg (72.7 mg/kg of live weight via i.v, 3 times a day) from d 100 of pregnancy until d 140. At d 140, ewes were euthanized and maternal mammary tissues were collected for analysis of the biochemical indices total DNA, RNA, protein, protein synthetic efficiency (protein:RNA), cell size (protein:DNA), transcriptional efficiency (RNA:DNA), and the abundance of mammalian target of rapamycin (mTOR) and mTORSer2448 protein. Cohort 2 was administered an identical l-Arg regimen as cohort 1, but from d 100 until parturition. Milk was collected over a 14-d period (d 1, 4, 7, 10, and 14) to assess milk yield and composition. In cohort 1, total mammary DNA (cell number) tended to be higher in l-Arg ewes, with no change in total mammary RNA or protein content, biochemical indices of protein synthetic efficiency, cell size or transcriptional efficiency, or mTOR protein abundance or phosphorylation. In cohort 2, milk composition analysis from l-Arg ewes showed lower (d 7-14) milk somatic cell counts, greater crude protein percentage from d 7 to 10 but lower at d 14, and altered absolute concentrations of some free AA (d 7 and 14) compared with controls. We propose that parenteral administration of l-Arg during late pregnancy is associated with increased mammary gland cellular content and decreased somatic cell counts during early lactation.

Highlights in this issue

American guidelines suggest that neonatal resuscitation is considered at 23 weeks of gestation, one week earlier than the Netherlands. Prenatal counselling practice at the threshold of viability also differed between the two countries, according to a survey by Schrijvers et al. 1. American neonatologists preferred more frequent and longer counselling sessions than Dutch neonatologists and discussed more intensive care topics and long-term complications. Both preferred a shared decision model, where parents and neonatologists agreed on whether to initiate treatment at the threshold of viability. The diagnosis of tongue-tie has increased more than 10-fold in some countries. A simple tongue-tie can be treated with a frenotomy, but even subjecting infants to a minor surgical procedure causes pain, stress and possibly long-term neurological harm. A global survey by Jin et al. 2 found that there were considerable professional and geographical differences in the diagnosis and treatment of infants with tongue-tie. A review by Hentschel 3 concluded that breastfeeding problems should be the only relevant criterion for carrying out a frenotomy in infancy. Paracetamol is widely used as an analgesic and fever-reducing drug. Although it is generally considered safe, it is a major cause of suspected poisoning in infancy. Benini et al. 4 report that paracetamol and ibuprofen were inappropriately used in 83% and 63% of cases in Italian paediatric emergency departments. Dan-Nielsen et al. 5 reviewed hospital records of preschool children with suspected paracetamol poisoning in three Danish hospitals and found that the incidence of significant poisoning was low (0.5%) and there were no cases of liver injury. Orzalesi 6 discusses the complex issue of pain management in children. There is no worldwide consensus on the best way to wean preterm infants from nasal continuous positive airway pressure (nCPAP). In a randomised crossover study, Brenne et al. 7 compared the breathing effort in 21 preterm infants during weaning from respiratory support. The infants were given high-flow nasal cannulae (HFNC) at 6 L/minute for four hours and nCPAP at 3 cm H2O for four hours, with a one-hour washout period between treatments. No difference in the breathing effort was found, and the authors concluded that HFNC could replace nCPAP when preterm infants are ready for weaning. Jonsson 8 comments on the findings. Healthy newborn infants use what is called the breast crawl to reach the maternal mammary gland by themselves and start nutritive sucking. Zanardo 9. point out that aspects of the first mother–baby interaction are not yet fully understood, but the mother's nipple-areola provides an explosion of sensory stimuli, which are recognised by her offspring. These include a wide variety of olfactory, visual, auditory and tactile stimuli. The most important sensory stimulus seems to be the olfactory one. In addition to the odour, the nipple-areola's temperature is higher than the surrounding area and may guide the newborn infant to the breast. Figures 1–5: Istockphoto.com.

Bisphenol S Alters the Lactating Mammary Gland and Nursing Behaviors in Mice Exposed During Pregnancy and Lactation.

High doses of estrogenic pharmaceuticals were once prescribed to women to halt lactation. Yet, the effects of low-level xenoestrogens on lactation remain poorly studied. We investigated the effects of bisphenol S (BPS), an estrogen receptor (ER) agonist, on the lactating mammary gland; the arcuate nucleus, a region of the hypothalamus important for neuroendocrine control of lactational behaviors; and nursing behavior in CD-1 mice. Female mice were exposed to vehicle, 2 or 200 µg BPS/kg/d from pregnancy day 9 until lactational day (LD) 20, and tissues were collected on LD21. Tissues were also collected from a second group at LD2. BPS exposure significantly reduced the fraction of the mammary gland comprised of lobules, the milk-producing units, on LD21, but not LD2. BPS also altered expression of Esr1 and ERα in the mammary gland at LD21, consistent with early involution. In the arcuate nucleus, no changes were observed in expression of signal transducer and activator of transcription 5, a marker of prolactin signaling, or ERα, suggesting that BPS may act directly on the mammary gland. However, observations of nursing behavior collected during the lactational period revealed stage-specific effects on both pup and maternal nursing behaviors; BPS-treated dams spent significantly more time nursing later in the lactational period, and BPS-treated pups were less likely to initiate nursing. Pup growth and development were also stunted. These data indicate that low doses of BPS can alter lactational behaviors and the maternal mammary gland. Together, they support the hypothesis that pregnancy and lactation are sensitive to low-dose xenoestrogen exposures.

Changes in milk composition in obese rats consuming a high-fat diet.

Maternal obesity programmes offspring development. We addressed maternal obesity effects induced by high-fat diets on maternal mammary gland (MG) structure and function and offspring brain, liver and fat outcomes. Mothers were fed control (C, n 5) or obesogenic (MO, n 5) diet from the time they were weaned through pregnancy beginning at 120 d, through lactation. At offspring postnatal day (PND) 20, milk leptin and nutrients were determined. At the end of lactation, maternal liver and MG fatty acid profile were measured. Desaturase (Δ6D and Δ5D) and elongase (ELOVL 5 and ELOVL 2) protein was measured by immunohistochemistry and Western blotting (WB) in the liver and WB in the MG. In mothers, liver, MG and milk fat content were higher in MO than in C. Liver arachidonic acid (AA) and EPA and MG EPA were lower in MO than in C. Liver desaturases were higher in MO. The MG was heavier in MO than in C, with decreased Δ5D expression in MO. Desaturases and elongases were immunolocalised in parenchymal cells of both groups. Milk yield, water, carbohydrate content, EPA and DHA were lower, whereas milk leptin and AA were higher in MO than in C. At PND 21 and 36, brain weight was less and fat depots were greater in MO offspring than in C. MO decreased male absolute brain weight but not female absolute brain weight. In conclusion, maternal obesity induced by an obesogenic diet negatively affects maternal liver and MG function with the production of significant changes in milk composition. Maternal obesity adversely affects offspring metabolism and development.

Reproductive toxicity of denosumab in cynomolgus monkeys

Denosumab is a monoclonal antibody that inhibits bone resorption by targeting RANKL, an essential mediator of osteoclast formation, function, and survival. Reproductive toxicity of denosumab was assessed in cynomolgus monkeys in an embryofetal development study (dosing GD20–50) and a pre-postnatal toxicity study (dosing GD20–parturition). In the embryofetal toxicity study, denosumab did not elicit maternal toxicity, fetal harm or teratogenicity. In the pre-postnatal toxicity study, there were increased stillbirths, and one maternal death due to dystocia. There was no effect on maternal mammary gland histomorphology, lactation, or fetal growth. In infants exposed in utero, there was increased postnatal mortality, decreased body weight gain, and decreased growth/development. Denosumab-related effects in infants were present in bones and lymph nodes. There was full recovery at 6 months of age from most bone-related changes observed earlier postpartum. The effects observed in mothers and infants were consistent with the pharmacological action of denosumab.

The effect of low-to-moderate-dose ethanol consumption on rat mammary gland structure and function and early postnatal growth of offspring

High levels of alcohol consumption during pregnancy can lead to growth deficits in early postnatal life. However, the effects of low-to-moderate alcohol consumption during pregnancy are less clearly defined. The aim of this study was to determine whether low-to-moderate ethanol (EtOH) consumption throughout pregnancy in the rat alters maternal mammary gland morphology and milk protein levels, thereby affecting lactation and the growth of pups after birth. Sprague-Dawley rats were fed an ad libitum liquid diet ± 6% vol/vol EtOH throughout pregnancy. Mammary glands from dams were collected at embryonic day (E) 20 or postnatal day (PN) 1, and expression of milk proteins (α-lactalbumin, β-casein, and whey acidic protein) was examined. In addition, relative amounts of alveoli, lactiferous ducts, adipose tissue, and blood vessels were determined at PN1. A subset of rats gave birth, and offspring growth and milk intake were recorded. Mammary gland weight was unaltered by EtOH, and stereological analysis showed no differences in gland structure compared with control. Although there were no significant changes in mammary gland gene expression at the RNA level, protein levels of α-lactalbumin were increased and whey acidic protein were decreased by EtOH. Offspring of EtOH-fed dams consumed less milk than controls in the lactational period; however, this did not alter their early postnatal growth. Overall, it appears that low-to-moderate-dose prenatal EtOH exposure does not significantly alter mammary gland development but may alter the composition of the various proteins found within the milk in a manner that maintains overall pup growth.

Effects of dietary fish oil and corn oil on rat mammary tissue

The effects, on the maternal mammary gland, of diets containing similar lipid percentages but differing in composition of polyunsaturated fatty acids (PUFA) have been assessed in rats during pregnancy and lactation. For this purpose, tuna fish oil (an n-3-PUFA-enriched oil) and corn oil (an n-6-PUFA-enriched oil) were included in diets at ratios such that the caloric inputs were the same as that of the control diet. As expected, the maternal diet affected the tissue composition of dams. Unexpectedly, only the tuna fish oil diet had an effect on pup growth, being associated with the pups being underweight between the ages of 11 and 21 days. The maternal mammary gland of rats fed the tuna fish oil diet displayed two main modifications: the size of cytoplasmic lipid droplets was increased when compared with those in control rats and the mammary epithelium showed an unusual formation of multilayers of cells. These results show that the tuna fish oil diet, during pregnancy and lactation, exerts specific effects on mammary cells and on the formation of lipid droplets. They suggest that this maternal diet affects the functioning of the mammary tissue.

Development of the hypothalamus and pituitary in platypus (Ornithorhynchus anatinus) and short‐beaked echidna (Tachyglossus aculeatus)

The living monotremes (platypus and echidnas) are distinguished by the development of their young in a leathery-shelled egg, a low and variable body temperature and a primitive teat-less mammary gland. Their young are hatched in an immature state and must deal with the external environment, with all its challenges of hypothermia and stress, as well as sourcing nutrients from the maternal mammary gland. The Hill and Hubrecht embryological collections have been used to follow the structural development of the monotreme hypothalamus and its connections with the pituitary gland both in the period leading up to hatching and during the lactational phase of development, and to relate this structural maturation to behavioural development. In the incubation phase, development of the hypothalamus proceeds from closure of the anterior neuropore to formation of the lateral hypothalamic zone and putative medial forebrain bundle. Some medial zone hypothalamic nuclei are emerging at the time of hatching, but these are poorly differentiated and periventricular zone nuclei do not appear until the first week of post-hatching life. Differentiation of the pituitary is also incomplete at hatching, epithelial cords do not develop in the pars anterior until the first week, and the hypothalamo-neurohypophyseal tract does not appear until the second week of post-hatching life. In many respects, the structure of the hypothalamus and pituitary of the newly hatched monotreme is similar to that seen in newborn marsupials, suggesting that both groups rely solely on lateral hypothalamic zone nuclei for whatever homeostatic mechanisms they are capable of at birth/hatching.

High-protein diet during gestation and lactation affects mammary gland mRNA abundance, milk composition and pre-weaning litter growth in mice

We evaluated the effect of a high-protein diet (HP) on pregnancy, lactational and rearing success in mice. At the time of mating, females were randomly assigned to isoenergetic diets with HP (40% w/w) or control protein levels (C; 20%). After parturition, half of the dams were fed the other diet throughout lactation resulting in four dietary groups: CC (C diet during gestation and lactation), CHP (C diet during gestation and HP diet during lactation), HPC (HP diet during gestation and C diet during lactation) and HPHP (HP diet during gestation and lactation). Maternal and offspring body mass was monitored. Measurements of maternal mammary gland (MG), kidney and abdominal fat pad masses, MG histology and MG mRNA abundance, as well as milk composition were taken at selected time points. HP diet decreased abdominal fat and increased kidney mass of lactating dams. Litter mass at birth was lower in HP than in C dams (14.8 v. 16.8 g). Dams fed an HP diet during lactation showed 5% less food intake (10.4 v. 10.9 g/day) and lower body and MG mass. On day 14 of lactation, the proportion of MG parenchyma was lower in dams fed an HP diet during gestation as compared to dams fed a C diet (64.8% v. 75.8%). Abundance of MG α-lactalbumin, β-casein, whey acidic protein, xanthine oxidoreductase mRNA at mid-lactation was decreased in all groups receiving an HP diet either during gestation and/or lactation. Milk lactose content was lower in dams fed an HP diet during lactation compared to dams fed a C diet (1.6% v. 2.0%). On days 14, 18 and 21 of lactation total litter mass was lower in litters of dams fed an HP diet during lactation, and the pups’ relative kidney mass was greater than in litters suckled by dams receiving a C diet. These findings indicate that excess protein intake in reproducing mice has adverse effects on offspring early in their postnatal growth as a consequence of impaired lactational function.

Epidermal growth factor and parathyroid hormone-related peptide mRNA in the mammary gland and their concentrations in milk: effects of postpartum hypoxia in lactating rats.

The physiological adaptations of the neonatal rat to hypoxia from birth include changes in gastrointestinal function and intermediary metabolism. We hypothesized that the hypoxic lactating dam would exhibit alterations in mammary gland function leading to changes in the concentration of milk peptides that are important in neonatal gastrointestinal development. The present study assessed the effects of chronic hypoxia on peptides produced by the mammary glands and present in milk. Chronic hypoxia decreased the concentration of epidermal growth factor (EGF) in expressed milk and pup stomach contents and decreased maternal mammary gland EGF mRNA. The concentration of parathyroid hormone-related protein (PTHrp) was unchanged in milk and decreased in pup stomach contents; however, mammary PTHLH mRNA was increased by hypoxia. There was a significant increase in adiponectin concentrations in milk from hypoxic dams. Chronic hypoxia decreased maternal body weight, and pair feeding normoxic dams an amount of food equivalent to hypoxic dam food intake decreased body weight to an equivalent degree. Decreased food intake did not affect the expression of EGF, PTHLH, or LEP mRNA in mammary tissue. The results indicated that chronic hypoxia modulated mammary function independently of hypoxia-induced decreases in maternal food intake. Decreased EGF and increased adiponectin concentrations in milk from hypoxic dams likely affect the development of neonatal intestinal function.

The body composition and metabolic status of twin- and triplet-bearing ewes and their fetuses in late pregnancy

Abstract This study investigated the body composition and metabolic status of twin- and triplet-bearing ewes and their fetuses in late pregnancy. The aim was to identify factors that could explain the lower survival rates of triplet lambs compared with twin lambs. Ten twin- and 10 triplet-bearing ewes and their fetuses were euthanased on either day 139 or 140 of pregnancy and fetal and placental measurements recorded. The weights of the gravid uterus ( P P P P = 0.05) individual cotyledon weight, resulting in no differences in either total fetal membrane plus cotyledon or total cotyledon weights. The absolute weight of many organs were significantly ( P P P The mean weight of the lightest triplet fetus within each triplet set was 31% lighter than that of the heaviest triplet ( P P P P = 0.05) greater kidney weights and tended to have heavier heart ( P = 0.07) and lungs ( P = 0.07). It is unknown why the relative organ weight relationships between the heaviest and lightest differ between twin and triplet fetuses. In conclusion this study has identified three factors which may contribute to the lower survival rates observed in triplet-compared to twin-born lambs; low fructose concentrations, lighter fetal weights, especially in one fetus within each triplet set, and maternal mammary gland increases that are not proportional to the increase in numbers of fetuses. While these findings are not novel, there were no other factors identified that could account the lower survival rates reported in triplet-born lambs compared to twins. The other only other significant differences identified were the proportionally lighter livers and hearts in triplets although the possible effects of these on survival is unknown.

Predicting neonatal perchlorate dose and inhibition of iodide uptake in the rat during lactation using physiologically-based pharmacokinetic modeling.

Perchlorate (ClO4-), a contaminant in drinking water, competitively inhibits active uptake of iodide (I-) into various tissues, including mammary tissue. During postnatal development, inhibition of I- uptake in the mammary gland and neonatal thyroid and the active concentration ClO4- in milk indicate a potentially increased susceptibility of neonates to endocrine disruption. A physiologically based pharmacokinetic (PBPK) model was developed to reproduce measured ClO4- distribution in the lactating and neonatal rat and predict resulting effects on I- kinetics from competitive inhibition at the sodium iodide symporter (NIS). Kinetic I- and ClO4- behavior in tissues with NIS (thyroid, stomach, mammary gland, and skin) was simulated with multiple subcompartments, Michaelis-Menten (M-M) kinetics and competitive inhibition. Physiological and kinetic parameters were obtained from literature and experiment. Systemic clearance and M-M parameters were estimated by fitting simulations to tissue and serum data. The model successfully describes maternal and neonatal thyroid, stomach, skin, and plasma, as well as maternal mammary gland and milk data after ClO4- exposure (from 0.01 to 10 mg/kg-day ClO4-) and acute radioiodide (2.1 to 33,000 ng/kg I-) dosing. The model also predicts I- uptake inhibition in the maternal thyroid, mammary gland, and milk. Model simulations predict a significant transfer of ClO4- through milk after maternal exposure; approximately 50% to 6% of the daily maternal dose at doses ranging from 0.01 to 10.0 mg ClO4-/kg-day, respectively. Comparison of predicted dosimetrics across life-stages in the rat indicates that neonatal thyroid I- uptake inhibition is similar to the adult and approximately tenfold less than the fetus.

Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation: a physiologically-based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat.

Perchlorate (ClO4-) disrupts endocrine homeostasis by competitively inhibiting the transport of iodide (I-) into the thyroid. The potential for health effects from human exposure to ClO4- in drinking water is not known, but experimental animal studies are suggestive of developmental effects from ClO4- induced iodide deficiency during gestation. Normal hormone-dependent development relies, in part, on synthesis of hormones in the fetal thyroid from maternally supplied iodide. Although ClO4- crosses the placenta, the extent of inhibition in the fetal thyroid is unknown. A physiologically-based pharmacokinetic (PBPK) model was developed to simulate ClO4- exposure and the resulting effect on iodide kinetics in rat gestation. Similar to concurrent model development for the adult male rat, this model includes compartments for thyroid, stomach, skin, kidney, liver, and plasma in both mother and fetus, with additional compartments for the maternal mammary gland, fat, and placenta. Tissues with active uptake are described with multiple compartments and Michaelis-Menten (M-M) kinetics. Physiological and kinetic parameters were obtained from literature and experiment. Systemic clearance, placental-fetal transport, and M-M uptake parameters were estimated by fitting model simulations to experimental data. The PBPK model is able to reproduce maternal and fetal iodide data over five orders of magnitude (0.36 to 33,000 ng/kg 131I-), ClO4- distribution over three orders of magnitude (0.01 to 10 mg/kg-day ClO4-) and inhibition of maternal thyroid and total fetal I- uptake. The model suggests a significant fetal ClO4- dose in late gestation (up to 82% of maternal dose). A comparison of model-predicted internal dosimetrics in the adult male, pregnant, and fetal rat indicates that the fetal thyroid is more sensitive to inhibition than that of the adult.

Hyperthyroidism affects lipid metabolism in lactating and suckling rats.

Two per thousand pregnant women have hyperthyroidism (HT), and although the symptoms are attenuated during pregnancy, they rebound after delivery, affecting infant development. To examine the effects of hyperthyroidism on lactation, we studied lipid metabolism in maternal mammary glands and livers of hyperthyroid rats and their pups. Thyroxine (10 microg/100 g body weight/d) or vehicle-treated rats were made pregnant 2 wk after commencement of treatment and sacrificed on days 7, 14, and 21 of lactation with the litters. Circulating triiodothyronine and tetraiodothyronine concentrations in the HT mothers were increased on all days. Hepatic esterified cholesterol (EC) and free cholesterol (FC) and triglyceride (TG) concentrations were diminished on days 14 and 21. Lipid synthesis, measured by incorporation of [3H]H2O into EC, FC, and TG, fatty acid synthase, and acetyl CoA carboxylase activities increased at day 14, while incorporation into FC and EC decreased at days 7 and 21, respectively. Mammary FC and TG concentrations were diminished at day 14; incorporation of [3H]H2O into TG decreased at days 7 and 21, and incorporation of [3H]H2O into FC increased at day 14. In the HT pups, growth rate was diminished, tetraiodothyronine concentration rose at days 7 and 14 of lactation, and triiodothyronine increased only at day 14. Liver TG concentrations increased at day 7 and fell at day 14, while FC increased at day 14 and only acetyl CoA carboxylase activity fell at day 14. Thus, hyperthyroidism changed maternal liver and mammary lipid metabolism, with decreased lipid concentration in spite of increased liver rate of synthesis and decreases in mammary synthesis. These changes, along with the mild hyperthyroidism of the litters, may have contributed to their reduced growth rate.

Coexposure to Ethanol with N-Nitrosodimethylamine or 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone during Lactation of Rats: Marked Increase in O6-Methylguanine–DNA Adducts in Maternal Mammary Gland and in Suckling Lung and Kidney

Use of alcoholic beverages increases risk of cancer at several target sites, including the breast. Of several possible mechanisms for this effect, competitive inhibition by ethanol of hepatic clearance of nitrosamines, resulting in increased dose delivery to posthepatic tissues, gives the quantitatively most pronounced enhancement. We investigated whether this effect would pertain to the mammary gland, and to ethanol and nitrosamines delivered translactationally to sucklings. Ethanol (1.6 g/kg) was administered by gavage to nursing Sprague–Dawley rats 10 min before 5 mg/kg N-nitrosodimethylamine (NDMA) or 50 mg/kg 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); treatment was on postnatal days 1, 7, or 14. Tissues taken 4 h later for analysis of O6-methylguanine in DNA were liver, blood, and mammary glands from the mothers, and liver, lung, kidney, and blood from the sucklings. Ethanol cotreatment resulted in a marked, 10-fold increase in O6-methylguanine adducts from NDMA in mammary gland, as well as smaller but significant increases in this tissue from NNK and in maternal blood cells from both chemicals; adducts in maternal liver decreased slightly. In the sucklings, ethanol cotreatment also lowered adducts in liver after NDMA or NNK treatment. After NDMA, adducts were also detected in suckling lung and kidney and were increased five- to 10-fold after ethanol coexposure. Adducts from either chemical, with or without ethanol, decreased markedly in all suckling tissues with development from postnatal day 1 to day 14. Thus ethanol coexposure with nitrosamines increases O6-methylguanine DNA adducts in mammary gland and strongly influences adduct formation in suckling tissues after translactational delivery.